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Yamane K, Morino K, Anazawa T, Nagai K, Sato A, Yoshimura M, Iwai T, Matsubara J, Fukuda A, Isoda H, Ogiso S, Uchida Y, Ito T, Ishii T, Hidaka Y, Ibi Y, Hatano E. Proposing oligo-recurrence criteria in pancreatic ductal adenocarcinoma: A stratified analysis of locoregional treatment benefits. Pancreatology 2025:S1424-3903(25)00077-8. [PMID: 40316466 DOI: 10.1016/j.pan.2025.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/17/2025] [Accepted: 04/20/2025] [Indexed: 05/04/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with high recurrence rates following curative resection. Locoregional treatment (LT), including metastasectomy, radiation therapy, and radiofrequency ablation, has shown potential survival benefits in selected patients with recurrent PDAC. However, criteria for selecting patients who may benefit from LT remain unclear. The aim of this study is to define oligo-recurrence in PDAC by evaluating the impact of LT on survival after recurrence (SAR). METHODS Among 586 patients who underwent curative pancreatectomy between 2006 and 2022, 380 developed recurrence and were included in this study. The primary outcome was SAR, with prognostic factors identified using multivariate Cox regression analysis. Subgroup analysis was performed to identify the patient profiles most likely to benefit from LT. RESULTS LT was performed in 79 patients (20.8 %) and not in 301 patients (79.2 %). Independent predictors of poor SAR included time to recurrence (TTR) ≤ 12 months, CA19-9 > 200 U/mL at recurrence, and multi-organ recurrence or ≥ 4 tumors (P < 0.001 for each). Subgroup analysis of these factors identified two groups with significant survival benefits from LT: patients with "TTR >12 months" and "single-organ recurrence (SOR) with ≤3 tumors," with or without "CA19-9 > 200 U/mL." CONCLUSIONS Patients with recurrent PDAC characterized by "TTR >12 months" and "SOR with ≤3 tumors" may achieve long-term survival with LT, leading to the proposal of defining them as having "oligo-recurrence" in PDAC.
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Affiliation(s)
- Kei Yamane
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koshiro Morino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterological Surgery, Tenri Hospital, Tenri, Japan
| | - Takayuki Anazawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Kazuyuki Nagai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Asahi Sato
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Michio Yoshimura
- Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Iwai
- Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junichi Matsubara
- Department of Medical Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyoshi Isoda
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Ogiso
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yu Hidaka
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yumiko Ibi
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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2
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Liu LL, Lin YK, Xiang ZL. The Value of Primary Tumor Resection in Patients with Liver Metastases: A 10-Year Outcome. Ann Surg Oncol 2025; 32:1083-1092. [PMID: 39496900 PMCID: PMC11698763 DOI: 10.1245/s10434-024-16386-3] [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: 04/03/2024] [Accepted: 10/07/2024] [Indexed: 11/06/2024]
Abstract
OBJECTIVE This study aimed to analyze the impact of primary tumor resection (PTR) on the prognosis of four common primary tumors with liver metastases, and to develop a prognostic model to visualize the PTR benefit rate of patients with liver metastases. MATERIALS AND METHODS Patients diagnosed with colorectal cancer liver metastases (CRLM), pancreatic cancer liver metastases (PLM), gastric cancer liver metastases (GLM), and breast cancer liver metastases (BLM) between 2004 and 2015 were retrospectively reviewed from the Surveillance, Epidemiology, and End Results (SEER) database and assigned to either the surgery or non-surgery groups. A 1:1 propensity score matching (PSM) was performed. Surgical patients who survived longer than the median cancer-specific survival (CSS) time for non-surgery patients constituted the benefit group. Logistic regression was conducted to explore the independent factors affecting surgical benefit, and a nomogram was established. RESULTS A total of 21,928 patients with liver metastases were included. After PSM for surgery and non-surgery patients, we found that PTR had a significant impact on the overall survival (OS) and CSS of CRLM, PLM, and BLM patients. In CRLM patients, age (p < 0.001), primary site (p = 0.006), grade (p = 0.009), N stage (p = 0.034), and histology (p = 0.006) affected the surgical benefit. In BLM patients, the independent factors were age (p = 0.002), race (p = 0.020), and radiotherapy (p = 0.043). And in PLM patients, chemotherapy was an independent factor associated with a survival benefit from PTR. CONCLUSION PTR improved OS and CSS in patients with CRLM, PLM, and BLM. A predictive model was established to identify suitable candidates for PTR in CRLM patients.
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Affiliation(s)
- Lin-Lin Liu
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu-Kun Lin
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zuo-Lin Xiang
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
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Dobos NK, Garay T, Herold M, Simon A, Madar-Dank V, Balka G, Gajdacsi J, Dank M, Szasz AM, Herold Z. Immune Marker and C-Reactive Protein Dynamics and Their Prognostic Implications in Modulated Electro-Hyperthermia Treatment in Advanced Pancreatic Cancer: A Retrospective Analysis. IMMUNO 2024; 4:385-399. [DOI: 10.3390/immuno4040025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Background: Previous research has suggested that modulated electro-hyperthermia (mEHT) can be used to induce anti-tumor immune effects and to extend patient survival. The use of mEHT in advanced pancreatic cancer is beneficial; however, its immune-mediating effects were never investigated. Methods: A retrospective observational study was conducted. Leukocyte counts, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and granulocyte-to-lymphocyte ratio (GLR) were measured at baseline, midpoint, and after mEHT treatment. Results: A total of 73 mEHT treated pancreatic cancer patients were included. The time elapsed between tumor diagnosis and the first mEHT treatment was 4.40 ± 5.70 months. While no change could be observed between the baseline and the first follow-up visits, the total white blood cell (WBC), neutrophil, and granulocyte count, CRP, NLR, and GLR were significantly higher at the second follow-up compared to both previous visits. Higher levels of the latter parameters following the last mEHT treatment were signaling significantly poor prognostic signs, and so were their longitudinal changes. Conclusions: After the initiation of mEHT, immune markers stabilize with the treatment, but this positive effect is eroded over time by progressive disease. Monitoring the changes in these markers and the occurrence of their increase is a prognostic marker of shorter survival.
