|
1
|
Kikuchi H, Osawa T, Matsushita Y, Kojima T, Sazuka T, Hatakeyama S, Goto K, Numakura K, Yamana K, Kandori S, Ueda K, Tanaka H, Kurahashi T, Bando Y, Kimura T, Nishiyama N, Kato T, Hara H, Ito Y, Kitamura H, Miyake H, Shinohara N. Validation of five prognostic models treated with axitinib beyond first-line nivolumab plus ipilimumab therapy for metastatic renal cell carcinoma: a Japanese multicenter retrospective study. Jpn J Clin Oncol 2025; 55:531-538. [PMID: 39893579 DOI: 10.1093/jjco/hyaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/16/2025] [Indexed: 02/04/2025] Open
Abstract
OBJECTIVE To validate multiple prognostic models in metastatic renal cell carcinoma patients who received second-line axitinib following first-line nivolumab plus ipilimumab therapy. METHODS Five prognostic models (ACL, albumin, C-reactive protein, and lactate dehydrogenase; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; ATP, axitinib treatment prediction; JMRC, Japanese metastatic renal cancer) to predict overall survival (OS) were validated and compared using data from 86 metastatic renal cell carcinoma patients who received second-line axitinib therapy following first-line nivolumab plus ipilimumab therapy at 34 hospitals affiliated with the Japan Urologic Oncology Group. RESULTS The Karnofsky performance status, time from initial diagnosis to first-line therapy, and hemoglobin, platelet, albumin, and C-reactive protein levels correlated with OS in univariate Cox regression analyses. Among these factors, only albumin had a significant impact on OS in the multivariate analysis. The integrated area under the curve (AUC) of the ACL, IMDC, MSKCC, ATP, and JMRC models were 0.78, 0.76, 0.76, 0.69, and 0.70, respectively. The ACL model showed a higher value than the others in the time-dependent AUC. CONCLUSIONS The accuracy of the five prognostic models (ACL, IMDC, MSKCC, ATP, and JMRC) created in the pre-immuno-oncology (IO) treatment cohort was maintained in the second-line axitinib group after nivolumab plus ipilimumab therapy. The ACL model demonstrated moderate accuracy in predicting OS with the fewest number of clinical variables.
Collapse
Affiliation(s)
- Hiroshi Kikuchi
- Department of Urology, Hokkaido University Hospital, N15 W7 Kita-ku, Sapporo 060-8638, Japan
| | - Takahiro Osawa
- Department of Urology, Hokkaido University Hospital, N15 W7 Kita-ku, Sapporo 060-8638, Japan
| | - Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu 431-3192, Japan
| | - Takahiro Kojima
- Department of Urology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa Ward, Nagoya 464-8681, Japan
| | - Tomokazu Sazuka
- Department of Urology, Graduate School of Medicine Chiba University, 1-8-1 Inohana, chuo-ku, Chiba 260-8670, Japan
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan
| | - Keisuke Goto
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Kazuyuki Numakura
- Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Kazutoshi Yamana
- Department of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan
| | - Shuya Kandori
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Hajime Tanaka
- Department of Urology, Institute of Science Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan
| | - Toshifumi Kurahashi
- Department of Urology, Hyogo Prefectural Cancer Center, 13-70, KITAOJICHO, Akashi, Hyogo 673-0021, Japan
| | - Yukari Bando
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, 3-25-8, Nishi-shinbashi. Minato-ku, Tokyo 105-8461, Japan
| | - Naotaka Nishiyama
- Department of Urology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Takuma Kato
- Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Hiroaki Hara
- Department of Urology, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Yoichi Ito
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
| | - Hiroshi Kitamura
- Department of Urology, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Hideaki Miyake
- Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan
| | - Nobuo Shinohara
- Department of Urology, Hokkaido University Hospital, N15 W7 Kita-ku, Sapporo 060-8638, Japan
- Department of Urology, Kushiro Rosai Hospital, 13-23 Nakazonocho, Kushiro 085-0052, Japan
| |
Collapse
|
|
2
|
Shiota M, Nemoto S, Ikegami R, Tanegashima T, Blas L, Miyake H, Takahashi M, Oya M, Tsuchiya N, Masumori N, Kobayashi K, Obara W, Shinohara N, Fujimoto K, Nozawa M, Ohba K, Ohyama C, Hashine K, Akamatsu S, Motoshima T, Mita K, Gotoh M, Tatarano S, Fujisawa M, Tomita Y, Mukai S, Ito K, Eto M. Predictive Model of Objective Response to Nivolumab Monotherapy for Advanced Renal Cell Carcinoma by Machine Learning Using Genetic and Clinical Data: The SNiP-RCC Study. JCO Clin Cancer Inform 2025; 9:e2400167. [PMID: 40279530 DOI: 10.1200/cci-24-00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/10/2024] [Accepted: 02/24/2025] [Indexed: 04/27/2025] Open
Abstract
PURPOSE Anti-PD-1 antibodies are widely used for cancer treatment, including in advanced renal cell carcinoma (RCC). However, the therapeutic response varies among patients. This study aimed to predict tumor response to nivolumab anti-PD-1 antibody treatment for advanced RCC by integrating genetic and clinical data using machine learning (ML). METHODS Clinical and single-nucleotide polymorphism (SNP) data obtained in the SNPs in nivolumab PD-1 inhibitor for RCC study, which enrolled Japanese patients treated with nivolumab monotherapy for advanced clear cell RCC, were used. A point-wise linear (PWL) algorithm, logistic regression with elastic-net regularization, and eXtreme Gradient Boosting were used in this study. AUC values for objective response and C-indices for progression-free survival (PFS) were calculated to evaluate the utility of the models. RESULTS Among the three ML algorithms, the AUC values to predict objective response were highest for the PWL algorithm among all the data sets. Three predictive models (clinical model, small SNP model, and large SNP model) were created by the PWL algorithm using the clinical data alone and using eight and 49 SNPs in addition to the clinical data. C-indices for PFS by the clinical model, small SNP model, and large SNP model were 0.522, 0.600, and 0.635, respectively. CONCLUSION The results demonstrated that the SNP models created by ML produced excellent predictions of tumor response to nivolumab monotherapy for advanced clear cell RCC and will be helpful in treatment decisions.
Collapse
Affiliation(s)
- Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shota Nemoto
- Industrial & Digital Business Unit, Hitachi, Ltd, Tokyo, Japan
| | - Ryo Ikegami
- Industrial & Digital Business Unit, Hitachi, Ltd, Tokyo, Japan
| | - Tokiyoshi Tanegashima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Leandro Blas
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideaki Miyake
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masayuki Takahashi
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Norihiko Tsuchiya
- Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Keita Kobayashi
- Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | | | - Masahiro Nozawa
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kojiro Ohba
- Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Katsuyoshi Hashine
- Department of Urology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan
| | - Shusuke Akamatsu
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takanobu Motoshima
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koji Mita
- Department of Urology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Momokazu Gotoh
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuichi Tatarano
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiko Tomita
- Department of Urology and Molecular Oncology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shoichiro Mukai
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Keiichi Ito
- Department of Urology, National Defense Medical College, Saitama, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
3
|
Takemura K, Heng DYC. Potential of neutrophil-to-eosinophil ratio as a new prognostic tool for patients with advanced renal cell carcinoma receiving first-line immuno-oncology combinations. BMJ ONCOLOGY 2024; 3:e000481. [PMID: 39886180 PMCID: PMC11256019 DOI: 10.1136/bmjonc-2024-000481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/01/2025]
Affiliation(s)
- Kosuke Takemura
- Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Daniel Y C Heng
- Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada
| |
Collapse
|
|
4
|
Messina C, Catalano M, Roviello G, Gandini A, Maruzzo M, De Giorgi U, Pedrazzoli P, Sbrana A, Zucal PA, Masini C, Naglieri E, Procopio G, Milella M, Catalano F, Fratino L, Pipitone S, Ricotta R, Panni S, Mollica V, Soraru M, Prati V, Atzori F, Di Napoli M, Messina M, Morelli F, Prati G, Nole F, Malgeri A, Tudini M, Vignani F, Cavo A, Signori A, Banna GL, Rescigno P, Buti S, Rebuzzi SE, Fornarini G. Long-term responders to nivolumab in previously treated advanced renal cell carcinoma: a sub-analysis of meet-URO15 study. Cancer Immunol Immunother 2024; 73:161. [PMID: 38954006 PMCID: PMC11219688 DOI: 10.1007/s00262-024-03741-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 05/20/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. MATERIALS AND METHODS A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. RESULTS A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. CONCLUSION This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.
Collapse
Affiliation(s)
- Carlo Messina
- Oncology Unit, A.R.N.A.S. Civico Palermo, Palermo, Italy
| | - Martina Catalano
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
| | - Annalice Gandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino of Genova, Genova, Italy
| | - Marco Maruzzo
- Oncology 1 Unit, Department of Oncology, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Ugo De Giorgi
- Department of Medical Oncology, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Paolo Pedrazzoli
- Dipartimento di Medicina Interna e Terapia Medica, Università Degli Studi di Pavia, Pavia, Italy
- Dipartimento Di Oncologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Andrea Sbrana
- Oncology Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Paolo Andrea Zucal
- Department of Biomedical Sciences, Humanitas University, Milano, Pieve Emanuele, Italy
- Department of Oncology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Milan, Rozzano, Italy
| | - Cristina Masini
- Medical Oncology Unit, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy
| | - Emanuele Naglieri
- Division of Medical Oncology, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Giuseppe Procopio
- SS Oncologia Medica Genitourinaria, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy
| | - Michele Milella
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and Verona University and Hospital Trust (AOUI Verona), Verona, Italy
| | - Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino of Genova, Genova, Italy
| | - Lucia Fratino
- Medical Oncology, Centro di Riferimento Oncologico di Aviano, National Cancer Institute, Aviano, Italy
| | | | - Riccardo Ricotta
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Stefano Panni
- Medical Oncology Unit, ASST - Istituti Ospitalieri Cremona Hospital, Cremona, Italy
| | - Veronica Mollica
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Mariella Soraru
- U. O. Oncologia, Ospedale Di Camposampiero, Camposampiero, Italy
| | | | - Francesco Atzori
- Medical Oncology Department, University Hospital, University of Cagliari, Cagliari, Italy
| | - Marilena Di Napoli
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Marco Messina
- UOC Oncologia Medica, Istituto Fondazione G. Giglio, Cefalù, Italy
| | - Franco Morelli
- Medical Oncology Department, Casa Sollievo Della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
| | - Giuseppe Prati
- Department of Oncology, Advanced Technologies AUSL - IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - Franco Nole
- Medical OncologyDivision of Urogenital & Head & Neck Tumors, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Andrea Malgeri
- Department of Medical Oncology, Fondazione Policlinico Campus Bio-Medico, Roma, Italy
| | | | - Francesca Vignani
- Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | - Alessia Cavo
- Oncology Unit, Villa Scassi Hospital, Genova, Italy
| | - Alessio Signori
- Department of Health Sciences, Section of Biostatistics, University of Genova, Genoa, Italy
| | - Giuseppe Luigi Banna
- Portsmouth Hospitals University NHS Trust, Portsmouth, P06 3LY, UK
- Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, P01 2UP, UK
| | - Pasquale Rescigno
- Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle Upon Tyne, UK
| | - Sebastiano Buti
- Oncology Unit, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Sara Elena Rebuzzi
- Medical Oncology Unit, Ospedale San Paolo, Savona, Italy
- Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genoa, Genoa, Italy
| | - Giuseppe Fornarini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino of Genova, Genova, Italy
| |
Collapse
|
|
5
|
Yamashita S, Hamamoto S, Furukawa J, Fujita K, Takahashi M, Miyake M, Ito N, Iwamoto H, Kohjimoto Y, Hara I. Association of lung immune prognostic index with survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Jpn J Clin Oncol 2024; 54:722-729. [PMID: 38485656 DOI: 10.1093/jjco/hyae031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 02/21/2024] [Indexed: 06/03/2024] Open
Abstract
OBJECTIVE Lung immune prognostic index is based on derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. Lung immune prognostic index has reported association with survival outcomes in patients with various malignancies undergoing treatment with immune checkpoint inhibitors. However, the prognostic impact of pre-treatment lung immune prognostic index in patients with metastatic renal cell carcinoma receiving nivolumab plus ipilimumab treatment remains unclear. This study examines the association between lung immune prognostic index and outcomes in this setting. METHODS We retrospectively evaluated 156 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab at eight institutions. We assessed the associations between pre-treatment lung immune prognostic index and survival outcomes including progression-free survival, second progression-free survival (PFS2), cancer-specific survival and overall survival. RESULTS Patients were classified into good (n = 84, 54%), intermediate (n = 52, 33%) and poor (n = 20, 13%) lung immune prognostic index groups. Progression-free survival did not significantly differ between lung immune prognostic index groups, but there was significant difference in PFS2, cancer-specific survival and overall survival. In multivariable Cox proportional hazard analyses, high pre-treatment lung immune prognostic index was a significant predictor of poor PFS2 (vs. good group, intermediate group: P = 0.01 and poor group: P = 0.04) and poor overall survival (vs. good group, intermediate group: P = 0.01 and poor group: P < 0.01). Moreover, the patients with poor lung immune prognostic index had significantly poorer cancer-specific survival than those with good LIPI (P < 0.01). CONCLUSIONS High pre-treatment LIPI is suggested by our results to be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.