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Affiliation(s)
- Nikolett Kitti Dobos
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, Hungary
| | - Tamas Garay
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, Hungary
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
| | - Magdolna Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Alexandra Simon
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, Hungary
| | | | - Gyula Balka
- Department of Pathology, University of Veterinary Medicine Budapest, H-1078 Budapest, Hungary
| | - Jozsef Gajdacsi
- Clinical Center, Semmelweis University, H-1083 Budapest, Hungary
| | - Magdolna Dank
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
| | - Attila Marcell Szasz
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
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4
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Wang LT, Yang J, Wu J, Lu WJ. Combined Therapy of Chemotherapy and Radiofrequency Ablation for Pancreatic Cancer Patients With Metachronous Hepatic Metastatic Lesions After Radical Pancreatic Resection. Cancer Control 2024; 31:10732748241274559. [PMID: 39150275 PMCID: PMC11329956 DOI: 10.1177/10732748241274559] [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: 03/28/2024] [Revised: 07/09/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024] Open
Abstract
PURPOSE Hepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence. METHODS This is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model. RESULTS Among the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival. CONCLUSION Combined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival.
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Affiliation(s)
- L. T. Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - J. Yang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - J. Wu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - W. J. Lu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Halle-Smith JM, Hall LA, Powell-Brett SF, Merali N, Frampton AE, Beggs AD, Moss P, Roberts KJ. Pancreatic Exocrine Insufficiency and the Gut Microbiome in Pancreatic Cancer: A Target for Future Diagnostic Tests and Therapies? Cancers (Basel) 2023; 15:5140. [PMID: 37958314 PMCID: PMC10649877 DOI: 10.3390/cancers15215140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature review is to summarise the current evidence linking PEI with microbiome dysbiosis, assess how microbiome composition may be impacted by PERT treatment, and look towards possible future diagnostic and therapeutic targets in this area. Early evidence in the literature reveals that there are complex mechanisms by which pancreatic secretions modulate the gut microbiome, so when these are disturbed, as in PEI, gut microbiome dysbiosis occurs. PERT has been shown to return the gut microbiome towards normal, so called rebiosis, in animal studies. Gut microbiome dysbiosis has multiple downstream effects in pancreatic cancer such as modulation of the immune response and the response to chemotherapeutic agents. It therefore represents a possible future target for future therapies. In conclusion, it is likely that the gut microbiome of pancreatic cancer patients with PEI exhibits dysbiosis and that this may potentially be reversible with PERT. However, further human studies are required to determine if this is indeed the case.
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Affiliation(s)
- James M. Halle-Smith
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK (K.J.R.)
- Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2GW, UK;
| | - Lewis A. Hall
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK (K.J.R.)
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Sarah F. Powell-Brett
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK (K.J.R.)
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Nabeel Merali
- Section of Oncology, Department of Clinical & Experimental Medicine, University of Surrey, Guildford GU2 7WG, UK (A.E.F.); (P.M.)
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Guildford GU2 7WG, UK
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK
| | - Adam E. Frampton
- Section of Oncology, Department of Clinical & Experimental Medicine, University of Surrey, Guildford GU2 7WG, UK (A.E.F.); (P.M.)
- Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Guildford GU2 7WG, UK
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK
| | - Andrew D. Beggs
- Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2GW, UK;
- Colorectal Surgery Department, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK
| | - Paul Moss
- Section of Oncology, Department of Clinical & Experimental Medicine, University of Surrey, Guildford GU2 7WG, UK (A.E.F.); (P.M.)
| | - Keith J. Roberts
- Hepatobiliary and Pancreatic Surgery Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK (K.J.R.)
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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6
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Halle-Smith JM, Powell-Brett S, Roberts K, Chatzizacharias NA. Resection of isolated liver oligometastatic disease in pancreatic ductal adenocarcinoma: Is there a survival benefit? A systematic review. World J Gastrointest Surg 2023; 15:1512-1521. [PMID: 37555114 PMCID: PMC10405113 DOI: 10.4240/wjgs.v15.i7.1512] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/22/2023] [Accepted: 05/05/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Presence of liver metastatic disease in pancreatic ductal adenocarcinoma (PDAC), either synchronous or metachronous after pancreatic resection, is a terminal diagnosis that warrants management with palliative intent as per all international practice guidelines. However, there is an increasing interest on any potential value of surgical treatment of isolated oligometastatic disease in selected cases. AIM To present the published evidence on surgical management of PDAC liver metastases, synchronous and metachronous, and compare the outcomes of these treatments to the current standard of care. METHODS A systematic review was performed in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to compare the outcomes of both synchronous and metachronous liver metastases resection to standard care. RESULTS 356 studies were identified, 31 studies underwent full-text review and of these 10 were suitable for inclusion. When synchronous resection of liver metastases was compared to standard care, most studies did not demonstrate a survival benefit with the exception of one study that utilised neoadjuvant treatment. However, resection of metachronous disease appeared to confer a survival advantage when compared to treatment with chemotherapy alone. CONCLUSION A survival benefit may exist in resection of selected cases of metachronous liver oligometastatic PDAC disease, after disease biology has been tested with time and systemic treatment. Any survival benefit is less clear in synchronous cases; however an approach with neoadjuvant treatment and consideration of resection in some selected cases may confer some benefit. Future studies should focus on pathways for selection of cases that may benefit from an aggressive approach.
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Affiliation(s)
- James M Halle-Smith
- Department of HPB and Liver Transplant, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2GW, United Kingdom
| | - Sarah Powell-Brett
- Department of HPB and Liver Transplant, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2GW, United Kingdom
| | - Keith Roberts
- Department of HPB and Liver Transplant, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2GW, United Kingdom
| | - Nikolaos A Chatzizacharias
- Department of HPB and Liver Transplant, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2GW, United Kingdom
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Turner MA, Cox KE, Neel N, Amirfakhri S, Nishino H, Clary BM, Hosseini M, Natarajan G, Mallya K, Mohs AM, Hoffman RM, Batra SK, Bouvet M. Highly Selective Targeting of Pancreatic Cancer in the Liver with a Near-Infrared Anti-MUC5AC Probe in a PDOX Mouse Model: A Proof-of-Concept Study. J Pers Med 2023; 13:jpm13050857. [PMID: 37241027 DOI: 10.3390/jpm13050857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Accurately identifying metastatic disease is critical to directing the appropriate treatment in pancreatic cancer. Mucin 5AC is overexpressed in pancreatic cancer but absent in normal pancreas tissue. The present proof-of-concept study demonstrates the efficacy of an anti-mucin 5AC antibody conjugated to an IR800 dye (MUC5AC-IR800) to preferentially label a liver metastasis of pancreatic cancer (Panc Met) in a unique patient-derived orthotopic xenograft (PDOX) model. In orthotopic models, the mean tumor to background ratio was 1.787 (SD ± 0.336), and immunohistochemistry confirmed the expression of MUC5AC within tumor cells. MUC5AC-IR800 provides distinct visualization of pancreatic cancer liver metastasis in a PDOX mouse model, demonstrating its potential utility in staging laparoscopy and fluorescence-guided surgery.