Collapse
Affiliation(s)
| | - Shuzo Hamamoto
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Junya Furukawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Masayuki Takahashi
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Makito Miyake
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Noriyuki Ito
- Department of Urology, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan
| | - Hideto Iwamoto
- Division of Urology, Department of Surgery, School of Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Yasuo Kohjimoto
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| | - Isao Hara
- Department of Urology, Wakayama Medical University, Wakayama, Japan
| |
Collapse
|
|
6
|
Kumar A, Yadav RP, Chatterjee S, Das M, Pal DK. Integration of bioinformatics analysis to identify possible hub genes and important pathways associated with clear cell renal cell carcinoma. Urologia 2024; 91:261-269. [PMID: 38159064 DOI: 10.1177/03915603231220435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
INTRODUCTION One of the most fatal urological malignancies is clear cell renal cell carcinoma (ccRCC), yet little is known about its pathophysiology or prognosis. This study is aimed at obtaining some novel biomarkers with diagnostic and prognostic meaning and may find out potential therapeutic targets for ccRCC. MATERIAL AND METHODS Using three publically accessible ccRCC gene expression profiles acquired from the Gene Expression Omnibus database, differentially expressed genes (DEG) were discovered and function enrichment analyses were carried out. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted by using the DAVID tool and a protein-protein interaction (PPI) network was constructed and visualized by Cytoscape. Then we identified 10 hub genes using the cytohubba plugin of Cytoscape based on degree score. The mRNA and protein expression of hub genes was analyzed by GEPIA and Human Protein Atlas (HPA) database. Then, prognosis analysis of hub genes was conducted using GEPIA 3.0 which consists of data from The Cancer Genome Atlas (TCGA). RESULTS We discovered 293 DEG which is highly enriched in several biological processes connected to immune-regulation and pathways linked to tumors, including HIF-1, PI3K-AKT, and metabolic pathways. In particular, C1QA, C1QB, FCER1G, and TYROBP were related to advanced clinical stage, high pathological grade, and poor survival in patients with ccRCC. CONCLUSIONS Further molecular biological studies are required to confirm the role of the putative biomarkers in human ccRCC. Our work highlighted the hub genes and pathways involved in the progression of ccRCC.
Collapse
Affiliation(s)
- Anshu Kumar
- Department of Urology, West Bengal Unversity of Health Sciences, Kolkata, India
| | - Ravi Prakash Yadav
- Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | | | - Madhusudan Das
- Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | - Dilip Kumar Pal
- Department of Urology, West Bengal Unversity of Health Sciences, Kolkata, India
| |
Collapse
|
|
7
|
Matsushita Y, Kojima T, Osawa T, Sazuka T, Hatakeyama S, Goto K, Numakura K, Yamana K, Kandori S, Fujita K, Ueda K, Tanaka H, Tomida R, Kurahashi T, Bando Y, Nishiyama N, Kimura T, Yamashita S, Kitamura H, Miyake H. Prognostic outcomes in patients with metastatic renal cell carcinoma receiving second-line treatment with tyrosine kinase inhibitor following first-line immune-oncology combination therapy. Int J Urol 2024; 31:526-533. [PMID: 38240169 DOI: 10.1111/iju.15396] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/04/2024] [Indexed: 05/05/2024]
Abstract
OBJECTIVES This study aimed to assess the prognostic outcomes in mRCC patients receiving second-line TKI following first-line IO combination therapy. METHODS This study retrospectively included 243 mRCC patients receiving second-line TKI after first-line IO combination therapy: nivolumab plus ipilimumab (n = 189, IO-IO group) and either pembrolizumab plus axitinib or avelumab plus axitinib (n = 54, IO-TKI group). Oncological outcomes between the two groups were compared, and prognostication systems were developed for these patients. RESULTS In the IO-IO and IO-TKI groups, the objective response rates to second-line TKI were 34.4% and 25.9% (p = 0.26), the median PFS periods were 9.7 and 7.1 months (p = 0.79), and the median OS periods after the introduction of second-line TKI were 23.1 and 33.5 months (p = 0.93), respectively. Among the several factors examined, non-CCRCC, high CRP, and low albumin levels were identified as independent predictors of both poor PFS and OS by multivariate analyses. It was possible to precisely classify the patients into 3 risk groups regarding both PFS and OS according to the positive numbers of the independent prognostic factors. Furthermore, the c-indices of this study were superior to those of previous systems as follows: 0.75, 0.64, and 0.61 for PFS prediction and 0.76, 0.70, and 0.65 for OS prediction by the present, IMDC, and MSKCC systems, respectively. CONCLUSIONS There were no significant differences in the prognostic outcomes after introducing second-line TKI between the IO-IO and IO-TKI groups, and the histopathology, CRP and albumin levels had independent impacts on the prognosis in mRCC patients receiving second-line TKI, irrespective of first-line IO combination therapies.
Collapse
Affiliation(s)
- Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takahiro Kojima
- Department of Urology, Aichi Cancer Center, Nagoya, Aichi, Japan
| | - Takahiro Osawa
- Department of Renal and Genitourinary Surgery, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Tomokazu Sazuka
- Department of Urology, Graduate School of Medicine and School of Medicine, Chiba University, Chiba, Chiba, Japan
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
| | - Keisuke Goto
- Department of Urology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Kazuyuki Numakura
- Department of Urology, Akita University Graduate School of Medicine, Akita, Akita, Japan
| | - Kazutoshi Yamana
- Department of Urology and Molecular Oncology, Niigata University Graduate school of medical and dental sciences, Niigata, Niigata, Japan
| | - Shuya Kandori
- Department of Urology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Hajime Tanaka
- Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryotaro Tomida
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Tokushima, Japan
| | - Toshifumi Kurahashi
- Department of Urology, Hyogo Prefectural Cancer Center, Akashi, Hyogo, Japan
| | - Yukari Bando
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Naotaka Nishiyama
- Department of Urology, Faculty of Medicine, University of Toyama, Toyama, Toyama, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shimpei Yamashita
- Department of Urology, Wakayama Medical University, Wakayama, Wakayama, Japan
| | - Hiroshi Kitamura
- Department of Urology, Faculty of Medicine, University of Toyama, Toyama, Toyama, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| |
Collapse
|
|
8
|
Sung AD, Koll T, Gier SH, Racioppi A, White G, Lew M, Free M, Agarwal P, Bohannon LM, Johnson EJ, Selvan B, Babushok DV, Frey NV, Gill SI, Hexner EO, Martin M, Perl AE, Pratz KW, Luger SM, Chao NJ, Fisher AL, Stadtmauer EA, Porter DL, Loren AW, Bhatt VR, Gimotty PA, McCurdy SR. Preconditioning Frailty Phenotype Influences Survival and Relapse for Older Allogeneic Transplantation Recipients. Transplant Cell Ther 2024; 30:415.e1-415.e16. [PMID: 38242440 PMCID: PMC11009062 DOI: 10.1016/j.jtct.2024.01.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/21/2024]
Abstract
Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST_3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST_3y. Estimates of RMST_3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT_3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT_3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted.
Collapse
Affiliation(s)
- Anthony D Sung
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Thuy Koll
- Division of Geriatrics, Gerontology, and Palliative Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Shannon H Gier
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Alessandro Racioppi
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Griffin White
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Meagan Lew
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Marcia Free
- Division of Geriatrics, Gerontology, and Palliative Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Priyal Agarwal
- Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Lauren M Bohannon
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Ernaya J Johnson
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Bharathi Selvan
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Daria V Babushok
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Noelle V Frey
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Saar I Gill
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth O Hexner
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - MaryEllen Martin
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Alexander E Perl
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Keith W Pratz
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Selina M Luger
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nelson J Chao
- Department of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina
| | - Alfred L Fisher
- Division of Geriatrics, Gerontology, and Palliative Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Edward A Stadtmauer
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - David L Porter
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Alison W Loren
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Vijaya R Bhatt
- Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Phyllis A Gimotty
- Department of Biostatistics, Epidemiology and Informatics Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shannon R McCurdy
- Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania.
| |
Collapse
|
|
9
|
Uhlig A, Bergmann L, Bögemann M, Fischer T, Goebell PJ, Leitsmann M, Reichert M, Rink M, Schlack K, Trojan L, Uhlig J, Woike M, Strauß A. Sunitinib for Metastatic Renal Cell Carcinoma: Real-World Data from the STAR-TOR Registry and Detailed Literature Review. Urol Int 2024; 108:198-210. [PMID: 38310863 DOI: 10.1159/000536563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 01/15/2024] [Indexed: 02/06/2024]
Abstract
INTRODUCTION We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting. METHODS We analyzed data of adult a/mRCC patients treated with sunitinib. Data were derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups. RESULTS A total of 116 study sites recruited 702 patients treated with sunitinib (73.1% male; median age 68.0 years; median Karnofsky index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug-related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients). CONCLUSIONS This study adds further real-world evidence of the persisting relevance of sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile. The STAR-TOR registry is also registered in the database of US library of medicine (NCT00700258).
Collapse
Affiliation(s)
- Annemarie Uhlig
- Department of Urology, University Medical Center Göttingen, Göttingen, Germany
| | - Lothar Bergmann
- Medical Clinic II, J.W. Goethe University, Frankfurt, Germany
| | - Martin Bögemann
- Department of Urology, University of Münster, Münster, Germany
| | | | - Peter J Goebell
- Department of Urology, University Clinic of Erlangen, Erlangen, Germany
| | | | - Mathias Reichert
- Department of Urology, University Medical Center Göttingen, Göttingen, Germany
| | - Michael Rink
- Department of Urology, Kath. Marienkrankenhaus gGmbH, Hamburg, Germany
| | - Katrin Schlack
- Department of Urology, University Hospital Münster, Münster, Germany
| | - Lutz Trojan
- Department of Urology, University Medical Center Göttingen, Göttingen, Germany
| | - Johannes Uhlig
- Institute for Diagnostic and Interventional Radiology, University Medical Center Göttingen, Göttingen, Germany
| | | | - Arne Strauß
- Department of Urology, University Medical Center Göttingen, Göttingen, Germany
| |
Collapse
|
|
10
|
Naik P, Dudipala H, Chen YW, Rose B, Bagrodia A, McKay RR. The incidence, pathogenesis, and management of non-clear cell renal cell carcinoma. Ther Adv Urol 2024; 16:17562872241232578. [PMID: 38434237 PMCID: PMC10906063 DOI: 10.1177/17562872241232578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/18/2024] [Indexed: 03/05/2024] Open
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer and is divided into two distinct subtypes, clear cell renal cell carcinoma (ccRCC) and non-clear cell renal cell carcinoma (nccRCC). Although many treatments exist for RCC, these are largely based on clinical trials performed in ccRCC and there are limited studies on the management of nccRCC. Non-clear cell RCC consists of multiple histological subtypes: papillary, chromophobe, translocation, medullary, collecting duct, unclassified, and other rare histologies. Due to variations in pathogenesis and therapeutic response, therapy should be tailored to specific variant histologies. For patients with localized nccRCC, surgical resection remains the gold standard. In the metastatic setting, the standard of care has yet to be clearly defined, and most guidelines recommend clinical trial participation. General therapeutic options include immunotherapy, either as monotherapy or in combination, targeted therapies such as vascular endothelial growth factor tyrosine kinase inhibitors and MET inhibitors, and chemotherapy in certain subtypes. Here we present a review of the incidence and pathogenesis of the various subtypes, as well as available clinical data to support therapeutic recommendations for these subtypes. We also highlight currently available clinical trials in nccRCC and future directions in investigating novel treatment modalities tailored to patients with variant histology.
Collapse
Affiliation(s)
- Priyanka Naik
- Undergraduate Studies, University of California, San Diego, La Jolla, CA, USA
| | - Harshitha Dudipala
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, 72 E Concord St, Boston, MA 02118, USA
| | - Yu-Wei Chen
- Department of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Brent Rose
- Department of Radiation Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Aditya Bagrodia
- Department of Urology, University of California, San Diego, La Jolla, CA, USA
| | - Rana R. McKay
- Department of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| |
Collapse
|
|
11
|
Hong X, Yu C, Bi J, Liu Q, Wang Q. TIGIT may Serve as a Potential Target for the Immunotherapy of Renal Cell Carcinoma. Adv Biol (Weinh) 2024; 8:e2300050. [PMID: 37690824 DOI: 10.1002/adbi.202300050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 08/25/2023] [Indexed: 09/12/2023]
Abstract
This study aims to explore whether TIGIT is an effective target for the immunotherapy of renal cell cancer (RCC) with PD-1 as a positive control. The expression of TIGIT and PD-1 in RCC and peripheral blood mononuclear cells (PBMC) and the correlation between TIGIT and PD-1 are evaluated. The expression of TIGIT and PD-1 is inhibited, and then the proliferation, apoptosis, and migration are assessed. TIGIT expression is positively related to the expression of PDCD1, BTLA, ICOS, and FOXP3 (p < 0.05). TIGIT expression in the PBMC, TIL, RCC, and adjacent normal tissues is higher than PD-1 expression. Blocking the TIGIT and PD-1 signaling pathways significantly inhibits the proliferation, migration, and invasion of RCC cells and promotes their apoptosis. These effects are more evident in TIGIT inhibitors than in PD-1 inhibitors. TIGIT inhibitor mainly regulates the expression of differential genes to achieve the reconstruction of immune killing and restore the killing effect on the RCC, and its mechanism by which TIGIT functions overlap that of PD-1 inhibitor. TIGIT may become a target for the immunotherapy of RCC, and there is a theoretical basis for the combination of TIGIT inhibitors and PD-1 inhibitors for the treatment of RCC.
Collapse
Affiliation(s)
- Xin Hong
- Department of Urology, Peking University International Hospital, Beijing, 102206, China
| | - Chengfan Yu
- Department of Urology, Peking University International Hospital, Beijing, 102206, China
| | - Jianlong Bi
- Department of Emergency, Peking University International Hospital, Beijing, 102206, China
| | - Qing Liu
- Department of Urology, Peking University International Hospital, Beijing, 102206, China
| | - Qiang Wang
- Department of Urology, Peking University International Hospital, Beijing, 102206, China
| |
Collapse
|
|
12
|
Strikic A, Kokeza J, Ogorevc M, Kelam N, Vukoja M, Dolonga P, Tomas SZ. Differential expression of HIF1A and its downstream target VEGFA in the main subtypes of renal cell carcinoma and their impact on patient survival. Front Oncol 2023; 13:1287239. [PMID: 38053655 PMCID: PMC10694430 DOI: 10.3389/fonc.2023.1287239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/03/2023] [Indexed: 12/07/2023] Open
Abstract
Renal cell carcinoma (RCC) represents around 3% of all cancers, with the most frequent histological types being clear-cell RCC (ccRCC), followed by papillary (pRCC) and chromophobe (chRCC). Hypoxia-inducible factors (HIFs), which promote the expression of various target genes, including vascular endothelial growth factor (VEGF) and the high- affinity glucose transporter 1, have an important role in the pathogenesis of RCC. This study investigated the immunohistochemical expression of HIF-1α and VEGF-A, showing significantly higher HIF-1α nuclear expression in pRCC compared to ccRCC, while there was no significant difference in VEGF-A protein expression between the analyzed histological RCC subtypes. The quantitative reverse transcription polymerase chain reaction for HIF1A showed no statistical difference between histological types. Data from publicly available RNA sequencing databases were analyzed and showed that, compared to healthy kidney tissue, VEGFA was significantly up-regulated in ccRCC and significantly down-regulated in pRCC. The comparison between histological subtypes of RCC revealed that VEGFA was significantly up-regulated in ccRCC compared to both pRCC and chRCC. There was no statistically significant difference in survival time between HIF1A high- and low-expression groups of patients. As for VEGFA expression, pRCC patients with low expression had a significantly higher survival rate compared to patients with high VEGFA expression.
Collapse
Affiliation(s)
- Ante Strikic
- Department of Oncology and Radiotherapy, University Hospital of Split, Split, Croatia
| | - Josipa Kokeza
- Department of Pulmonology, University Hospital of Split, Split, Croatia
| | - Marin Ogorevc
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Split, Croatia
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Split, Croatia
| | - Martina Vukoja
- Laboratory of Morphology, Department of Histology and Embryology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
| | - Petar Dolonga
- University of Split School of Medicine, Split, Croatia
| | - Sandra Zekic Tomas
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, Split, Croatia
- Department of Pathology, University of Split School of Medicine, Split, Croatia
| |
Collapse
|
|
13
|
Lemelin A, Takemura K, Heng DYC, Ernst MS. Prognostic Models in Metastatic Renal Cell Carcinoma. Hematol Oncol Clin North Am 2023; 37:925-935. [PMID: 37270385 DOI: 10.1016/j.hoc.2023.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
As many new systemic therapy options have recently emerged, the standard of care for patients with metastatic renal cell carcinoma (mRCC) is gradually changing. The increasing complexity of treatment options requires more personalized treatment strategies. This evolution in the systemic therapy landscape comes with a need for validated stratification models that facilitate decision making and patient counseling for clinicians through a risk-adapted approach. This article summarizes the available evidence on risk stratification and prognostic models for mRCC, including the International mRCC Database Consortium and Memorial Sloan Kettering Cancer Center models, as well as their association with clinical outcomes.
Collapse
Affiliation(s)
- Audreylie Lemelin
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, cc 110, 1331 - 29th Street Southwest, Calgary, Alberta T2N 4N2, Canada
| | - Kosuke Takemura
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, cc 110, 1331 - 29th Street Southwest, Calgary, Alberta T2N 4N2, Canada
| | - Daniel Y C Heng
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, cc 110, 1331 - 29th Street Southwest, Calgary, Alberta T2N 4N2, Canada.
| | - Matthew S Ernst
- Department of Oncology, Tom Baker Cancer Centre, University of Calgary, cc 110, 1331 - 29th Street Southwest, Calgary, Alberta T2N 4N2, Canada
| |
Collapse
|
|
14
|
Blas L, Shiota M, Miyake H, Takahashi M, Oya M, Tsuchiya N, Masumori N, Matsuyama H, Obara W, Shinohara N, Fujimoto K, Nozawa M, Ohba K, Ohyama C, Hashine K, Akamatsu S, Kamba T, Mita K, Gotoh M, Tatarano S, Fujisawa M, Tomita Y, Mukai S, Ito K, Tanegashima T, Tokunaga S, Eto M. Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study. Int J Urol 2023; 30:788-796. [PMID: 37528632 DOI: 10.1111/iju.15265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 07/18/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.
Collapse
Affiliation(s)
- Leandro Blas
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masayuki Takahashi
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Norihiko Tsuchiya
- Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hideyasu Matsuyama
- Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University School of Medicine, Morioka, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | | | - Masahiro Nozawa
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Kojiro Ohba
- Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Katsuyoshi Hashine
- Department of Urology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Shusuke Akamatsu
- Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomomi Kamba
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koji Mita
- Department of Urology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Momokazu Gotoh
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuichi Tatarano
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiko Tomita
- Department of Urology and Molecular Oncology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shoichiro Mukai
- Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Keiichi Ito
- Department of Urology, National Defense Medical College, Saitama, Japan
| | - Tokiyoshi Tanegashima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoji Tokunaga
- Medical Information Center, Kyushu University Hospital, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
15
|
Lazure P, Campbell MT, Augustyniak M, Jaimes EA, Bilen MA, Lemke EA, Cohen EP, Jacobs G. Identifying the Needs of Health Care Providers in Advanced First-Line Renal Cell Carcinoma: A Mixed-Methods Research. Clin Genitourin Cancer 2023; 21:e299-e308. [PMID: 37045712 DOI: 10.1016/j.clgc.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023]
Abstract
INTRODUCTION Systemic treatments for metastatic or unresectable renal cell carcinoma (mRCC) are rapidly evolving. This study aimed at investigating challenges in the care of mRCC to inform future educational interventions for health care providers (HCPs). MATERIALS AND METHODS The sequential mixed-method design consisted of a qualitative phase (semistructured interviews) followed by a quantitative phase (online surveys). Participants included US-based medical oncologists, nephrologists, physician assistants, nurse practitioners, and registered nurses. Interview transcripts were thematically analyzed. Survey data was descriptively and inferentially analyzed. RESULTS Forty interviews and 265 surveys were completed. Analysis revealed four challenges in the care of mRCC patients. A challenge in staying current with emerging evidence and treatment recommendations was found with 33% of surveyed HCPs reporting suboptimal skills interpreting published evidence on the efficacy and safety of emerging agents. A challenge weighing patient health and preferences in treatment decisions was found, especially among HCPs with 3 to 10 years of practice (37%) who reported suboptimal skills in assessing patients' tolerance to side effects. Promoting a collaborative care approach to the management of immune-related adverse events was a challenge, specifically related to barriers involving nephrologists (eg, diverging treatment goals). Breakdowns in communication were reported (46% of HCPs), especially in the monitoring of side effects and treatment adherence. CONCLUSION This study revealed key challenges faced by HCPs when treating and managing patients with mRCC across multiple providers. Future interventions (eg, community of practice) should aim to address the identified gaps and promote a team-based approach to care that strengthens the complementary competencies of HCPs involved.
Collapse
Affiliation(s)
| | | | | | | | - Mehmet A Bilen
- Winship Cancer Institute of Emory University, Atlanta, GA
| | | | - Eric P Cohen
- New York University School of Medicine, New York, NY
| | | |
Collapse
|
|
16
|
Bruchbacher A, Netsch C, Gross AJ. [First-line treatment of metastatic renal cell carcinoma]. UROLOGIE (HEIDELBERG, GERMANY) 2023:10.1007/s00120-023-02141-1. [PMID: 37410165 DOI: 10.1007/s00120-023-02141-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Accepted: 06/06/2023] [Indexed: 07/07/2023]
Abstract
In recent years the first-line treatment of metastatic renal cell carcinoma was revolutionized by the introduction of checkpoint inhibitors (CPI). Within a few years several combined modality treatments with CPI and tyrosine kinase inhibitors (TKI) have proven to be effective and safe in the application. According to the guidelines, up to five different combined modality treatments can now be considered, depending on the risk profile. Based on the current data situation, a direct distinction between the treatments cannot be made as no comparative studies are available. Therefore, the decision for a particular treatment is often guided by individual factors. In particular, a clear processing of the patient with the respective risk factors and tumor identity is essential. Hence, it is all the more important to discuss complex cases in an interdisciplinary tumor board.
Collapse
Affiliation(s)
- Andreas Bruchbacher
- Abteilung für Urologie, Asklepios Klink Barmbek, Rübenkamp, 22307, Hamburg, Deutschland.
| | - Christopher Netsch
- Abteilung für Urologie, Asklepios Klink Barmbek, Rübenkamp, 22307, Hamburg, Deutschland
| | - Andreas J Gross
- Abteilung für Urologie, Asklepios Klink Barmbek, Rübenkamp, 22307, Hamburg, Deutschland
| |
Collapse
|
|
17
|
Ayoub CH, Abou Chawareb E, Kasti AE, Alhalabi E, El-Asmar JM, Abou Mrad A, El Hajj A. The 5-item frailty index predicts 30-day morbidity and mortality in radical nephrectomy patients: A propensity matched analysis. Urol Oncol 2023; 41:329.e1-329.e7. [PMID: 37120371 DOI: 10.1016/j.urolonc.2023.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/19/2023] [Accepted: 03/24/2023] [Indexed: 05/01/2023]
Abstract
PURPOSE To assess the ability of the 5-item frailty index (5-IFi) score to predict 30-day morbidity and mortality post-radical nephrectomy (RN). METHODS ACS-NSQIP database was used to select patients who underwent RN from 2011 to 2020. 5-IFi score was calculated by assigning a point for each of the following comorbidities: chronic obstructive pulmonary disease or pneumonia, congestive heart failure, dependent functional status, hypertension, and diabetes. Patients were divided into 3 frailty groups 0, 1, and ≥2. Patient demographics, medical comorbidities, prolonged length of stay, and prolonged operative time were compared between different groups; mortality and morbidity using the Clavien-Dindo classification (CVD). Multivariable logistic regression models and propensity score matching were performed as a sensitivity analysis to control for possible confounders. RESULTS Cohort consisted of 36,682 patients whereby 5-IFi class 0, 1, and ≥2 included 11,564 (31.5%), 16,571 (45.2%), and 8,547 (25.3%) patients respectively. A multivariable analysis and propensity score matching revealed that patients with 5-IFi classes 1 and ≥ 2 were more likely to have a prolonged length of stay (OR = 1.11, 1.3, respectively) and to mortality (OR = 1.85 for frailty class ≥2); in addition to CVD class 1 & 2 (OR = 1.51, OR = 1.13, respectively), and CVD ≥ 4 (OR = 1.41, 1.86, respectively) as compared to 5-IFi class 0 (P < 0.001). CONCLUSION The 5-IFi score was found to be an independent predictor of prolonged length of stay, morbidity, and mortality after RN. This tool can play a major role in preoperative risk assessment and patient counseling based on individualized risks.
Collapse
Affiliation(s)
- Christian Habib Ayoub
- Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Elia Abou Chawareb
- Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Abdallah El Kasti
- Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Eliane Alhalabi
- Department of Anesthesiology, Henry Ford Health System, Detroit, MI
| | - Jose M El-Asmar
- Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Anthony Abou Mrad
- American University of Beirut Medical School, American University of Beirut, Beirut, Lebanon
| | - Albert El Hajj
- Department of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon..
| |
Collapse
|
|
18
|
Kadono Y, Konaka H, Nohara T, Izumi K, Anai S, Fujimoto K, Koguchi T, Ishibashi K, Kawai N, Nakane K, Iba A, Masumori N, Takahara S, Mizokami A. Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study. Cancers (Basel) 2023; 15:2745. [PMID: 37345082 DOI: 10.3390/cancers15102745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/25/2023] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. METHODS This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. RESULTS Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. CONCLUSIONS There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.
Collapse
Affiliation(s)
- Yoshifumi Kadono
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Hiroyuki Konaka
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
- Department of Urology, Japanese Red Cross Society Kanazawa Hospital, Kanazawa 921-8162, Japan
| | - Takahiro Nohara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Kouji Izumi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| | - Satoshi Anai
- Department of Urology, Nara Medical University, Kashihara 634-8522, Japan
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University, Kashihara 634-8522, Japan
| | - Tomoyuki Koguchi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
| | - Kei Ishibashi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Ishibashi Urology Clinic, Koriyama 963-8002, Japan
| | - Noriyasu Kawai
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Keita Nakane
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akinori Iba
- Department of Urology, Wakayama Medical University, Wakayama 641-8509, Japan
| | - Naoya Masumori
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Shizuko Takahara
- Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, Kanazawa 920-8641, Japan
| | - Atsushi Mizokami
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan
| |
Collapse
|
|
19
|
Kim JK, Lee S, Hong SK, Kwak C, Jeong CW, Kang SH, Hong SH, Kim YJ, Chung J, Hwang EC, Kwon TG, Byun SS, Jung YJ, Lim J, Kim J, Oh H. Machine learning based prediction for oncologic outcomes of renal cell carcinoma after surgery using Korean Renal Cell Carcinoma (KORCC) database. Sci Rep 2023; 13:5778. [PMID: 37031280 PMCID: PMC10082844 DOI: 10.1038/s41598-023-30826-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 03/02/2023] [Indexed: 04/10/2023] Open
Abstract
We developed a novel prediction model for recurrence and survival in patients with localized renal cell carcinoma (RCC) after surgery and a novel statistical method of machine learning (ML) to improve accuracy in predicting outcomes using a large Asian nationwide dataset, updated KOrean Renal Cell Carcinoma (KORCC) database that covered data for a total of 10,068 patients who had received surgery for RCC. After data pre-processing, feature selection was performed with an elastic net. Nine variables for recurrence and 13 variables for survival were extracted from 206 variables. Synthetic minority oversampling technique (SMOTE) was used for the training data set to solve the imbalance problem. We applied the most of existing ML algorithms introduced so far to evaluate the performance. We also performed subgroup analysis according to the histologic type. Diagnostic performances of all prediction models achieved high accuracy (range, 0.77-0.94) and F1-score (range, 0.77-0.97) in all tested metrics. In an external validation set, high accuracy and F1-score were well maintained in both recurrence and survival. In subgroup analysis of both clear and non-clear cell type RCC group, we also found a good prediction performance.