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Affiliation(s)
- Michael A Turner
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Kristin E Cox
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Nicholas Neel
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Siamak Amirfakhri
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Hiroto Nishino
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Bryan M Clary
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA
| | | | - Kavita Mallya
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Aaron M Mohs
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Robert M Hoffman
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
- AntiCancer, Inc., San Diego, CA 92111, USA
| | - Surinder K Batra
- Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael Bouvet
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
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8
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Matsuki R, Okano N, Hasui N, Kawaguchi S, Momose H, Kogure M, Suzuki Y, Nagashima F, Sakamoto Y. Trends in the surgical treatment for pancreatic cancer in the last 30 years. Biosci Trends 2022; 16:198-206. [PMID: 35732435 DOI: 10.5582/bst.2022.01250] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Pancreatic cancer has the poorest prognosis among digestive cancers. During the 1990s, the 5-year survival rate of surgical patients with pancreatic cancer was 14% in Japan. However, survival rates have increased to 40% in the 2020s due to the refinement of surgical procedures and the introduction of perioperative chemotherapy. Several pivotal randomized controlled trials have played an indispensable role to establish each standard treatment strategy. Resectability of pancreatic cancer can be classified into resectable, borderline resectable, and unresectable based on the anatomic configuration, and multidisciplinary treatment strategies for each classification have been revised rapidly. Investigation of superior perioperative adjuvant treatments for resectable and borderline resectable pancreatic cancer and the establishment of optimal conversion surgery for unresectable pancreatic cancer are the progressive subjects.
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Affiliation(s)
- Ryota Matsuki
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Nobuhiro Hasui
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Shohei Kawaguchi
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Hirokazu Momose
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Masaharu Kogure
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Yutaka Suzuki
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Department of Hepato-Biliary-Pancreatic Surgery, Kyorin University Hospital, Tokyo, Japan
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9
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Mangieri CW, Valenzuela CD, Erali RA, Shen P, Howerton R, Clark CJ. Prognostic Effect of Aberrant Right Hepatic Artery with Pancreaticoduodenectomy: Focus on Hepatic Recurrence. Ann Surg Oncol 2022; 29:3219-3228. [DOI: 10.1245/s10434-022-11341-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/31/2021] [Indexed: 11/18/2022]
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10
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Yan X, Ning ZY, Wang P, Zhuang LP, Xu LT, Zhu ZF, Sheng J, Shen YH, Hua YQ, Meng ZQ. Combined ablation-chemotherapy versus chemotherapy alone for pancreatic cancer with liver metastasis: a propensity score matching study. Expert Rev Gastroenterol Hepatol 2021; 15:1047-1056. [PMID: 33356652 DOI: 10.1080/17474124.2021.1869937] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objectives: To retrospectively assess the efficacy of combined ablation-chemotherapy in comparison to that of chemotherapy alone in patients with liver metastasized pancreatic ductal adenocarcinoma (lmPDAC).Methods: In total 104 patients with hepatic oligo metastasized PDAC were identified; among them, 74 patients underwent combined thermal ablation-chemotherapy, and 30 patients underwent chemotherapy alone. Through propensity score matching, 1:1 matching of the combined ablation-chemotherapy group and chemotherapy group was achieved. The primary endpoint of this study was overall survival (OS). Clinical and tumor-related factors affecting OS were also analyzed through univariate and multivariate analyses using the Cox risk model.Results: For patients treated with combined ablation-chemotherapy, the median OS was 10.77 months, while it was 5.77 months for patients treated with chemotherapy alone (P = 0.011). The survival benefit for patients treated with combined ablation-chemotherapy was still preserved in the matched cohort, with a median OS of 8.17 months compared to 5.77 months in the chemotherapy group. Univariate and multivariate analyses in the matched population also showed treatment with combined ablation-chemotherapy was an independent prognostic factor (P < 0.05).Conclusions: For patients with liver metastases from pancreatic cancer, the combined use of thermal ablation and systemic chemotherapy offers a chance for a better survival outcome.
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Affiliation(s)
- Xia Yan
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhou-Yu Ning
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Peng Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Li-Ping Zhuang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Li-Tao Xu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhen-Feng Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jie Sheng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ye-Hua Shen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yong-Qiang Hua
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhi-Qiang Meng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Cancer minimally invasive treatment center, Fudan University Shanghai Cancer Center, Shanghai, China
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11
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Fu N, Jiang Y, Weng Y, Chen H, Deng X, Shen B. Worth it or not? Primary tumor resection for stage IV pancreatic cancer patients: A SEER-based analysis of 15,836 cases. Cancer Med 2021; 10:5948-5963. [PMID: 34288562 PMCID: PMC8419755 DOI: 10.1002/cam4.4147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/19/2021] [Accepted: 06/27/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Primary tumor resection (PTR) as a treatment option for patients with stage IV pancreatic cancer (PC) is controversial. PATIENTS AND METHODS Stage IV PC patients, with treatment data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER), were screened. The main outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS We enrolled 15,836 stage IV PC patients in this study. Propensity score-matched analyses revealed improved OS and CSS of patients receiving chemotherapy plus PTR versus chemotherapy (median survival time [MSTOS ]: 13 vs. 9 months, p = 0.024; MSTCSS : 14 vs. 10 months, p = 0.035), and chemoradiotherapy plus PTR versus chemoradiotherapy (MSTOS : 14 vs. 7 months, p = 0.044; MSTCSS : 14 vs. 7 months, p = 0.066). Multivariate adjusted analyses further confirmed these results. Stratified with different metastatic modalities, multivariate analyses suggested that PTR significantly improved the OS and CSS among patients with ≤1 metastatic organ, and that patients with brain metastasis might not benefit from chemotherapy treatment. CONCLUSION PTR improves the OS and CSS of stage IV PC patients on the basis of chemotherapy or chemoradiotherapy, provided that the metastases involve ≤1 organ. Chemotherapy, however, should be carefully considered in patients with metastases involving the brain.