Collapse
Affiliation(s)
- Jung Kwon Kim
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Sangchul Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Kyu Hong
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
| | - Cheol Kwak
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
- Department of Urology, Seoul National University Hospital, Seoul, Korea
| | - Chang Wook Jeong
- Department of Urology, Seoul National University College of Medicine, Seoul, Korea
- Department of Urology, Seoul National University Hospital, Seoul, Korea
| | - Seok Ho Kang
- Department of Urology, Korea University Anam Hospital, Seoul, Korea
| | - Sung-Hoo Hong
- Department of Urology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - Yong-June Kim
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Jinsoo Chung
- Department of Urology, National Cancer Center, Goyang, Korea
| | - Eu Chang Hwang
- Department of Urology, Chonnam National University Medical School, Gwangju, Korea
| | - Tae Gyun Kwon
- Department of Urology, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - Seok-Soo Byun
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
- Department of Medical Device Development, Seoul National University College of Medicine, Seoul, Korea.
| | - Yu Jin Jung
- Department of Medical Device Development, Seoul National University College of Medicine, Seoul, Korea
| | | | | | | |
Collapse
|
|
20
|
Meagher MF, Mir MC, Minervini A, Kriegmair M, Heck M, Porpiglia F, Van Bruwaene S, Linares E, Hevia V, D’Anna M, Veccia A, Roussel E, Claps F, Palumbo C, Marchioni M, Afari J, Saitta C, Liu F, Rubio J, Campi R, Mari A, Amiel T, Checcucci E, Musquera M, Guruli G, Pavan N, Albersen M, Antonelli A, Klatte T, Autorino R, McKay RR, Derweesh IH. Proposal for a Two-Tier Re-classification of Stage IV/M1 domain of Renal Cell Carcinoma into M1 (“Oligometastatic”) and M2 (“Polymetastatic”) subdomains: Analysis of the Registry for Metastatic Renal Cell Carcinoma (REMARCC). Front Oncol 2023; 13:1113246. [PMID: 37064092 PMCID: PMC10092360 DOI: 10.3389/fonc.2023.1113246] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/12/2023] [Indexed: 03/31/2023] Open
Abstract
PurposeWe hypothesized that two-tier re-classification of the “M” (metastasis) domain of the Tumor-Node-Metastasis (TNM) staging of Renal Cell Carcinoma (RCC) may improve staging accuracy than the current monolithic classification, as advancements in the understanding of tumor biology have led to increased recognition of the heterogeneous potential of metastatic RCC (mRCC).MethodsMulticenter retrospective analysis of patients from the REMARCC (REgistry of MetAstatic RCC) database. Patients were stratified by number of metastases into two groups, M1 (≤3, “Oligometastatic”) and M2 (>3, “Polymetastatic”). Primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS). Cox-regression and Kaplan-Meier (KMA) analysis were utilized for outcomes, and receiver operating characteristic analysis (ROC) was utilized to assess diagnostic accuracy compared to current “M” staging.Results429 patients were stratified into proposed M1 and M2 groups (M1 = 286/M2 = 143; median follow-up 19.2 months). Cox-regression revealed M2 classification as an independent risk factor for worsened all-cause mortality (HR=1.67, p=0.001) and cancer-specific mortality (HR=1.74, p<0.001). Comparing M1-oligometastatic vs. M2-polymetastatic groups, KMA revealed significantly higher 5-year OS (36% vs. 21%, p<0.001) and 5-year CSS (39% vs. 17%, p<0.001). ROC analyses comparing OS and CSS, for M1/M2 reclassification versus unitary M designation currently in use demonstrated improved c-index for OS (M1/M2 0.635 vs. unitary M 0.500) and CSS (M1/M2 0.627 vs. unitary M 0.500).ConclusionSubclassification of Stage “M” domain of mRCC into two clinical substage categories based on metastatic burden corresponds to distinctive tumor groups whose oncological potential varies significantly and result in improved predictive capability compared to current staging.
Collapse
Affiliation(s)
- Margaret F. Meagher
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
| | - Maria C. Mir
- Department of Urology, Fundacion Instituto Valenciano Oncologia, Valencia, Spain
| | - Andrea Minervini
- Department of Urology, University of Florence, Careggi Hospital, Florence, Italy
| | | | - Matthias Heck
- Department of Urology, Technical University of Munich, Munich, Germany
| | - Francesco Porpiglia
- Department of Urology, University of Turin-San Luigi Gonzaga Hospital, Orbassano, Italy
| | | | | | - Vital Hevia
- Department of Urology, Hospital Ramon y Cajal, Madrid, Spain
| | - Maurizio D’Anna
- Department of Urology, Hospital Clinic, Carrer de Villarroel, Barcelona, Spain
| | - Alessandro Veccia
- Department of Urology, Virginia Commonwealth University (VCU) Medical Center, Richmond, VA, United States
| | | | - Francesco Claps
- Department of Urology, University of Trieste, Trieste, Italy
| | - Carlotta Palumbo
- Department of Urology, Spedali Civili Hospital, University of Brescia, Brescia, Italy
| | - Michele Marchioni
- Department of Urology, University “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
| | - Jonathan Afari
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
| | - Cesare Saitta
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
| | - Franklin Liu
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
| | - Jose Rubio
- Department of Urology, Fundacion Instituto Valenciano Oncologia, Valencia, Spain
| | - Riccardo Campi
- Department of Urology, University of Florence, Careggi Hospital, Florence, Italy
| | - Andrea Mari
- Department of Urology, University of Florence, Careggi Hospital, Florence, Italy
| | - Thomas Amiel
- Department of Urology, Technical University of Munich, Munich, Germany
| | - Enrico Checcucci
- Department of Urology, University of Turin-San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Mireia Musquera
- Department of Urology, Hospital Clinic, Carrer de Villarroel, Barcelona, Spain
| | - Georgi Guruli
- Department of Urology, University of Trieste, Trieste, Italy
| | - Nicola Pavan
- Department of Urology, University of Trieste, Trieste, Italy
| | | | - Alessandro Antonelli
- Department of Urology, Spedali Civili Hospital, University of Brescia, Brescia, Italy
| | - Tobias Klatte
- Department of Urology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
| | - Riccardo Autorino
- Department of Urology, Virginia Commonwealth University (VCU) Medical Center, Richmond, VA, United States
| | - Rana R. McKay
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
| | - Ithaar H. Derweesh
- Department of Urology, University of California (UC) San Diego School of Medicine, La Jolla, CA, United States
- *Correspondence: Ithaar H. Derweesh,
| |
Collapse
|
|
21
|
Surgical Approach in Metastatic Renal Cell Carcinoma: A Literature Review. Cancers (Basel) 2023; 15:cancers15061804. [PMID: 36980688 PMCID: PMC10046362 DOI: 10.3390/cancers15061804] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/02/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
The treatment of metastatic renal cell carcinoma has undergone considerable advances in the last two decades. Cytoreductive nephrectomy and metastasectomy retains a role in patients with a limited metastatic burden. The choice of optimal treatment regimen remains a matter of debate. The article summarises the current role of surgery in metastatic kidney cancer.
Collapse
|
|
22
|
Gonilski-Pacin D, Ciancio del Giudice N, Elguero B, Arzt E. Expression of RSUME is associated with poor prognosis in clear cell Renal Carcinoma: involvement of ROS related metabolism. Clin Genitourin Cancer 2023; 21:393-402.e5. [PMID: 37059686 DOI: 10.1016/j.clgc.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 03/16/2023] [Accepted: 03/18/2023] [Indexed: 04/08/2023]
Abstract
INTRODUCTION RSUME (RWD domain-containing protein SUMO Enhancer), RWD domain containing 3 (RWDD3) gene product, is upregulated by hypoxia and expressed in organs prone to develop von Hippel-Lindau (VHL) syndrome tumors. MATERIALS AND METHODS We evaluated RSUME prognostic value in clear cell renal cell carcinoma (ccRCC) based mainly on the dataset (KIRC) from patients in The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and one-way analysis of variance (ANOVA) followed by Tukey's test were used to evaluate relationships between clinicopathological features and RSUME expression and univariate and multivariate Cox regression analysis methods were used to evaluate prognostic factors. The biological function of RSUME was assessed by gene set enrichment analysis (GSEA). For validation, total amount of ROS was detected in ccRCC cell lines using dichlorofluorescin diacetate. RESULTS RSUME is highly expressed in tumor tissues compared with normal tissues (P = .006, P = .039, P = .002, P = .036, P < .001) and associates with tumor T (P = .018) and tumor M (P = .036) advanced stages and higher extent cysts (P = .005). RSUME expression appears to be an independent risk factor for overall survival (OS) (P = .002) and disease-specific survival (DSS) (P = .026) in ccRCC patients. GSEA showed enrichment of relevant glycerophospholipid- and ROS-related pathways in RSUME high-expression phenotype. ROS diminished levels in RSUME-silenced ccRCC cell lines validated RSUME relevance in ROS-related pathways. CONCLUSION RSUME high expression may predict poor prognosis in ccRCC and impact through its action on metabolism and ROS related pathways.
Collapse
|
|
23
|
Chen C, Chen LY, Yang RX, Zhang JX, Shao PF, Xu HG. Identification of IRF-associated molecular subtypes in clear cell renal cell carcinoma to characterize immunological characteristics and guide therapy. Front Oncol 2023; 12:1118472. [PMID: 36741716 PMCID: PMC9892447 DOI: 10.3389/fonc.2022.1118472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Recently studies have identified a critical role for interferon regulatory factor (IRF) in modulating tumour immune microenvironment (TME) infiltration and tumorigenesis. METHODS Based on IRF1-9 expression profiles, we classified all ccRCC samples into three molecular subtypes (clusters A-C) and characterized the prognosis and immune infiltration of these clusters. IRFscore constructed by principal component analysis was performed to quantify IRF-related subtypes in individual patients. RESULTS We proved that IRFscore predicted multiple patient characteristics, with high IRFscore group having poorer prognosis, suppressed TME, increased T-cell exhaustion, increased TMB and greater sensitivity to anti- PD-1/CTLA-4 therapies. Furthermore, analysis of metastatic ccRCC (mccRCC) molecular subtypes and drug sensitivity proved that low IRFscore was more sensitive to targeted therapies. Moreover, IRFscore grouping can be well matched to the immunological and molecular typing of ccRCC. qRT-PCR showed differential expression of IRFs in different cell lines. CONCLUSIONS Evaluating IRF-related molecular subtypes in individual ccRCC patients not only facilitates our understanding of tumour immune infiltration, but also provides more effective clinical ideas for personalised treatment.
Collapse
Affiliation(s)
- Can Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, China
| | - Lin-Yuan Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, China
| | - Rui-Xia Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, China
| | - Jie-Xin Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, China
| | - Peng-Fei Shao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hua-Guo Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, Jiangsu, China
| |
Collapse
|
|
24
|
Metastatic Renal Cell Carcinoma to the Soft Tissue 27 Years after Radical Nephrectomy: A Case Report. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59010150. [PMID: 36676774 PMCID: PMC9866450 DOI: 10.3390/medicina59010150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023]
Abstract
Background and Objectives: Approximately 20-40% of patients affected with renal cell carcinoma (RCC) develop either distant metastatic or locally recurring disease following radical nephrectomy. Soft tissue, skin, and the central nervous system are less common metastatic sites. We present the case of a patient who has received a diagnosis of RCC; it was found that she had no metastases at the time of nephrectomy but had metastases in the soft tissue and subcutaneous tissue of the scalp 27 years later. As far as we can tell, this is the longest period elapsed between primary renal tumor and subcutaneous/soft tissue metastasis; moreover, this case is the first report of a combined soft tissue/subcutaneous metastasis from RCC. Case presentation: A 73-year-old woman underwent right radical nephrectomy 27 years earlier for clear cell renal cell carcinoma (CCRCC). She presented at our unit because she noticed swelling in the left temporal region; after radiological exams, a benign lesion was suspected. The patient underwent surgical eradication, but the massive bleeding did not allow the removal of the lesion. A biopsy of the mass was performed and the histological examination was consistent with RCC metastases. Conclusions: Metastases from renal cell carcinoma to the subcutaneous and soft tissues are rare. It is essential to take into account RCC metastases in the differential diagnostic of the new starting mass of the head and neck, and the necessity for close and continuous surveillance of patients diagnosed with renal cancer even after a long disease-free period should be emphasized.
Collapse
|
|
25
|
Katsimperis S, Tzelves L, Bellos T, Pikramenos K, Manolitsis I, Tsikopoulos I, Mitsogiannis I. Cytoreductive nephrectomy for synchronous metastatic renal cell carcinoma. Is there enough evidence? Arch Ital Urol Androl 2022; 94:476-485. [PMID: 36576474 DOI: 10.4081/aiua.2022.4.476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/02/2022] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE To assess the role of Cytoreductive Nephrectomy for synchronous metastatic Renal Cell Carcinoma patients in the Systemic Therapy era and beyond regarding the Overall Survival, the optimal sequence between Systemic Therapy and Cytoreductive Nephrectomy and prognostic factors. METHODS The systematic review was conducted in accordance with the PRISMA guidelines. Bibliographic search was performed in Medline (PubMed), ClinicalTrials.gov, and Cochrane Library-Cochrane Central Register of Controlled Trials (CENTRAL). Studies included were those indexed from 2005 in an attempt to limit those conducted in the cytokine era. Risk of bias assessment was performed by two authors (K.S and T.L) using the Cochrane Collaborative Risk of Bias tool for randomized trials, the Cochrane Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies. RESULTS Cytoreductive nephrectomy was associated with improved overall survival in all but one of the observational studies. While in all of these studies the unvariable analysis showed improved overall survival in favor of the cytoreductive nephrectomy group in some studies the subgroup analysis showed no benefit. Regarding the optimal sequence, deferred cytoreductive nephrectomy demonstrated better results in more studies than upfront cytoreductive nephrectomy but a advantage was not clearly certain. In the analysis of possible prognostic factors for overall survival with cytoreductive nephrectomy, most common prognostic factors found were age (in 8 studies), tumor histology (in 7 studies), number of metastasis (in 6 studies), and T stage. CONCLUSIONS Cytoreductive nephrectomy can still play an important role in wisely selected patients, although the role of cytoreductive nephrectomy in the new immunotherapy era needs to be defined.