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Affiliation(s)
- Ningzhen Fu
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
| | - Yu Jiang
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
| | - Yuanchi Weng
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
| | - Hao Chen
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
| | - Xiaxing Deng
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
| | - Baiyong Shen
- Department of General SurgeryPancreatic Disease CenterRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Jiao Tong University School of MedicineResearch Institute of Pancreatic DiseaseShanghaiChina
- State Key Laboratory of Oncogenes and Related GenesShanghaiChina
- Shanghai Jiao Tong UniversityInstitute of Translational MedicineShanghaiChina
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12
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Charles Jacob HK, Charles Richard JL, Signorelli R, Kashuv T, Lavania S, Vaish U, Boopathy R, Middleton A, Boone MM, Sundaram R, Dudeja V, Saluja AK. Modulation of Early Neutrophil Granulation: The Circulating Tumor Cell-Extravesicular Connection in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2021; 13:cancers13112727. [PMID: 34072942 PMCID: PMC8198339 DOI: 10.3390/cancers13112727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Circulating tumor cells (CTCs) found in the blood of pancreatic cancer patients show a worse prognosis to therapy if they are seen in clusters of cells with neutrophils or platelets or with other cell types than when they are seen as singlets. We wanted to investigate if there is a secondary mode of communication between the CTCs and neutrophils that causes them to associate. We describe for the first time an extravesicular (EV) mediated communication between CTCs and neutrophils that modulates early transcriptome changes that can cause neutrophils to partially degranulate and form associations. We also identify the protein cargo carried in such EVs and how when added to naïve neutrophils, they can modulate transcriptomic changes in neutrophils partially disarming them to form clusters rather than undergo specialized cell death, which is characterized by release of condensed chromatin (NETs) and granular contents termed as NETosis. Abstract Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters.
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Affiliation(s)
- Harrys Kishore Charles Jacob
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
| | - John Lalith Charles Richard
- School of Biosciences, Engineering and Technology (SBET), VIT Bhopal University, Madhya Pradesh 466114, India;
| | | | - Tyler Kashuv
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33146, USA;
| | - Shweta Lavania
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
| | - Utpreksha Vaish
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
| | - Ranjitha Boopathy
- Department of Life Sciences, Shiv Nadar University, Greater Noida 201304, India;
| | - Ashley Middleton
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
| | | | - Ramakrishnan Sundaram
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
| | - Vikas Dudeja
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
- Department of Life Sciences, Shiv Nadar University, Greater Noida 201304, India;
| | - Ashok Kumar Saluja
- Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (H.K.C.J.); (S.L.); (A.M.); (R.S.); (V.D.)
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, FL 33136, USA
- Correspondence: ; Tel.: +1-305-243-2703
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13
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Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma. Pharmaceutics 2021; 13:pharmaceutics13010103. [PMID: 33466892 PMCID: PMC7830403 DOI: 10.3390/pharmaceutics13010103] [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: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original tumoral cells and their microenvironment to establish a metastatic niche. Traditionally, cancer therapy has focused on metastasis prevention by systematic treatments or direct surgical re-sectioning. However, metastasis can still occur. More recently, new therapies direct their attention to targeting cancer stem cells. As they propose, these cells could be the orchestrators of the metastatic niche. In this review, we describe conventional and novel developments in cancer therapeutics for liver and lung metastasis. We further discuss the resistance mechanisms of targeted therapy, the advantages, and disadvantages of diverse treatment approaches, and future novel strategies to enhance cancer prognosis.
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14
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Zuo D, Qian JJ, Dong Y, Wang WP, Tian XF, Qiu YJ, Dietrich CF. Incidentally Detected Liver Metastases during Pancreas Contrast-enhanced Ultrasound. BIO INTEGRATION 2021; 2. [DOI: 10.15212/bioi-2021-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2023] Open
Abstract
Abstract
Purpose: The purpose of current study was to investigate the value of the late-phase enhancement features of pancreas contrast-enhanced ultrasound (CEUS) in the detection of liver metastases in patients with pancreatic ductal adenocarcinomas (PDAC).
Methods: From October 2020 to March 2021, 86 patients were prospectively enrolled. The gold standard of liver metastatic and PDAC lesions were based on histopathologically diagnoses and multiple imaging modalities results. B-mode ultrasound (BMUS) was performed to detect suspected liver metastases before CEUS. During the late phase of pancreas CEUS, the entire liver was scanned again to detect hypoenhanced liver metastases. Liver metastases were confirmed by biopsy and histopathological results. The number and size of liver metastases detected by BMUS and during CEUS late phase were recorded and compared.
Results: Suspected liver metastases were detected in 14 patients by BMUS (n = 23). During the late phase of CEUS, hypoenhanced liver metastases were detected in 23 patients (n = 87). When compared with BMUS, whole-liver scan during the late phase of CEUS detected more isoechoic, small, or superficially located lesions. Compared with BMUS, the specificity, sensitivity, positive predictive value, and negative predictive value of CEUS in diagnosing of liver metastases in PDAC patients were significantly improved (96.72% vs. 100%, 48% vs. 92%, 85.71% vs. 100%, and 83.10% vs. 96.83%, respectively) (P < 0.05).
Conclusion: The late phase whole liver scan during CEUS of pancreas helps to detect more liver metastases, which is important for further clinical decision-making.
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15
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Moro L, Simoneschi D, Kurz E, Arbini AA, Jang S, Guaragnella N, Giannattasio S, Wang W, Chen YA, Pires G, Dang A, Hernandez E, Kapur P, Mishra A, Tsirigos A, Miller G, Hsieh JT, Pagano M. Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis. Nat Cell Biol 2020; 22:1130-1142. [PMID: 32839549 PMCID: PMC7484425 DOI: 10.1038/s41556-020-0560-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
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Affiliation(s)
- Loredana Moro
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.
| | - Daniele Simoneschi
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
| | - Emma Kurz
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
| | - Arnaldo A Arbini
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - Shaowen Jang
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
| | - Nicoletta Guaragnella
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "A. Moro", Bari, Italy
| | - Sergio Giannattasio
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Wei Wang
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
- Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Yu-An Chen
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Geoffrey Pires
- Department of Neurology, New York University Grossman School of Medicine, New York, NY, USA
| | - Andrew Dang
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Elizabeth Hernandez
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Payal Kapur
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ankita Mishra
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
- Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Aristotelis Tsirigos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - George Miller
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA
- Department of Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Jer-Tsong Hsieh
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
- Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
- Howard Hughes Medical Institute, New York, NY, USA.