Collapse
|
|
26
|
Cabanillas G, Montoya-Cerrillo D, Kryvenko ON, Pal SK, Arias-Stella JA. "Collecting duct carcinoma of the kidney: diagnosis and implications for management". Urol Oncol 2022; 40:525-536. [PMID: 34116936 DOI: 10.1016/j.urolonc.2021.04.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 04/07/2021] [Accepted: 04/28/2021] [Indexed: 01/13/2023]
Abstract
Collecting duct carcinoma of the kidney is a rare and aggressive subtype of renal cell carcinoma (RCC) arising from the distal convoluted tubules. At the time of diagnosis, patients are more frequently symptomatic, with advanced locoregional stage, and have metastatic disease. The 2016 WHO Classification of Tumours of the Urinary System defined diagnostic criteria for this entity. However, the diagnostic features continue to evolve, with typical, but not entirely specific, histologic and immunophenotypic characteristics. In addition, the lack of consistent molecular alterations makes collecting duct carcinoma a diagnosis of exclusion, with historical cases being re-classified as fumarate hydratase deficient RCC, ALK rearranged RCC, renal medullary carcinoma or high-grade urothelial carcinoma. The rarity and poor prognosis of the tumor makes it difficult to reach consensus guidelines to guide therapy. In this manuscript we review the clinicopathologic features of collecting duct carcinoma including pathologic diagnostic criteria, molecular characteristics and differential diagnosis, and their possible implications for management.
Collapse
Affiliation(s)
- Gerardo Cabanillas
- Internal Medicine Department, Pacifica Hospital of the Valley, Serra Medical Group, Sun Valley, CA
| | | | - Oleksandr N Kryvenko
- Department of Pathology and Laboratory Medicine; Department of Urology; Sylvester Comprehensive Cancer Center, University of Miami / Jackson Memoria Hospital, Miami, FL
| | - Sumanta K Pal
- Department of Medical Oncology & Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA
| | | |
Collapse
|
|
27
|
Junker K, Hallscheidt P, Wunderlich H, Hartmann A. Diagnostics and prognostic evaluation in renal cell tumors: the German S3 guidelines recommendations. World J Urol 2022; 40:2373-2379. [PMID: 35294581 PMCID: PMC9512865 DOI: 10.1007/s00345-022-03972-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 02/18/2022] [Indexed: 11/28/2022] Open
Abstract
The German guidelines on renal cell carcinoma (RCC) have been developed at highest level of evidence based on systematic literature review. In this paper, we are presenting the current recommendations on diagnostics including preoperative imaging and imaging for stage evaluation as well as histopathological classification. The role of tumor biopsy is further discussed. In addition, different prognostic scores and the status of biomarkers in RCC are critically evaluated.
Collapse
Affiliation(s)
- Kerstin Junker
- Department of Urology and Pediatric Urology, Saarland Medical Center, Saarland University, Kirrberger Str., 66421, Homburg, Germany.
| | - Peter Hallscheidt
- Gemeinschaftspraxis für Radiologie und Nuklearmedizin, Worms, Germany
| | - Heiko Wunderlich
- Department of Urology and Pediatric Urology, St. Georg-Klinikum, Eisenach, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Erlangen-Nuremberg, Erlangen, Germany
| |
Collapse
|
|
28
|
Chen C, Yang R, Zhang J, Xu H. Construction and validation of a prognostic model for kidney renal clear cell carcinoma based on podocyte-associated genes. Cancer Med 2022; 11:3549-3562. [PMID: 35373928 PMCID: PMC9554457 DOI: 10.1002/cam4.4733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/14/2022] [Accepted: 03/23/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND As the most common renal malignancy, kidney renal clear cell carcinoma (KIRC) has a high prevalence and death rate as well as a poor response to treatment. Developing an efficient prognostic model is essential for accurately predicting the outcome and therapeutic benefit of KIRC patients. METHODS Gene expression profiles of podocyte-associated genes (PAGs) were obtained from The Cancer Genome Atlas and GEO datasets. Cox regression and Lasso regression analyses were then used for filtering prognosis-associated PAGs. Risk score (RS) was computed from these genetic characteristics. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were applied for ascertaining the prognostic value. Stratified analysis was used to sufficiently validate model performance. Concordance index was used to compare the predictive ability of different models. Immuno-infiltration analysis and immunophenoscore were utilized for the prediction of patient reaction to immune checkpoint inhibitors (ICIs). RESULTS WT1, ANLN, CUBN, OSGEP, and RHOA were significantly associated with KIRC prognosis. Prognostic analysis indicated that high-RS patients have a significantly poorer outcome. Cox regression analysis demonstrated a potential for RS to be an independent prognostic factor. Pathway enrichment results indicated a lower enrichment of cancer-related biological pathways in the low-RS subgroup. Immune infiltration analysis and IPS demonstrated greater responsiveness to ICIs in the high RS group. CONCLUSIONS This podocyte-associated KIRC prognostic model can effectively predict KIRC prognosis and immunotherapy response, which may help to provide clinicians with more effective treatment strategies.
Collapse
Affiliation(s)
- Can Chen
- Department of Laboratory Medicinethe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Branch of National Clinical Research Center for Laboratory MedicineNanjingChina
| | - Rui‐Xia Yang
- Department of Laboratory Medicinethe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Branch of National Clinical Research Center for Laboratory MedicineNanjingChina
| | - Jie‐Xin Zhang
- Department of Laboratory Medicinethe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Branch of National Clinical Research Center for Laboratory MedicineNanjingChina
| | - Hua‐Guo Xu
- Department of Laboratory Medicinethe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Branch of National Clinical Research Center for Laboratory MedicineNanjingChina
| |
Collapse
|
|
29
|
Xu Z, Chen S, Liu R, Chen H, Xu B, Xu W, Chen M. Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway. Mol Cancer 2022; 21:146. [PMID: 35840930 PMCID: PMC9284792 DOI: 10.1186/s12943-022-01607-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 06/19/2022] [Indexed: 02/07/2023] Open
Abstract
Background Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs in clear cell renal cell carcinoma (cRCC) remain largely elusive. Method Differentially expressed circRNAs in cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A expression was validated in cRCC tissues and cell lines via qRT-PCR. Sanger sequencing was used to identify the backsplicing site of circPOLR2A. In vitro and in vivo functional experiments were performed to evaluate the role of circPOLR2A in cRCC malignancy. RNA pull-down, mass spectrometry, RIP, FISH and immunofluorescence assays were used to identify and validate the circPOLR2A-interacting proteins. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting. The m6A modification in circPOLR2A was validated by the meRIP assay. Results Bioinformatics analysis revealed that circPOLR2A was highly expressed in cRCC tissues and metastatic cRCC tissues. CircPOLR2A expression was associated with tumor size and TNM stage in cRCC patients. In vitro and in vivo functional assays revealed that circPOLR2A accelerated cRCC cell proliferation, migration, invasion and angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested that circPOLR2A could interact with UBE3C and PEBP1 proteins, and that UBE3C could act as a specific ubiquitin E3 ligase for the PEBP1 protein. The UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein which could inactivate the ERK signaling pathway. Rescue experiments revealed that the PEBP1 protein was the functional downstream target of circPOLR2A. Furthermore, m6A modification in circPOLR2A was confirmed, and the m6A reader YTHDF2 could regulate circPOLR2A expression. Conclusion Our study demonstrated that circPOLR2A modulated the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, and further activated the ERK pathway during cRCC progression and metastasis. The m6A reader, YTHDF2, regulated circPOLR2A expression in cRCC. Hence, circPOLR2A could be a potential target for the diagnosis and treatment of cRCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01607-8.
Collapse
Affiliation(s)
- Zhipeng Xu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.,Urology Research Center, Southeast University Medical School, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China
| | - Shuqiu Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.,Urology Research Center, Southeast University Medical School, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China
| | - Ruiji Liu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.,Urology Research Center, Southeast University Medical School, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China
| | - Hui Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, People's Republic of China
| | - Bin Xu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China.,Urology Research Center, Southeast University Medical School, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China
| | - Weizhang Xu
- Department of Urology, Jiangsu Institute of Cancer Research & Jiangsu Cancer Hospital, No.42 Baiziting Road, Nanjing, 210000, People's Republic of China.
| | - Ming Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China. .,Urology Research Center, Southeast University Medical School, No.87 Dingjiaqiao Road, Nanjing, 210009, People's Republic of China. .,Department of Urology, Nanjing Lishui District People's Hospital, No.86 Chongwen Road, Nanjing, 211200, People's Republic of China.
| |
Collapse
|
|
30
|
Monti M, Lunardini S, Magli IA, Campi R, Primiceri G, Berardinelli F, Amparore D, Terracciano D, Lucarelli G, Schips L, Ferro M, Marchioni M. Micro-RNAs Predict Response to Systemic Treatments in Metastatic Renal Cell Carcinoma Patients: Results from a Systematic Review of the Literature. Biomedicines 2022; 10:biomedicines10061287. [PMID: 35740309 PMCID: PMC9220270 DOI: 10.3390/biomedicines10061287] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/17/2022] [Accepted: 05/24/2022] [Indexed: 12/17/2022] Open
Abstract
Locally advanced or metastatic renal cell carcinomas (mRCCs) account for up to 15% of all kidney cancer diagnoses. Systemic therapies (with or without surgery) represent gold standard treatments, mostly based on tyrosine kinase inhibitors in association with immunotherapy. We provide an overview of the current knowledge of miRNAs as predictors of treatment resistance. A systematic review of the literature was carried out in January 2022 following the PICO methodology. Overall, we included seven studies—four testing plasmatic miRNAs, two exosomal miRNAs, and one urinary miRNA. A total of 789 patients were included (354 for plasmatic miRNAs, 366 for urinary miRNAs, and 69 for exosomal miRNAs). Several miRNAs were tested within the included studies, but six plasmatic (miR9-5-p¸ miR-192, miR193-3p, miR-501-3p¸ miR-221, miR-376b-3p) one urinary (miR-30a-5p), and three exosomal (miR-35-5p, miR-301a-3p, miR-1293) were associated with resistance to systemic treatments or treatment failure in mRCC patients. Results showed a fair accuracy of these biomarkers in predicting treatment resistance and overall survival. However, to date, the biomarkers tested have not been validated and their clinical uses are not recommended. Nevertheless, the literature results are encouraging; future large clinical trials are warranted to validate the effectiveness of these tools in clinical decision-making.
Collapse
Affiliation(s)
- Martina Monti
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Susanna Lunardini
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Igino Andrea Magli
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Riccardo Campi
- Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, 50134 Florence, Italy;
| | - Giulia Primiceri
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Francesco Berardinelli
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Daniele Amparore
- Department of Oncology, School of Medicine, San Luigi Hospital, University of Turin, Orbassano, 10124 Turin, Italy;
| | - Daniela Terracciano
- Department of Translational Medical Sciences, University ‘Federico II’, 80138 Naples, Italy;
| | - Giuseppe Lucarelli
- Department of Emergency & Organ Transplantation—Urology, Andrology & Kidney Transplantation Unit, University of Bari, 70121 Bari, Italy;
| | - Luigi Schips
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 10060 Milan, Italy
- Correspondence:
| | - Michele Marchioni
- Department of Medical Oral and Biotechnological Science, “G. d’Annunzio” University of Chieti and Pescara, 66100 Chieti, Italy; (M.M.); (S.L.); (I.A.M.); (G.P.); (F.B.); (L.S.); (M.M.)
| |
Collapse
|
|
31
|
Lv Z, Feng HY, Wang T, Ma X, Zhang X. Preoperative systemic inflammation response index indicates poor prognosis in patients treated with resection of renal cell carcinoma with inferior vena cava tumor thrombus. Urol Oncol 2022; 40:167.e9-167.e19. [PMID: 35042663 DOI: 10.1016/j.urolonc.2021.11.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/02/2021] [Accepted: 11/29/2021] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To evaluate the prognostic value of systemic Inflammation Response Index (SIRI) in patients with renal cell carcinoma and inferior vena cava tumor thrombus (RCC-IVCTT) treated with radical nephrectomy and IVCTT thrombectomy. METHODS We retrospectively reviewed the clinical data of 144 consecutive patients with RCC-IVCTT who received radical nephrectomy and IVCTT thrombectomy at our center from January 2008 to August 2018. Receiver operating characteristic curve analysis was performed to calculate the optimal cutoff value of preoperative SIRI. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazard models were constructed to identify the independent prognostic factor for OS and PFS. The Harrell concordance index (C-index) was used to assess whether preoperative SIRI could improve the predictive accuracy of the existent prognostic models including Tumor, Node, Metastasis (TNM) stage model, University of California at Los Angeles Integrated Staging System (UISS) model and Stage, Size, Grade and Necrosis (SSIGN) model. RESULTS Elevated preoperative SIRI was significantly correlated with clinicopathologic features that are associated with tumor progression. Patients were divided into a high or low SIRI group by the optimal cutoff value of SIRI. Patients in the high SIRI group had longer postoperative hospital stays and lost more blood during surgery. Kaplan Meier curve showed that high SIRI was correlated with decreased OS (P = 0.036) and PFS (P = 0.039) for patients with RCC-IVCTT after surgery. Increased preoperative SIRI was an independently risk factor for decreased OS (P = 0.038) and PFS (P = 0.021). To evaluate PFS, integrating SIRI to each model led to an increased predictive accuracy of 13.2% for TNM staging model (P = 0.007), 14.4% for UISS model (P = 0.000), 12.9% for SSIGN model (P = 0.003). To evaluate OS, integrating SIRI to each model led to an increased predictive accuracy of 13.2% for TNM staging model (P = 0.006), 12.8% for UISS model (P = 0.004), 12.4% for SSIGN model (P = 0.008). CONCLUSIONS Preoperative SIRI serves as an independent predictor of prognosis for patients with RCC-IVCTT after surgery. Adding preoperative SIRI to the established prognostic models enhance their predictive accuracy.
Collapse
Affiliation(s)
- Zheng Lv
- Department of Urology, The Tianjin Third Central Hospital Affiliated of Nankai University; Department of Urology, The third Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Hua-Yi Feng
- Medical School of Chinese PLA, Beijing, China; Department of Urology, The third Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Tao Wang
- Medical School of Chinese PLA, Beijing, China; Department of Urology, The third Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xin Ma
- Department of Urology, The third Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.
| | - Xu Zhang
- Department of Urology, The third Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.
| |
Collapse
|
|
32
|
Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC registry. Clin Genitourin Cancer 2022; 20:326-333. [DOI: 10.1016/j.clgc.2022.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/27/2021] [Accepted: 03/21/2022] [Indexed: 12/18/2022]
|
|
33
|
Fontes-Sousa M, Magalhães H, Oliveira A, Carneiro F, dos Reis FP, Madeira PS, Meireles S. Reviewing Treatment Options for Advanced Renal Cell Carcinoma: Is There Still a Place for Tyrosine Kinase Inhibitor (TKI) Monotherapy? Adv Ther 2022; 39:1107-1125. [PMID: 35025061 PMCID: PMC8756748 DOI: 10.1007/s12325-021-02007-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023]
Abstract
Renal cell carcinoma (RCC) comprises a highly heterogeneous group of kidney tumours built upon distinct genetic- and epigenetic-driven mechanisms and molecular pathways. Therefore, responsiveness to treatment is considerably variable across patients, adding an extra layer of complexity to the already challenging therapeutic decision process. The last decade brought an unprecedented shift in the medical approach to advanced or metastatic RCC; in fact, immunotherapy-based combinations have significantly transformed the therapeutic arsenal and clinical outcomes of these patients. These strategies were quickly adopted by international guidelines committees as the new standards of care. However, this enhanced efficacy comes at the expense of tolerability, with a predictable negative impact on patients' quality of life. Moreover, subgroup and post hoc analyses of the major clinical trials have shown that not all patients benefit equally from these innovative approaches. In this context, a group of experts on kidney cancer met and discussed the state of the art in the field, with a special emphasis on the appropriateness of using monotherapy with an anti-angiogenesis tyrosine kinase inhibitor (TKI) to treat specific subgroups of patients with RCC. This article reviews the main topics that were considered to be pertinent for that discussion and establishes the profile of patients for whom TKI monotherapy remains a sensible frontline option by avoiding overtreatment and an unnecessary exposure to treatment-related toxicity.
Collapse
Affiliation(s)
| | - Helena Magalhães
- Hospital Pedro Hispano (Unidade Local de Saúde de Matosinhos), Rua Dr. Eduardo Torres, 4464-513 Senhora da Hora, Portugal
| | - Alicia Oliveira
- Hospital do Espírito Santo de Évora, Largo do Sr. da Pobreza, 7000-811 Évora, Portugal
| | - Filipa Carneiro
- Medical oncology department, Instituto Português de Oncologia Do Porto, Rua Dr. António Bernardino de Almeida 865, 4200-072 Porto, Portugal
| | - Filipa Palma dos Reis
- Hospital de Santo António Dos Capuchos (Centro Hospitalar Universitário de Lisboa Central), Alameda Santo António Dos Capuchos, 1169-050 Lisbon, Portugal
| | - Pedro Silvestre Madeira
- Instituto Português de Oncologia de Coimbra, Av. Prof. Dr. Bissaya Barreto No. 98, 3000-075 Coimbra, Portugal
| | - Sara Meireles
- Hospital de São João (Centro Hospitalar Universitário de São João), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| |
Collapse
|
|
34
|
Pal SK, Puente J, Heng DYC, Glen H, Koralewski P, Stroyakovskiy D, Alekseev B, Parnis F, Castellano D, Ciuleanu T, Lee JL, Sunela K, O'Hara K, Binder TA, Peng L, Smith AD, Rha SY. Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial. Eur Urol 2022; 82:283-292. [PMID: 35210132 DOI: 10.1016/j.eururo.2021.12.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/19/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. OBJECTIVE To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. DESIGN, SETTING, AND PARTICIPANTS A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor-targeted therapy (prior anti-programmed death-1/programmed death ligand-1 therapy permitted). INTERVENTION Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. RESULTS AND LIMITATIONS The ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25-39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27-42]; odds ratio: 0.88; 90% CI 0.59-1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. CONCLUSIONS The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. PATIENT SUMMARY In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used.
Collapse
Affiliation(s)
- Sumanta K Pal
- Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Javier Puente
- Medical Oncology Department, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain
| | - Daniel Y C Heng
- Department of Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada
| | - Hilary Glen
- Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | | | - Daniil Stroyakovskiy
- Chemotherapeutic Department, Moscow City Oncology Hospital, Moscow, Russian Federation
| | - Boris Alekseev
- Moscow Hertzen Oncology Institute, Moscow, Russian Federation (Alekseev)
| | - Francis Parnis
- Medical Oncology, Adelaide Cancer Center, Adelaide, Australia
| | - Daniel Castellano
- Medical Oncology Department, Hospital Universitario 12 de Octubre (CIBERONC), Madrid, Spain
| | - Tudor Ciuleanu
- Medical Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Jae Lyun Lee
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kaisa Sunela
- Department of Oncology, Tampere University Hospital, Tampere, Finland
| | | | | | | | | | - Sun Young Rha
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea.
| |
Collapse
|
|
35
|
Mao W, Wang K, Wu Y, Ni J, Zhang H, Wang Y, Wu Z, Liu R, Geng J, Chen S, Chen M. Prognostic Significance of Modified Advanced Lung Cancer Inflammation Index in Patients With Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy: A Multi-Institutional, Propensity Score Matching Cohort Study. Front Nutr 2022; 8:781647. [PMID: 35127784 PMCID: PMC8811296 DOI: 10.3389/fnut.2021.781647] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/24/2021] [Indexed: 12/19/2022] Open
Abstract
Background We conducted a multi-institutional clinical study to assess the prognostic value of the advanced lung cancer inflammatory index (ALI) and modified ALI (mALI) in patients with renal cell carcinoma (RCC). Methods We collected 440 patients who underwent laparoscopic nephrectomy at three centers from 2014 to 2019. ALI was defined as body mass index (BMI) × serum albumin (ALB)/neutrophil-to-lymphocyte ratio (NLR) and mALI as L3 muscle index × ALB/NLR. Kaplan-Meier curves, receiver operating characteristic (ROC) curves and Cox survival analysis were used to assess the effect of ALI and mALI on overall survival (OS). In addition, we performed 1:1 propensity score matching (PSM) for the high mALI and low mALI groups to further explore the impact of mALI on survival in RCC patients. Results The optimal cut-off values for ALI and mALI were 40.6 and 83.0, respectively. Based on the cut-off values, we divided the patients into high ALI and low ALI groups, high mALI and low mALI groups. ALI and mALI were significantly associated with the AJCC stage, Fuhrman grade, T stage, and M stage. Low ALI (p = 0.002) or low mALI (p < 0.001) was associated with poorer prognosis. ROC curves showed that mALI was a better predictor of OS than ALI. Multivariate Cox regression analysis showed that low mALI (aHR = 2.22; 95% CI 1.19–4.13, p = 0.012) was an independent risk factor for OS in RCC patients who underwent nephrectomy, while ALI (aHR = 1.40; 95% CI 0.73–2.66, p = 0.309) was not significantly associated. Furthermore, after PSM analysis, we found that mALI remained an independent risk factor for OS (aHR = 2.88; 95% CI 1.33–6.26, p = 0.007) in patients with RCC. Conclusions For RCC patients undergoing laparoscopic nephrectomy, low ALI and low mALI were associated with poor prognosis, and preoperative mALI can be used as a potential independent prognostic indicator for RCC patients.
Collapse
Affiliation(s)
- Weipu Mao
- Department of Urology, Shidong Hospital of Yangpu District, Shanghai, China
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Keyi Wang
- Department of Urology, Shidong Hospital of Yangpu District, Shanghai, China
| | - Yuan Wu
- Department of Urology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China
| | - Jinliang Ni
- Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Houliang Zhang
- Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Yidi Wang
- Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Zonglin Wu
- Department of Urology, Shidong Hospital of Yangpu District, Shanghai, China
| | - Ruiji Liu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
| | - Jiang Geng
- Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
- Jiang Geng
| | - Shuqiu Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
- Shuqiu Chen
| | - Ming Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China
- *Correspondence: Ming Chen
| |
Collapse
|
|
36
|
Owusuaa C, Dijkland SA, Nieboer D, van der Heide A, van der Rijt CCD. Predictors of Mortality in Patients with Advanced Cancer-A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:328. [PMID: 35053493 PMCID: PMC8774229 DOI: 10.3390/cancers14020328] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/31/2021] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
To timely initiate advance care planning in patients with advanced cancer, physicians should identify patients with limited life expectancy. We aimed to identify predictors of mortality. To identify the relevant literature, we searched Embase, MEDLINE, Cochrane Central, Web of Science, and PubMed databases between January 2000-April 2020. Identified studies were assessed on risk-of-bias with a modified QUIPS tool. The main outcomes were predictors and prediction models of mortality within a period of 3-24 months. We included predictors that were studied in ≥2 cancer types in a meta-analysis using a fixed or random-effects model and summarized the discriminative ability of models. We included 68 studies (ranging from 42 to 66,112 patients), of which 24 were low risk-of-bias, and 39 were included in the meta-analysis. Using a fixed-effects model, the predictors of mortality were: the surprise question, performance status, cognitive impairment, (sub)cutaneous metastases, body mass index, comorbidity, serum albumin, and hemoglobin. Using a random-effects model, predictors were: disease stage IV (hazard ratio [HR] 7.58; 95% confidence interval [CI] 4.00-14.36), lung cancer (HR 2.51; 95% CI 1.24-5.06), ECOG performance status 1+ (HR 2.03; 95% CI 1.44-2.86) and 2+ (HR 4.06; 95% CI 2.36-6.98), age (HR 1.20; 95% CI 1.05-1.38), male sex (HR 1.24; 95% CI 1.14-1.36), and Charlson comorbidity score 3+ (HR 1.60; 95% CI 1.11-2.32). Thirteen studies reported on prediction models consisting of different sets of predictors with mostly moderate discriminative ability. To conclude, we identified reasonably accurate non-tumor specific predictors of mortality. Those predictors could guide in developing a more accurate prediction model and in selecting patients for advance care planning.
Collapse
Affiliation(s)
- Catherine Owusuaa
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;
| | - Simone A. Dijkland
- Department of Public Health, Erasmus MC, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (S.A.D.); (D.N.); (A.v.d.H.)
| | - Daan Nieboer
- Department of Public Health, Erasmus MC, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (S.A.D.); (D.N.); (A.v.d.H.)
| | - Agnes van der Heide
- Department of Public Health, Erasmus MC, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (S.A.D.); (D.N.); (A.v.d.H.)
| | - Carin C. D. van der Rijt
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;
| |
Collapse
|
|
37
|
Ito T, Mizutani K, Takahara K, Ando R, Yasui T, Shiroki R, Koie T, Miyake H. Assessment of prognostic factors in previously treated Japanese patients with metastatic renal cell carcinoma who received nivolumab: An observational multi-institute study. Mol Clin Oncol 2021; 16:17. [PMID: 34881037 DOI: 10.3892/mco.2021.2446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 03/03/2021] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to evaluate the prognosis of Japanese patients with metastatic renal cell carcinoma (mRCC) receiving nivolumab and to identify factors predicting the overall survival (OS) in this cohort of patients. This study retrospectively assessed the outcomes of 77 consecutive Japanese patients with mRCC who were treated using either 1 or 2 molecular-targeted agents followed by nivolumab in routine clinical practice. The best responses to nivolumab observed were as follows: Complete response in 3 patients, partial response in 27, stable disease in 33 and progressive disease in 14; therefore, the objective response rate in the 77 patients was 39.0%. During the median follow-up period of 11 months after the introduction of nivolumab, the median progression-free survival and OS were 7 months and not reached, respectively. On multivariate analysis of several parameters, age, Karnofsky Performance Status (KPS) and neutrophil counts were demonstrated to be independently associated with OS in the 77 patients. By dividing these patients into 3 groups according to 3 risk factors, it was possible to stratify the OS; however, the International Metastatic Renal Cell Carcinoma Database Consortium model was unable to classify the OS. These results suggested that age, KPS and neutrophil counts were useful predictors of OS in previously treated patients with mRCC who received nivolumab.
Collapse
Affiliation(s)
- Toshiki Ito
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kosuke Mizutani
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Kiyoshi Takahara
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Ryosuke Ando
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Science, Nagoya, Aichi 467-8601, Japan
| | - Takahiro Yasui
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Science, Nagoya, Aichi 467-8601, Japan
| | - Ryoichi Shiroki
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan
| | - Takuya Koie
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| |
Collapse
|
|
38
|
Cytoreductive Nephrectomy in the Management of Metastatic Renal Cell Carcinoma: Is There Still a Debate? Curr Urol Rep 2021; 22:54. [PMID: 34654989 DOI: 10.1007/s11934-021-01073-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE OF REVIEW The aim of this review was to summarize the evidence on the current role of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). RECENT FINDINGS Since the advent of systemic targeted therapies for mRCC treatment, the role of CN has been questioned. Several retrospective observational studies demonstrated a therapeutic benefit for CN, while recent prospective randomized trials have challenged this evidence. As such, patient selection has become of paramount importance in this setting. The role of CN on mRCC treatment is still object of debate. In carefully selected patients, CN remains an important option as a component of a multimodal therapeutic approach. As systemic therapies for mRCC continue to evolve, future trials are needed to evaluate the benefits and limits of CN in the immunotherapy era, tailoring the treatment sequence and selecting the patients who are most likely to benefit from surgical interventions.
Collapse
|
|
39
|
Mao W, Sun S, He T, Jin X, Wu J, Xu B, Zhang G, Wang K, Chen M. Systemic Inflammation Response Index is an Independent Prognostic Indicator for Patients with Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy: A Multi-Institutional Cohort Study. Cancer Manag Res 2021; 13:6437-6450. [PMID: 34429652 PMCID: PMC8379394 DOI: 10.2147/cmar.s328213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/09/2021] [Indexed: 12/27/2022] Open
Abstract
Background We conducted a multicenter clinical study to examine the prognostic value of the systemic inflammation response index (SIRI) in renal cell carcinoma (RCC) patients. Methods We collected patients who underwent nephrectomy from 2014 to 2019 at three centers (343 in the training group and 100 in the validation group). SIRI was created based on hemoglobin and lymphocyte to monocyte ratio (LMR). Kaplan–Meier curves and receiver operating characteristic (ROC) curves were used to analyze the effect of LMR, hemoglobin and SIRI on overall survival (OS) and cancer-specific survival (CSS) effects. Results In both the training and validation groups, SIRI was a better predictor of OS and CSS than LMR and hemoglobin. A total of 192 (56.0%) patients were included in grade 1, 108 (31.5%) in grade 2, and 43 (12.5%) in grade 3 based on SIRI in the training group. Higher SIRI was associated with worse prognosis. Multivariate cox regression analysis showed that SIRI was an independent prognostic risk factor for OS (grade 3 vs grade 1: HR=4.93; 95% CI 2.21–11.00, p < 0.001) and CSS (grade 3 vs grade 1: HR=6.29; 95% CI 2.28–17.39, p < 0.001) in patients with RCC. In addition, SIRI-based prognostic nomograms were able to better predict OS and CSS in RCC patients. Conclusion SIRI is an independent prognostic factor for patients undergoing laparoscopic nephrectomy for RCC, and a prognostic nomogram covering SIRI can better predict survival of RCC patients.