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16
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Schwarz C, Fitschek F, Primavesi F, Stättner S, Margonis GA, Weiss MA, Stavrou GA, Oldhafer KJ, Kornprat P, Wundsam H, Fischer I, Längle F, Függer R, Hauer A, Klug R, Kieler M, Prager G, Schindl M, Stremitzer S, Bodingbauer M, Sahora K, Kaczirek K. Metachronous hepatic resection for liver only pancreatic metastases. Surg Oncol 2020; 35:169-173. [PMID: 32889249 DOI: 10.1016/j.suronc.2020.08.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/22/2020] [Accepted: 08/02/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND The value of liver resection (LR) for metachronous pancreatic ductal adenocarcinoma (PDAC) metastases remains controversial. However, in light of increasing safety of liver resections, surgery might be a valuable option for metastasized PDAC in selected patients. METHODS We performed a retrospective, multicenter study including patients undergoing hepatectomy for metachronous PDAC liver metastases between 2004 and 2015 to analyze postoperative outcome and overall survival. All patients were operated with curative intent. Patients with oligometastatic metachronous liver metastasis with definitive chemotherapy (n = 8) served as controls. RESULTS Overall 25 patients in seven centers were included in this study. The median age at the time of LR was 63.8 years (56.9-69.9) and the median number of metastases in the liver was 1 (IQR 1-2). There were eight non-anatomical resections (32%), 15 anatomical minor (60%) and 2 major LR (8%). Postoperative complications occurred in eleven patients (eight Clavien-Dindo grade I complications (32%) and three grade IIIa complications (12%), respectively). The 30-day mortality was 0%. The median length of stay was 8.6 days (IQR 5-11). Median overall survival following LR was 36.8 months compared to 9.2 months in patients with metachronous liver metastasis with chemotherapy (p = 0007). DISCUSSION Liver resection for metachronous PDAC metastasis is safe and feasible in selected patients. To address general applicability and to find factors for patient selection, larger trials are urgently warranted.
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Affiliation(s)
- C Schwarz
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
| | - F Fitschek
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
| | - F Primavesi
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Austria
| | - S Stättner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Austria
| | - G A Margonis
- Department of Surgery, Johns Hopkins University, Baltimore, USA
| | - M A Weiss
- Department of Surgery, Northwell Health Cancer Institute, New York, USA
| | - G A Stavrou
- Department of Surgery, Division of HPB Surgery, Asklepios Campus Barmbek, Hamburg, Germany; Semmelweis University Budapest, Asklepios Campus Hamburg, Germany
| | - K J Oldhafer
- Department of Surgery, Division of HPB Surgery, Asklepios Campus Barmbek, Hamburg, Germany; Semmelweis University Budapest, Asklepios Campus Hamburg, Germany
| | - P Kornprat
- Department of Surgery, Medical University Graz, Graz, Austria
| | - H Wundsam
- Department of Surgery, Hospital Sisters of Mercy Linz, Linz, Austria
| | - I Fischer
- Department of Surgery, Hospital Sisters of Mercy Linz, Linz, Austria
| | - F Längle
- Department of Surgery, LK Wiener Neustadt, Wiener Neustadt, Austria
| | - R Függer
- Department of Surgery, Hospital Sisters of Mercy Linz, Linz, Austria
| | - A Hauer
- Department of Surgery, KH Horn, Austria
| | - R Klug
- Department of Surgery, KH Horn, Austria
| | - M Kieler
- Department of Internal Medicine/Division of Oncology, Medical University Vienna, Austria
| | - G Prager
- Department of Internal Medicine/Division of Oncology, Medical University Vienna, Austria
| | - M Schindl
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
| | - S Stremitzer
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
| | - M Bodingbauer
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
| | - K Sahora
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria.
| | - K Kaczirek
- Department of Surgery/Division of General Surgery, Medical University Vienna, Austria
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17
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Höhn P, Braumann C, Nöpel-Dünnebacke S, Munding J, Uhl W, Luu AM. Recurrence of Pancreatic Ductal Adenocarcinoma after Complete Histopathological Remission Caused by FOLFIRINOX. Visc Med 2020; 37:149-153. [PMID: 33981756 DOI: 10.1159/000509231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/08/2020] [Indexed: 02/03/2023] Open
Abstract
We previously reported 2 cases of pathologic complete response (pCR) of a pancreatic cancer (PC) following neoadjuvant FOLFIRINOX treatment. We now complete our report by a follow-up on both patients. Patient 1 achieved a disease-free survival of 12 months after initial resection until she developed a singular hepatic metastasis. Treatment by FOLFIRINOX and complete removal of the metastasis by atypical liver resection after 6 months allowed for another 12 months of disease control. After intra-abdominal tumor recurrence and development of intracerebral metastases, the patient died 34 months after primary diagnosis. Patient 2 developed hepatic tumor recurrence only 3 months after initial resection. However, treatment by FOLFIRINOX led to a stable disease for 27 months after resection and was followed by atypical liver resection of multiple segments. Six months later, another hepatic recurrence was suspected. Via next-generation sequencing (NGS) of the tumor genome, a deleterious mutation in the ataxia telangiectasia-mutated (ATM) gene, causing a BRCAness, was detected. After initial treatment by FOLFOX, maintenance therapy with the poly-ADP-ribose-polymerase (PARP) inhibitor olaparib was initiated. The patient is now alive for 54 months after initial diagnosis of metastasized pancreatic adenocarcinoma. Tumor recurrence is possible even after pCR of PC and remains challenging. In case of multifocal tumor recurrence, chemotherapy remains the standard treatment. Recently, genetic sequencing allows individualized treatments. In selected cases, highly specialized teams can offer a variety of therapeutic options leading to previously unseen clinical courses.