Collapse
Affiliation(s)
- Weipu Mao
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China.,Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, 210009, People's Republic of China.,Department of Urology, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, 211200, People's Republic of China
| | - Si Sun
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China
| | - Ting He
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China
| | - Xin Jin
- Department of Urology, Taizhou People's Hospital, Taizhou, 225700, People's Republic of China
| | - Jianping Wu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China
| | - Bin Xu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China
| | - Guangyuan Zhang
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China
| | - Keyi Wang
- Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, People's Republic of China
| | - Ming Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, People's Republic of China.,Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, 210009, People's Republic of China.,Department of Urology, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, 211200, People's Republic of China
| |
Collapse
|
|
40
|
Impact of Body Mass Index on Survival of Metastatic Renal Cancer. J Kidney Cancer VHL 2021; 8:49-54. [PMID: 34414066 PMCID: PMC8336599 DOI: 10.15586/jkcvhl.v8i2.169] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 07/19/2021] [Indexed: 12/16/2022] Open
Abstract
Obesity has been established as a risk factor for renal cell carcinoma (RCC). Recently, studies have described obesity as a probable protecting factor in the metastatic stage of RCC. In this study, we assessed the relationship between body mass index (BMI) and overall survival in patients under systemic therapy. The correlation between BMI and overall median survival was studied in 76 patients diagnosed with metastatic RCC under systemic therapy. The groups were divided into overweight and obesity (BMI > 25 kg/m2) and underweight or normal (BMI < 25 kg/m2). Statistical analysis was performed using the Cox regression model adjusted by gender. A total of 76 patients were studied: 16 women (21%) and 60 men (79%). The median BMI was 27.96 kg/m2; 24 patients (31.6%) had low BMI and 52 (68.4%) had high BMI. Median overall survival in the group with BMI > 25 kg/m2 was 17 months (95% confidence interval [CI]: 13–34 months), while in the group with BMI ≤ 25 kg/m2, it was 14 months (95% CI: 8–20 months). When adjusted by gender, the group with BMI > 25 kg/m2 presented a hazards ratio of 0.54 (95% CI: 0.30–0.96), P = 0.044 (Log Rank). A high BMI significantly acts as a protecting factor. We observed an increased overall survival of overweight and obese patients within the context of metastatic RCC under systemic treatment. These data confirm the findings published in other studies that suggest the role of lipid metabolism in this type of tumors.
Collapse
|
|
41
|
Metastatic Lesion of the Tibia from Renal Cell Carcinoma. Case Rep Oncol Med 2021; 2021:2428820. [PMID: 34373797 PMCID: PMC8349284 DOI: 10.1155/2021/2428820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/20/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction Renal cell carcinoma is responsible for 3% of all cancers, with the highest incidence occurring in Western countries. Additionally, in patients with osseous metastasis, only 3% occur within the tibia. Rarely, a patient presents with a primary complaint of lower limb pain in advanced metastatic renal cell carcinoma. Case Presentation. The patient arrived at the emergency department with a primary complaint of left ankle pain. Ankle X-rays demonstrated a lytic lesion involving the medial malleolus with possible metastatic disease. CT scan confirmed a tumor within the right kidney. The patient was treated with a laparoscopic radical nephrectomy with histopathologic confirmation of clear cell renal cell carcinoma. Biopsy was then performed of the tibial lesion, confirming metastatic clear cell renal cell carcinoma. The tibial lesion was treated with local radiotherapy, and because of the progression of the tibia lesion, a decision was made to amputate the leg. Additionally, the patient was enrolled to sunitinib treatment and was disease free at one year of follow-up. 13 months after diagnosis of cancer, she was suffering a major stroke of the brain that caused her to die. Conclusion The treatment of patients with osseous metastases of renal cell cancer depends on the number of metastases, location of metastases, and overall health of the patient. We performed an overview of available literature and provided a summary regarding the use of cytoreductive nephrectomy, local therapy, target therapy, and bone-targeting agents in the treatment of metastatic renal cell cancer.
Collapse
|
|
42
|
Lee CH, Shah AY, Rasco D, Rao A, Taylor MH, Di Simone C, Hsieh JJ, Pinto A, Shaffer DR, Girones Sarrio R, Cohn AL, Vogelzang NJ, Bilen MA, Gunnestad Ribe S, Goksel M, Tennøe ØK, Richards D, Sweis RF, Courtright J, Heinrich D, Jain S, Wu J, Schmidt EV, Perini RF, Kubiak P, Okpara CE, Smith AD, Motzer RJ. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 2021; 22:946-958. [PMID: 34143969 DOI: 10.1016/s1470-2045(21)00241-2] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/06/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING Eisai and Merck Sharp & Dohme.
Collapse
Affiliation(s)
- Chung-Han Lee
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Amishi Yogesh Shah
- Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Drew Rasco
- Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX, USA
| | - Arpit Rao
- Division of Hematology, Oncology, and Transplantation, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Matthew H Taylor
- Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA
| | | | - James J Hsieh
- Department of Medicine, Oncology Division, Washington University School of Medicine, St Louis, MO, USA
| | - Alvaro Pinto
- Servicio de Oncología, Hospital Universitario La Paz, Madrid, Spain
| | - David R Shaffer
- Medical Oncology, US Oncology Research, New York Oncology Hematology, Albany, NY, USA
| | | | - Allen Lee Cohn
- Medical Oncology, US Oncology Research, Rocky Mountain Cancer Center, Denver, CO, USA
| | - Nicholas J Vogelzang
- Department of Medical Oncology, US Oncology Research, US Oncology Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
| | - Mehmet Asim Bilen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | | | - Musaberk Goksel
- Medical Oncology, Alaska Clinical Research Center, Anchorage, AK, USA
| | | | - Donald Richards
- Department of Oncology, US Oncology Research, Texas Oncology-Tyler, Tyler, TX, USA
| | - Randy F Sweis
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Jay Courtright
- Department of Oncology, US Oncology Research, Texas Oncology, Dallas, TX, USA
| | - Daniel Heinrich
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Sharad Jain
- Department of Oncology, US Oncology Research, Texas Oncology-Denton, Denton, TX, USA
| | - Jane Wu
- Biostatistics, Eisai, Woodcliff Lake, NJ, USA
| | | | | | - Peter Kubiak
- Clinical Research, Eisai, Woodcliff Lake, NJ, USA
| | | | | | - Robert J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
43
|
Breton C, Aparicio T, Le Malicot K, Ducreux M, Lecomte T, Bachet JB, Taieb J, Legoux JL, De Gramont A, Bennouna J, Bouché O, Boussari O, Manfredi S, Gornet JM. Predictive factors of severe early treatment-related toxicity in patients receiving first-line treatment for metastatic colorectal cancer: Pooled analysis of 2190 patients enrolled in Fédération Francophone de Cancérologie Digestive (FFCD) trials. Eur J Cancer 2021; 153:40-50. [PMID: 34130228 DOI: 10.1016/j.ejca.2021.04.040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/25/2021] [Indexed: 11/29/2022]
Abstract
AIM Few studies have explored the association between baseline characteristics and the occurrence of early toxicities in patients treated with first-line chemotherapy for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Individual patient data of 2190 patients enrolled in 10 prospective FFCD (Fédération Francophone de Cancérologie Digestive) trials were analysed. Severe early toxicity was defined as the occurrence of grade ≥III toxicity within 3 months after initiation of chemotherapy (ET3). RESULTS Patients received monotherapy based on 5-FU (n = 1068), a cytotoxic doublet (n = 395) or tritherapy with a cytotoxic doublet plus anti-VEGF agent or a cytotoxic triplet (n = 727). The patients received 5-FU (100%), Irinotecan (39.6%), Oxaliplatin (13.4%), Bevacizumab (29.6%) or Aflibercept (1.8%). ET3 occurred in 244 patients (22.8%) with monotherapy, 248 patients (62.8%) with doublet and 392 patients (53.9%) with tritherapy. The most frequent ET3s were related to biological abnormalities and/or gastrointestinal, general and vascular disorders. The prognostic factors for the occurrence of an ET3 in multivariate analysis were a performance status of 2 rather than 0-1 (OR 2.57; 95% CI [1.16, 5.73]; p = 0.02), tritherapy versus monotherapy (OR 2.31; 95% CI [0.84, 6.33]; p = 0.02), alkaline phosphatase > 300 UI/l (OR 3.07; 95% CI [1.79, 5.27]; p < 0.001) and non-resected primary tumour versus resection (OR 1.59; 95% CI [1.06, 2.39]; p = 0.02). Median overall survival in patients without ET3 was significantly longer than that in patients with ET3 (HR 0.87; 95% CI [0.80-0.96]; p = 0.004). CONCLUSION ET3 is frequent whatever the treatment regimen and is associated with certain baseline characteristics. The clinical impact of ET3 on prognosis in mCRC warrants further investigation.
Collapse
Affiliation(s)
- Clémence Breton
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint Louis, Université de Paris, Paris, France
| | - Thomas Aparicio
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint Louis, Université de Paris, Paris, France
| | - Karine Le Malicot
- FFCD, EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - Michel Ducreux
- Gustave Roussy Cancer Campus, Villejuif, Université Paris-Saclay, France
| | - Thierry Lecomte
- Hôpital universitaire de Tours, Université de Tours, Tours, France
| | - Jean-Baptiste Bachet
- Assistance Publique-Hôpitaux de Paris, Hôpital La Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Julien Taieb
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Université de Paris, SIRIC CARPEM, Paris, France
| | | | | | - Jaafar Bennouna
- Hôpital universitaire de Nantes, Université de Nantes, Nantes, France
| | - Olivier Bouché
- Hôpital universitaire de Reims, Université de Reims Champagne-Ardenne, Reims, France
| | - Olayide Boussari
- FFCD, EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - Sylvain Manfredi
- FFCD, EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - Jean-Marc Gornet
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint Louis, Université de Paris, Paris, France.
| |
Collapse
|
|
44
|
Malleo G, Salvia R, Maggino L, Marchegiani G, D'Angelica M, DeMatteo R, Kingham P, Pulvirenti A, Sereni E, Jarnagin WR, Bassi C, Allen PJ, Butturini G. Long-term Outcomes After Surgical Resection of Pancreatic Metastases from Renal Clear-Cell Carcinoma. Ann Surg Oncol 2021; 28:3100-3108. [PMID: 33575870 PMCID: PMC8119267 DOI: 10.1245/s10434-021-09649-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Pancreatic metastases (PM) from renal cell carcinoma (RCC) are uncommon. We herein describe the long-term outcomes associated with pancreatectomy at two academic institutions, with a specific focus on 10-year survival. METHODS This investigation was limited to patients undergoing pancreatectomy for PM between 2000 and 2008 at the University of Verona and Memorial Sloan Kettering Cancer Center, allowing a potential for 10 years of surveillance. The probabilities of further RCC recurrence and RCC-related death were estimated using a competing risk analysis (method of Fine and Gray) to account for patients who died of other causes during follow-up. RESULTS The study population consisted of 69 patients, mostly with isolated metachronous PM (77%). The median interval from nephrectomy to pancreatic metastasectomy was 109 months, whereas the median post-pancreatectomy follow-up was 141 months. The 10-year cumulative incidence of new RCC recurrence was 62.7%. In the adjusted analysis, the relative risk of repeated recurrence was significantly higher in PM synchronous to the primary RCC (sHR = 1.27) and in patients receiving extended pancreatectomy (sHR = 3.05). The 10-year cumulative incidence of disease-specific death was 25.5%. The only variable with an influence on disease-specific death was the recurrence-free interval following metastasectomy (sHR = 0.98). In patients with repeated recurrence, the 10-year cumulative incidence of RCC-related death was 35.4%. CONCLUSION In a selected group of patients followed for a median of 141 months and mostly with isolated metachronous PM, resection was associated with a high possibility of long-term disease control in surgically fit patients with metastases confined to the pancreas.
Collapse
Affiliation(s)
- Giuseppe Malleo
- Unit of General and Pancreatic Surgery-DSCOMI University of Verona, Verona, Italy.
| | - Roberto Salvia
- Unit of General and Pancreatic Surgery-DSCOMI University of Verona, Verona, Italy
| | - Laura Maggino
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
| | - Giovanni Marchegiani
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
| | - Michael D'Angelica
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronald DeMatteo
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Peter Kingham
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alessandra Pulvirenti
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elisabetta Sereni
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
| | - William R Jarnagin
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Claudio Bassi
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
| | - Peter J Allen
- The Hepato-Biliary and Pancreatic Unit, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Surgery, Duke University, Durham, NC, USA
| | - Giovanni Butturini
- Unit of General and Pancreatic Surgery, Department of Surgery and Oncology, University of Verona Hospital Trust, Verona, Italy
- Unit of Pancreatic Surgery, Pederzoli Hospital, Peschiera del Garda, Italy
| |
Collapse
|
|
45
|
Porubsky S, Nientiedt M, Kriegmair MC, Siemoneit JHH, Sandhoff R, Jennemann R, Borgmann H, Gaiser T, Weis CA, Erben P, Hielscher T, Popovic ZV. The prognostic value of galactosylceramide-sulfotransferase (Gal3ST1) in human renal cell carcinoma. Sci Rep 2021; 11:10926. [PMID: 34035403 PMCID: PMC8149814 DOI: 10.1038/s41598-021-90381-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 05/11/2021] [Indexed: 12/30/2022] Open
Abstract
Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.
Collapse
Affiliation(s)
- Stefan Porubsky
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.,Institute of Pathology, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | - Malin Nientiedt
- Department of Urology and Urosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Maximilian C Kriegmair
- Department of Urology and Urosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jörn-Helge Heinrich Siemoneit
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Roger Sandhoff
- Lipid Pathobiochemistry Group, German Cancer Research Center, Heidelberg, Germany
| | - Richard Jennemann
- Lipid Pathobiochemistry Group, German Cancer Research Center, Heidelberg, Germany
| | - Hendrik Borgmann
- Department of Urology, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | - Timo Gaiser
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Cleo-Aron Weis
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Philipp Erben
- Department of Urology and Urosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Thomas Hielscher
- Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Zoran V Popovic
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
| |
Collapse
|
|
46
|
Li S, Cheng Y, Cheng G, Xu T, Ye Y, Miu Q, Cao Q, Yang X, Ruan H, Zhang X. High SAA1 Expression Predicts Advanced Tumors in Renal Cancer. Front Oncol 2021; 11:649761. [PMID: 34084746 PMCID: PMC8168437 DOI: 10.3389/fonc.2021.649761] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/14/2021] [Indexed: 11/17/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most frequent malignant tumor of the kidney. 30% of patients with RCC are diagnosed at an advanced stage. Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of RCC. Currently, advanced ccRCC lacks reliable diagnostic and prognostic markers. We explored the potential of SAA1 as a diagnostic and prognostic marker for advanced ccRCC. In this study, we mined and analyzed the public cancer databases (TCGA, UALCAN and GEPIA) to conclude that SAA1 was up-regulated at mRNA and protein levels in advanced ccRCC. We further found that hypomethylation of SAA1 promoter region was responsible for its high expression in ccRCC. Receiver operating characteristic curve (ROC) indicated that high SAA1 levels could distinguish advanced ccRCC patients from normal subjects (p < 0.0001). Kaplan-Meier curve analysis showed that high SAA1 levels predicted poor overall survival time (p < 0.0001) and poor disease-free survival time (p = 0.0003). Finally, the functional roles of SAA1 were examined using a si-SAA1 knockdown method in RCC cell lines. Our results suggest that SAA1 may possess the potential to serve as a diagnostic and prognostic biomarker for advanced ccRCC patients. Moreover, targeting SAA1 may represent as a novel therapeutic target for advanced ccRCC patients.
Collapse
Affiliation(s)
- Sen Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongbiao Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gong Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianbo Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuzhong Ye
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Miu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Cao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiong Yang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailong Ruan
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
47
|
Tamura K, Osawa T, Takeuchi A, Minami K, Nakai Y, Ueda K, Ozawa M, Uemura M, Sugimoto M, Ohba K, Suzuki T, Anai S, Shindo T, Kusakabe N, Komiyama M, Tanaka K, Yokomizo A, Kohei N, Shinohara N, Miyake H. External validation of the albumin, C-reactive protein and lactate dehydrogenase model in patients with metastatic renal cell carcinoma receiving second-line axitinib therapy in a Japanese multi-center cohort. Jpn J Clin Oncol 2021; 51:810-818. [PMID: 33479762 DOI: 10.1093/jjco/hyaa264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Indexed: 11/13/2022] Open
Abstract
PURPOSE To externally validate the utility of the albumin, C-reactive protein and lactate dehydrogenase model to predict the overall survival of previously treated metastatic renal cell carcinoma patients. PATIENTS AND METHODS The ability of the albumin, C-reactive protein and lactate dehydrogenase model to predict overall survival was validated and compared with those of other prognostication models using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib therapy at 36 hospitals belonging to the Japan Urologic Oncology Group. RESULTS The following factors in this cohort were independently associated with poor overall survival in a multivariate analysis: a low Karnofsky performance status, <1 year from diagnosis to targeted therapy, a high neutrophil count, and low albumin, elevated C-reactive protein, and elevated lactate dehydrogenase, and the Japan Urologic Oncology Group model was newly developed based on the presence/absence of these independent factors. In this cohort, 151 (35.9%), 125 (27.7%) and 145 (34.4%) patients were classified into the favorable, intermediate and poor risk groups, respectively, according to the albumin, C-reactive protein and lactate dehydrogenase model; however, the proportions of patients in the intermediate risk group stratified by the Japan Urologic Oncology Group, Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models were >50%. The superiority of the albumin, C-reactive protein and lactate dehydrogenase model to the Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models, but not the Japan Urologic Oncology Group model, was demonstrated by multiple statistical analyses. CONCLUSIONS The utility of the albumin, C-reactive protein and lactate dehydrogenase model as a simple and objective prognostication tool was successfully validated using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib.
Collapse
Affiliation(s)
- Keita Tamura
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Osawa
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keita Minami
- Department of Urology, Sapporo City General Hospital, Sapporo, Japan
| | - Yasutomo Nakai
- Department of Urology, Osaka International Cancer Institute, Osaka, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University Hospital, Kurume, Japan
| | - Michinobu Ozawa
- Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Motohide Uemura
- Department of Urology, Osaka University Hospital, Suita, Japan
| | - Mikio Sugimoto
- Department of Urology, Kagawa University, Takamatsu, Japan
| | - Kojiro Ohba
- Department of Urology, Nagasaki University Hospital, Nagasaki, Japan
| | - Toshihiro Suzuki
- Department of Urology, Shinshu University Hospital, Matsumoto, Japan
| | - Satoshi Anai
- Department of Urology, Nara Medical University, Kashihara, Japan
| | - Tetsuya Shindo
- Department of Urology, Sapporo Medical University, Sapporo, Japan
| | | | - Motokiyo Komiyama
- Department of Urology, National Cancer Center Hospital, Chiba, Japan
| | - Ken Tanaka
- Department of Urology, University of Tsukuba Hospital, Tsukuba, Japan
| | - Akira Yokomizo
- Department of Urology, Harasanshin Hospital, Fukuoka, Japan
| | - Naoki Kohei
- Department of Urology, Shizuoka General Hospital, Shizuoka, Japan
| | - Nobuo Shinohara
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | |
Collapse
|
|
48
|
Martín C, Enrico D, Mas L, Patane AK, Arrieta O, Soria T, Cardona AF, Ruiz‐Patiño A, Ruiz R, Rioja P, Lozano S, Zatarain‐Barrón ZL, Barrón F, Puparelli C, Tsou F, Corassa MP, Freitas HC, Cordeiro de Lima VC, Rojas L, Ordóñez‐Reyes C, Corrales L, Sotelo C, Rodríguez J, Ricaurte L, Ávila J, Archila P, Rosell R, Cuello M, Remon J, CLICaP. Characteristics and outcomes of thymomas in Latin America: Results from over 10 years of experience (CLICaP-LATimus). Thorac Cancer 2021; 12:1328-1335. [PMID: 33729676 PMCID: PMC8088938 DOI: 10.1111/1759-7714.13901] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/06/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Thymomas are a group of rare neoplasms of the anterior mediastinum. The objective of this study was to describe the demographics, clinical characteristics and treatment approaches in Latin America. METHODS This was a retrospective multicenter cohort study including patients with histologically proven thymomas diagnosed between 1997 and 2018. Demographics, clinicopathological characteristics and therapeutic outcomes were collected locally and analyzed in a centralized manner. RESULTS A total of 135 patients were included. Median age at diagnosis was 53 years old (19-84), 53.3% (n = 72) of patients were female and 87.4% had an ECOG performance score ranging from 0-1. A total of 47 patients (34.8%) had metastatic disease at diagnosis. Concurrent myasthenia gravis occurred in 21.5% of patients. Surgery was performed in 74 patients (54.8%), comprising 27 (20%) tumorectomies and 47 (34.8%) thymectomies. According to the Masaoka-Koga system, overall survival (OS) at five-years was 73.4%, 63.8% and 51%, at stages I-II, III-IVA and IVB, respectively (p = 0.005). Furthermore, patients with low lactate dehydrogenase (LDH) (≤373 IU/L) at baseline and myasthenia gravis concurrence showed significantly better OS (p = 0.001 and p = 0.008, respectively). In multivariate analysis, high LDH levels (HR 2.8 [95% confidence interval [CI]: 1.1-7.8]; p = 0.036) at baseline and not performing a surgical resection (HR 4.1 [95% CI: 1.3-12.7]; p = 0.016) were significantly associated with increased risk of death. CONCLUSIONS Our data provides the largest insight into the clinical characteristics and outcomes of patients with thymomas in Latin America. Survival in patients with thymomas continues to be very favorable, especially when subjected to adequate local control.
Collapse
Affiliation(s)
- Claudio Martín
- Thoracic Oncology UnitAlexander Fleming Cancer InstituteBuenos AiresArgentina
| | - Diego Enrico
- Clinical Oncology DepartmentAlexander Fleming Cancer InstituteBuenos AiresArgentina
| | - Luis Mas
- Thoracic Oncology Unit, Oncology DepartmentInstituto Nacional de Enfermedades Neoplásicas – INENLimaPeru
| | | | - Oscar Arrieta
- Thoracic Oncology UnitInstituto Nacional de Cancerología‐ INCanMéxico CityMexico
| | - Tannia Soria
- Thoracic Oncology UnitHospital SOLCAQuitoEcuador
| | - Andrés F. Cardona
- Clinical and Traslational Oncology GroupClinica del CountryBogotáColombia
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
- Molecular Oncology and Biology Systems Research Group (Fox‐G)Universidad el BosqueBogotáColombia
| | - Alejandro Ruiz‐Patiño
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
- Molecular Oncology and Biology Systems Research Group (Fox‐G)Universidad el BosqueBogotáColombia
| | - Rossana Ruiz
- Thoracic Oncology Unit, Oncology DepartmentInstituto Nacional de Enfermedades Neoplásicas – INENLimaPeru
| | - Patricia Rioja
- Thoracic Oncology Unit, Oncology DepartmentInstituto Nacional de Enfermedades Neoplásicas – INENLimaPeru
| | - Sophia Lozano
- Thoracic Oncology Unit, Oncology DepartmentInstituto Nacional de Enfermedades Neoplásicas – INENLimaPeru
| | | | - Feliciano Barrón
- Thoracic Oncology UnitInstituto Nacional de Cancerología‐ INCanMéxico CityMexico
| | - Carmen Puparelli
- Thoracic Oncology UnitAlexander Fleming Cancer InstituteBuenos AiresArgentina
| | - Florencia Tsou
- Thoracic Oncology UnitAlexander Fleming Cancer InstituteBuenos AiresArgentina
| | | | - Helano C. Freitas
- Department of Medical OncologyA C Camargo Cancer CenterSão PauloBrazil
| | | | - Leonardo Rojas
- Clinical and Traslational Oncology GroupClinica del CountryBogotáColombia
- Molecular Oncology and Biology Systems Research Group (Fox‐G)Universidad el BosqueBogotáColombia
- Oncology DepartmentClínica ColsanitasBogotáColombia
| | | | - Luis Corrales
- Thoracic Oncology UnitHospital San Juan de Dios/Centro de Investigación y Manejo del Cáncer (CIMCA)San JoséCosta Rica
| | - Carolina Sotelo
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
| | - July Rodríguez
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
| | - Luisa Ricaurte
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
| | - Jenny Ávila
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
| | - Pilar Archila
- Foundation for Clinical and Applied Cancer Research – FICMACBogotáColombia
| | - Rafael Rosell
- Cancer Biology and Precision Medicine Program at the Catalan Institute of OncologyHospital Germans Trias i PujolBarcelonaSpain
| | - Mauricio Cuello
- Medical Oncology Department, Hospital de ClínicasUniversidad de la Republica – UdeLARMontevideoUruguay
| | - Jordi Remon
- Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM‐CIOCC)Hospital HM Delfos, HM HospitalesBarcelonaSpain
| | | |
Collapse
|
|
49
|
Demlová R, Turjap M, Peš O, Kostolanská K, Juřica J. Therapeutic Drug Monitoring of Sunitinib in Gastrointestinal Stromal Tumors and Metastatic Renal Cell Carcinoma in Adults-A Review. Ther Drug Monit 2021; 42:20-32. [PMID: 31259881 DOI: 10.1097/ftd.0000000000000663] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.
Collapse
Affiliation(s)
- Regina Demlová
- Department of Pharmacology, Medical Faculty, Masaryk University, Brno
| | - Miroslav Turjap
- Department of Clinical Pharmacy, University Hospital Ostrava, Ostrava
| | - Ondřej Peš
- Department of Biochemistry, Medical Faculty, Masaryk University
| | | | - Jan Juřica
- Department of Pharmacology, Medical Faculty, Masaryk University, Masaryk Memorial Cancer Institute; and.,Department of Human Pharmacology and Toxicology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| |
Collapse
|
|
50
|
Liu Y, Huang Z, Cheng G, Shou Y, Xu J, Liu D, Yang H, Liang H, Zhang X. Development of a four-gene prognostic model for clear cell renal cell carcinoma based on transcriptome analysis. Genomics 2021; 113:1816-1827. [PMID: 33838279 DOI: 10.1016/j.ygeno.2021.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 03/07/2021] [Accepted: 04/04/2021] [Indexed: 02/07/2023]
Abstract
This study aimed to develop a prognostic model for clear cell renal cell carcinoma (ccRCC) based on transcriptome analysis. We screened Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database for gene expression data and clinical characteristics of ccRCC. After differentially expression analysis, we identified 533 key genes of the development of ccRCC. Next, a weighted gene co-expression network analysis (WGCNA) was executed to investigate the association between differentially expressed genes and clinical characteristics. Then, based on protein-protein interaction (PPI) network, least absolute shrinkage and selection operator (LASSO) regression and Cox regression, a four-gene (COL4A5, ABCB1, NR3C2 and PLG) prognostic model has been constructed in TCGA training cohort. Finally, we examined the predictive power of this model with survival analysis and receiver operating characteristic (ROC) curve both in training cohort and in validation cohorts. And we found this model was significantly correlated with infiltrating immune cells. The four-gene prognosis model could be a potential prediction tool with high accuracy and reliability for ccRCC patients.
Collapse
Affiliation(s)
- Yuenan Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Ziwei Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Gong Cheng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Yi Shou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Jiaju Xu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Di Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Hongmei Yang
- Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, China
| | - Huageng Liang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
| |
Collapse
|