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Affiliation(s)
- Philipp Höhn
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Chris Braumann
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Stefanie Nöpel-Dünnebacke
- Department of Hematology, Oncology and Palliative Care, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Johanna Munding
- Institute of Pathology, Ruhr University Bochum, Bochum, Germany
| | - Waldemar Uhl
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas Minh Luu
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
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18
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Jin T, Dai C, Xu F. Surgical and local treatment of hepatic metastasis in pancreatic ductal adenocarcinoma: recent advances and future prospects. Ther Adv Med Oncol 2020; 12:1758835920933034. [PMID: 32636941 PMCID: PMC7313332 DOI: 10.1177/1758835920933034] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/07/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with increasing incidence and mortality. More than half of PDAC patients develop metastases, with the liver being the most common site. Patients with pancreatic ductal adenocarcinoma with liver metastases (PCLM) have a very limited scope for surgery due to aggressive tumor behavior and poor prognosis. However, with the improvements in preoperative systemic therapy and perioperative outcomes, an increasing number of patients are being considered for surgical management. However, the best choice of surgical treatment and criteria for selecting suitable PCLM patients who may benefit from surgical treatment remains controversial. Palliative local treatments, such as ablation, locoregional chemotherapy, and brachytherapy, which are less invasive and have fewer contraindications and complications, are the preferred alternatives to surgery. The present study reviews the advances in the management of PCLM, with focus on resection and local therapies.
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Affiliation(s)
- Tianqiang Jin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chaoliu Dai
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Feng Xu
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, China
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19
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Gupta R, Leon F, Thompson CM, Nimmakayala R, Karmakar S, Nallasamy P, Chugh S, Prajapati DR, Rachagani S, Kumar S, Ponnusamy MP. Global analysis of human glycosyltransferases reveals novel targets for pancreatic cancer pathogenesis. Br J Cancer 2020; 122:1661-1672. [PMID: 32203219 PMCID: PMC7251111 DOI: 10.1038/s41416-020-0772-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/12/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Several reports have shown the role of glycosylation in pancreatic cancer (PC), but a global systematic screening of specific glycosyltransferases (glycoTs) in its progression remains unknown. METHODS We demonstrate a rigorous top-down approach using TCGA-based RNA-Seq analysis, multi-step validation using RT-qPCR, immunoblots and immunohistochemistry. We identified six unique glycoTs (B3GNT3, B4GALNT3, FUT3, FUT6, GCNT3 and MGAT3) in PC pathogenesis and studied their function using CRISPR/Cas9-based KD systems. RESULTS Serial metastatic in vitro models using T3M4 and HPAF/CD18, generated in house, exhibited decreases in B3GNT3, FUT3 and GCNT3 expression on increasing metastatic potential. Immunohistochemistry identified clinical significance for GCNT3, B4GALNT3 and MGAT3 in PC. Furthermore, the effects of B3GNT3, FUT3, GCNT3 and MGAT3 were shown on proliferation, migration, EMT and stem cell markers in CD18 cell line. Talniflumate, GCNT3 inhibitor, reduced colony formation and migration in T3M4 and CD18 cells. Moreover, we found that loss of GCNT3 suppresses PC progression and metastasis by downregulating cell cycle genes and β-catenin/MUC4 axis. For GCNT3, proteomics revealed downregulation of MUC5AC, MUC1, MUC5B including many other proteins. CONCLUSIONS Collectively, we demonstrate a critical role of O- and N-linked glycoTs in PC progression and delineate the mechanism encompassing the role of GCNT3 in PC.
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Affiliation(s)
- Rohitesh Gupta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Frank Leon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Christopher M Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ramakrishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Saswati Karmakar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Palanisamy Nallasamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Seema Chugh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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20
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Wattenberg MM, Asch D, Yu S, O'Dwyer PJ, Domchek SM, Nathanson KL, Rosen MA, Beatty GL, Siegelman ES, Reiss KA. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer 2020; 122:333-339. [PMID: 31787751 PMCID: PMC7000723 DOI: 10.1038/s41416-019-0582-7] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 08/23/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. METHODS Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. RESULTS The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068). CONCLUSION Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.
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Affiliation(s)
- Max M Wattenberg
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniella Asch
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Shun Yu
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter J O'Dwyer
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Susan M Domchek
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Katherine L Nathanson
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Mark A Rosen
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gregory L Beatty
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Evan S Siegelman
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kim A Reiss
- Division of Hematology-Oncology, Department of Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
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21
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The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction. Cancer Lett 2020; 474:82-93. [PMID: 31954769 DOI: 10.1016/j.canlet.2020.01.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 12/05/2019] [Accepted: 01/10/2020] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and novel therapeutic strategies are urgently needed. Recently, expression of the C-C chemokine receptor 5 (CCR5) and its ligands has been found to play an important role in cancer progression and metastasis. In this study, we blocked the CCR5 receptor by the FDA approved antagonist maraviroc (MVC) in Suit2-007 and MIA-PaCa-2 human PDAC cells. The treatment significantly inhibited their proliferation and induced apoptosis of exposed cells as evidenced by caspases activation and increased Bax levels. Moreover, MVC inhibited the cell cycle by down regulating the proteins of the complexes of cyclin dependent kinase (CDK) 4/6 - Cyclin D and CDK2 - Cyclin E, as well as by increasing the protein levels of CDK inhibitors p18, p21 and p27. In line with this, MVC caused significant retardation of Suit2-007 cells growing in a PDAC liver metastasis xenograft model (p < 0.05). These results suggest that maraviroc could be a promising treatment strategy for PDAC patients with liver metastases.
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22
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Damanakis AI, Ostertag L, Waldschmidt D, Kütting F, Quaas A, Plum P, Bruns CJ, Gebauer F, Popp F. Proposal for a definition of "Oligometastatic disease in pancreatic cancer". BMC Cancer 2019; 19:1261. [PMID: 31888547 PMCID: PMC6937989 DOI: 10.1186/s12885-019-6448-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/11/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival. METHODS Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. RESULTS Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009). CONCLUSION We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.
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Affiliation(s)
- Alexander I Damanakis
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
| | - Luisa Ostertag
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Dirk Waldschmidt
- Department of Gastroenterology, University Hospital of Cologne, Cologne, Germany
| | - Fabian Kütting
- Department of Gastroenterology, University Hospital of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Patrick Plum
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Felix Popp
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
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23
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Wei M, Shi S, Hua J, Xu J, Yu X. Simultaneous resection of the primary tumour and liver metastases after conversion chemotherapy versus standard therapy in pancreatic cancer with liver oligometastasis: protocol of a multicentre, prospective, randomised phase III control trial (CSPAC-1). BMJ Open 2019; 9:e033452. [PMID: 31818843 PMCID: PMC6924808 DOI: 10.1136/bmjopen-2019-033452] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/24/2019] [Accepted: 11/18/2019] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Approximately 50% of pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed with distant metastasis, especially liver metastasis. The current standard treatment for these stage IV patients is palliative chemotherapy. There is increasing agreement that synchronous PDAC and liver metastasis resection may benefit highly selected patients. Thus, the Chinese Study Group for Pancreatic Cancer (CSPAC)-1 trial is being launched to establish a strategy for selecting PDAC patients with liver oligometastases who may benefit from synchronous resection after conversion chemotherapy. METHODS AND ANALYSIS In this study, liver oligometastasis is defined as no more than three metastatic lesions irrespective of their distribution within the liver lobes. The trial contains two steps. In the first step, 1000 to 1200 needle biopsy-confirmed PDAC patients with liver oligometastases are eligible for inclusion. Candidates will receive first-line chemotherapy. The RECIST V.1.1 criteria combined with tumour markers will be applied to evaluate the tumour response to chemotherapy every two cycles. Pancreatic cancer and hepatic metastasis resectability will be identified by multidisciplinary teams. Approximately 300 patients who meet our criteria will enter the second step and be randomly assigned at a 1:1 ratio to simultaneous resection of the primary pancreatic cancer lesion and liver oligometastases if no extensive metastatic sites are found during surgery or standard chemotherapy. Postoperative chemotherapy is recommended, and regimen selection should be based on the preoperative chemotherapy regimen. The primary endpoint is real overall survival (from enrolment to death). This study was activated in July 2018 and is expected to complete accrual within 5 years. ETHICS AND DISSEMINATION This trial has been approved by the Clinical Research Ethics Committee of Fudan University Shanghai Cancer Centre. Written informed consent will be obtained from all participants. Serious adverse events will be reported. Trial results will be submitted for peer-reviewed publication. TRIAL REGISTRATION NUMBER NCT03398291; Pre-results.
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Affiliation(s)
- Miaoyan Wei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
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24
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Conversion surgery for initially unresectable pancreatic cancer: current status and unresolved issues. Surg Today 2019; 49:894-906. [PMID: 30949842 DOI: 10.1007/s00595-019-01804-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 02/17/2019] [Indexed: 12/16/2022]
Abstract
Pancreatic cancer is one of the most lethal of all malignancies. One of the reasons for the dismal prognosis is that most diagnoses are made when the disease is either locally advanced or metastatic. Recent advances in chemotherapy and chemoradiotherapy (CRT) enable "conversion surgery" to be performed for selected patients with initially unresectable pancreatic cancer following favorable responses to preoperative treatment. Using FOLFIRINOX as preoperative treatment, the resection rate was reported as 6-44% of patients with locally advanced cancer and the prognosis of these patients was favorable. Even for metastasized cancer, recent reports show the effectiveness of conversion surgery, which has achieved 27-56 months of median overall survival. However, there are many unanswered questions about conversion surgery. The optimal regimen and duration of preoperative treatment remain unclear and there is still debate regarding the safety and effectiveness of vascular resection, which is often required for curative resection of locally advanced cancer. Accumulation of more data on conversion surgery is required to establish the safety and effectiveness of this treatment. In this review, we summarize the current status and unresolved issues about conversion surgery for initially unresectable pancreatic cancer.
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25
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Al-Taee KMK, Zepp M, Berger I, Berger MR, Adwan H. Pancreatic carcinoma cells colonizing the liver modulate the expression of their extracellular matrix genes. Genes Cancer 2018; 9:215-231. [PMID: 30603057 PMCID: PMC6305105 DOI: 10.18632/genesandcancer.179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liver is the main target of pancreatic ductal adenocarcinoma (PDAC) metastasis. Here, a rat model was used for analysing gene expression modulations during liver colonization. ASML PDAC cells were injected to isogenic rats and re-isolated at various stages of liver colonization for RNA isolation or re-cultivation. Microarrays were used for analysing mRNA and miRNA profiles of expression. The results were partially confirmed by (q) RT-PCR and western blot. Selected genes were knocked down by siRNA transfection and the resulting cell behaviour was analysed. The ratio of up- and down regulated genes decreased from 20:1 (early stage) to 1.2:1 (terminal stage). Activation of cancer relevant gene categories varied between stages of liver colonization, with a nadir in the intermediate stage. The cells' environment triggered up to hundredfold changed expression for collagens, matrix metalloproteinases and chemokines. These modulations in mRNA expression were related to respective changes at miRNA levels. Gene expression knockdown of Mmp2 and Ccl20, which were highly modulated in vivo, was correlated with reduced proliferation and migration in vitro. Thus, target genes and temporal alterations in expression were identified, which can serve as basis for future therapeutic or diagnostic purposes.
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Affiliation(s)
- Khamael M K Al-Taee
- Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany
| | - Michael Zepp
- Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany
| | - Irina Berger
- Institute of Pathology, Klinikum Kassel, Mönchebergstraße, Kassel
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany
| | - Hassan Adwan
- Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany.,German University of Cairo, Cairo, Egypt
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26
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Sun JH, Zhou TY, Zhang YL, Zhou GH, Nie CH, Zhu TY, Chen SQ, Wang BQ, Ye S, Shen Y, Guo H, Wang WL, Zheng SS. Efficacy of transcatheter arterial chemoembolization for liver metastases arising from pancreatic cancer. Oncotarget 2018; 8:39746-39755. [PMID: 28099930 PMCID: PMC5503649 DOI: 10.18632/oncotarget.14642] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 12/27/2016] [Indexed: 12/19/2022] Open
Abstract
PURPOSE The aim of the study was to evaluate the efficacy of transcatheter arterial chemoembolization (TACE) in treating patients with liver metastases from pancreatic cancer, and explore the prognostic risk factors. RESULTS Three of the 27 patients were totally recovered, and 12 were partially alleviated. The total efficacy rate was 55.6% (15/27). The median survival time was 13.6 months, and the 0.5-, 1-, 2-, 3-, and 5-year survival rates were 70.4% (19/27), 48.1% (13/27), 22.2% (6/27), 14.8 (4/27), 11.1% (3/27), respectively. None of the groups showed any severe complications. Univariate analysis showed that pathological type, concomitant therapies for liver metastasis, vascular supply, CA199 levels and extrahepatic metastasis were related to prognosis (P < 0.05). Multivariate analysis indicated that pancreatic cancer pathology and extrahepatic metastasis were independent risk factors influencing patients' prognosis (χ2 = 13.182, 17.989, P < 0.05). METHODS The clinical records of 27 patients with lliver metastases from pancreatic cancer diagnosed at the First Affiliated Hospital of Zhejiang University between May 2009 and May 2015 were retrospectively analyzed. The short-term and long-term efficacy and toxic side effects of TACE were observed. The prognostic risk factors were analyzed using Cox (proportional hazards) regression model. CONCLUSION TACE is an effective therapy for treating liver metastases from pancreatic malignancy. Pathological type and extrahepatic metastasis of pancreatic tumor are independent risk factors for patients' prognosis. The prognosis of patients with liver metastasis from pancreatic neuroendocrine neoplasm is superior to that of extrahepatic metastasis.
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Affiliation(s)
- Jun-Hui Sun
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tan-Yang Zhou
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yue-Lin Zhang
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Guan-Hui Zhou
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chun-Hui Nie
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tong-Yin Zhu
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Sheng-Qun Chen
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bao-Quan Wang
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Song Ye
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yan Shen
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hua Guo
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei-Lin Wang
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shu-Sen Zheng
- Hepatobiliary and Pancreatic Interventional Treatment Center, Division of Hepatobiliary and Pancreatic Surgery, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, China.,Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Zhejiang, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
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27
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Schwarz C, Kaczirek K, Bodingbauer M. Liver resection for non-colorectal metastases. Eur Surg 2018; 50:113-116. [PMID: 29875799 PMCID: PMC5968069 DOI: 10.1007/s10353-018-0528-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/09/2018] [Indexed: 12/28/2022]
Abstract
Whereas liver resection for colorectal metastasis has become standard of care, hepatectomy in patients with non-colorectal metastases remains controversial, mainly due to a heterogeneous tumor biology and missing data from prospective trials. This review aims at giving an overview about the indications and limits of liver surgery in patients with an advanced disease of a non-colorectal malignancy. Even though prospective trials are largely missing, results from retrospective studies indicate a survival benefit for liver resection in selected patients. Thus, in metastasized patients, treatment strategies should be developed in a multidisciplinary tumor board including an experienced liver surgeon.
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Affiliation(s)
- Christoph Schwarz
- Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Klaus Kaczirek
- Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Martin Bodingbauer
- Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
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28
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Mean platelet volume predicts survival in pancreatic cancer patients with synchronous liver metastases. Sci Rep 2018; 8:6014. [PMID: 29662100 PMCID: PMC5902615 DOI: 10.1038/s41598-018-24539-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 04/03/2018] [Indexed: 02/06/2023] Open
Abstract
Most pancreatic cancer (PC) patients manifest multiple liver metastases at the time of diagnosis. Activated platelets play a key role in tumor growth and tumor metastases. Mean platelet volume (MPV) is a platelet index and is altered in patients with malignancies. This study aimed to evaluate whether MPV can effectively predict death in PC patients with synchronous liver metastases. The clinical data of 411 PC patients with synchronous liver metastases between January 1, 2006 and December 31, 2013 were retrospectively analyzed. Subjects were divided into two groups by MPV levels. Clinicopathological data were collected retrospectively and relationships between MPV levels and clinical parameters were evaluated. Survival analysis was performed. Increased MPV was not significantly correlated with tumor location, tumor size, and CA19.9. The Kaplan-Meier analysis showed that the overall survival of patients with MPV > 8.7 fL was significantly shorter than that of those with MPV ≤ 8.7 fL (log-rank p < 0.001). Multivariable Cox proportional hazards model identified MPV as an independent poor prognostic factor for overall survival. In conclusion, elevated MPV is associated with worse survival outcome in PC patients with synchronous liver metastases. Further studies are warranted.
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29
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Dhayat SA, Mirgorod P, Lenschow C, Senninger N, Anthoni C, Vowinkel T. Challenges in pancreatic adenocarcinoma surgery - National survey and current practice guidelines. PLoS One 2017; 12:e0173374. [PMID: 28267771 PMCID: PMC5340358 DOI: 10.1371/journal.pone.0173374] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 02/20/2017] [Indexed: 01/05/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers in Europe and the USA. There is consensus that radical tumor surgery is the only viable option for any long-term survival in patients with PDAC. So far, limited data are available regarding the routine surgical management of patients with advanced PDAC in the light of surgical guidelines. Methods A national survey on perioperative management of patients with PDAC and currently applied criteria on their tumor resectability in German university and community hospitals was carried out. Results With a response rate of 81.6% (231/283) a total of 95 (41.1%) participating departments practicing pancreatic surgery in Germany are certified as competence and reference centers for surgical diseases of the pancreas in 2016. More than 95% of them indicate to carry out structured and interdisciplinary therapies along with an interdisciplinary pre- and postoperative tumor board. The majority of survey respondents prefer the pylorus-preserving partial pancreatoduodenectomy (93.1%) with standard lymphadenectomy for cancer of the pancreatic head. Intraoperative histological evaluation of the resection margins is used regularly by 99% of the survey respondents. 98.7% of survey respondents carry out partial or complete vein resection, 126 respondents (54.5%) would resect tumor adjacent arteries, and 102 respondents (44.2%) would perform metastasectomy if complete PDAC resection (R0) is possible. Conclusion Evidence-based and standardized pancreatic surgery is practiced by a large number of hospitals in Germany. However, a significant number of survey respondents support an extended radical tumor resection in patients with advanced PDAC even when not indicated by current clinical guidelines.
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Affiliation(s)
- Sameer A. Dhayat
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
- * E-mail:
| | - Philip Mirgorod
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
| | - Christina Lenschow
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
| | - Norbert Senninger
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
| | - Christoph Anthoni
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
| | - Thorsten Vowinkel
- Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany
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