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Vonica RC, Butuca A, Morgovan C, Pumnea M, Cipaian RC, Frum A, Dobrea CM, Vonica-Tincu AL, Pacnejer AM, Ghibu S, Batar F, Gligor FG. Bevacizumab-Insights from EudraVigilance Database on the Assessments of the Safety Profile of Monoclonal Antibodies Used as Targeted Cancer Treatment. Pharmaceuticals (Basel) 2025; 18:501. [PMID: 40283938 PMCID: PMC12030381 DOI: 10.3390/ph18040501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/22/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.
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Affiliation(s)
- Razvan Constantin Vonica
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Manuela Pumnea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Remus Calin Cipaian
- Clinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
- County Clinical Emergency Hospital of Sibiu, 2–4 Corneliu Coposu Str., 550245 Sibiu, Romania
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Aliteia-Maria Pacnejer
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timişoara, Romania
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Florina Batar
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
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Elbouhi M, Ouabane M, Tabti K, Badaoui H, Abdessadak O, El Alaouy MA, Elkamel K, Lakhlifi T, Sbai A, Ajana MA, Bouachrine M. Computational evaluation of 1,2,3-triazole-based VEGFR-2 inhibitors: anti-angiogenesis potential and pharmacokinetic assessment. J Biomol Struct Dyn 2025; 43:2549-2559. [PMID: 38193897 DOI: 10.1080/07391102.2023.2301686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 11/20/2023] [Indexed: 01/10/2024]
Abstract
The vascular endothelial growth factor (VEGF) and its cell surface receptor, as well as the human VEGFR-2 domain kinase, are some of the signaling pathways that have received the most attention in this field. This study aimed to identify novel molecules as VEGFR-2 inhibitors using 3D-QSAR modeling based on 1,2,3-triazole. Docking studies and dynamic simulations were performed to analyze novel interactions with the inhibitors and validate the molecular docking, dynamic simulations, and ADMET analyses. The optimized CoMSIA/SEH model showed good statistical results, and molecular docking and molecular dynamics simulations demonstrated stability of M3 ligand with the receptor and provided insight into ligand-receptor interactions. The newly developed compounds performed well in ADMET evaluations and showed promising results using Lipinski's rule of five, suggesting that the molecule M3 could be a useful anti-angiogenesis agent. In conclusion, this study provides insights into the structure-activity relationship of VEGFR-2 inhibitors and identifies M3 as a potential new anti-angiogenesis drug. The methodology used in this study can be applied to other similar drug targets to discover new and potent inhibitors.
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Affiliation(s)
- Mhamed Elbouhi
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Mohamed Ouabane
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Kamal Tabti
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Hassan Badaoui
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Oumayma Abdessadak
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Moulay Ahfid El Alaouy
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Khalid Elkamel
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Tahar Lakhlifi
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Abdelouahid Sbai
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Mohammed Aziz Ajana
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
| | - Mohammed Bouachrine
- Molecular Chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science, Moulay Ismail University, Meknes, Morocco
- Higher School of Technology (EST Khenifra), Sultan Moulay Slimane University, Beni-Mellal, Morocco
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3
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Parikh ND, Jones P, Salgia R, Bhan I, Grinspan LT, Jou JH, Zhou K, Jalal P, Roccaro G, Rangnekar AS, Benhammou JN, Pillai A, Mehta N, Wedd J, Yang JD, Kim AK, Duarte-Rojo A, Oloruntoba OO, Tevar A, Au JS, Blain Y, Rao S, Catalano OA, Lewis S, Mendiratta-Lala M, King K, Sachdev L, Lee EW, Bruno J, Kamel I, Tolosa C, Kao K, Badawi T, Przybyszewski EM, Quirk L, Nathani P, Haydel B, Leven E, Wong N, Albertian R, Chen A, Aloor FZ, Mohamed IB, Elkheshen A, Marvil C, Issac G, Clinton JW, Woo SM, Yum J, Rieger E, Hutchison AL, Turner DA, Alsudaney M, Hernandez P, Xu Z, Khalid A, Barrick B, Wang B, Tapper EB, Hao W, Singal AG. Development and Validation of a Noninvasive Model for the Detection of High-Risk Varices in Patients With Unresectable Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:281-290.e4. [PMID: 39089513 DOI: 10.1016/j.cgh.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND & AIMS Noninvasive variceal risk stratification systems have not been validated in patients with hepatocellular carcinoma (HCC), which presents logistical barriers for patients in the setting of systemic HCC therapy. We aimed to develop and validate a noninvasive algorithm for the prediction of varices in patients with unresectable HCC. METHODS We performed a retrospective cohort study in 21 centers in the United States including adult patients with unresectable HCC and Child-Pugh A5-B7 cirrhosis diagnosed between 2007 and 2019. We included patients who completed an esophagogastroduodonoscopy (EGD) within 12 months of index imaging but before HCC treatment. We divided the cohort into a 70:30 training set and validation set, with the goal of maximizing negative predictive value (NPV) to avoid EGD in low-risk patients. RESULTS We included 707 patients (median age, 64.6 years; 80.6% male; 74.0% White). Median time from HCC diagnosis to EGD was 47 (interquartile range, 114) days, with 25.0% of patients having high-risk varices. A model using clinical variables alone achieved an NPV of 86.3% in the validation cohort, whereas a model integrating clinical and imaging variables had an NPV 97.4% in validation. The clinical and imaging model would avoid EGDs in more than half of low-risk patients while misclassifying 7.7% of high-risk patients. CONCLUSIONS A model incorporating clinical and imaging data can accurately predict the absence of high-risk varices in patients with HCC and avoid EGD in many low-risk patients before the initiation of systemic therapy, thus expediting their care and avoiding treatment delays.
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Affiliation(s)
- Neehar D Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Patricia Jones
- Department of Internal Medicine, University of Miami, Miami, Florida
| | - Reena Salgia
- Department of Internal Medicine, Henry Ford Health, Detroit, Michigan
| | - Irun Bhan
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Lauren T Grinspan
- Department of Internal Medicine, The Mount Sinai Hospital, New York, New York
| | - Janice H Jou
- Department of Internal Medicine, Oregon Health Science University, Portland, Oregon
| | - Kali Zhou
- Department of Internal Medicine, University of Southern California, Los Angeles, California
| | - Prasun Jalal
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Giorgio Roccaro
- Department of Internal Medicine, Emory University, Atlanta, Georgia
| | - Amol S Rangnekar
- Department of Internal Medicine, Georgetown University, Washington, District of Columbia
| | - Jihane N Benhammou
- Department of Internal Medicine, University of California Los Angeles, Los Angeles, California
| | - Anjana Pillai
- Department of Internal Medicine, University of Chicago, Chicago, Illinois
| | - Neil Mehta
- Department of Internal Medicine, University of San Francisco, San Francisco, California
| | - Joel Wedd
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Ju Dong Yang
- Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Amy K Kim
- Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Andres Duarte-Rojo
- Department of Internal Medicine, Northwestern University, Chicago, Illinois
| | | | - Amit Tevar
- Department of Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jennifer S Au
- Department of Internal Medicine, Scripps Health, San Diego, California
| | - Yamile Blain
- Department of Radiology, University of Miami, Miami, Florida
| | - Sanjana Rao
- Department of Radiology, University of Miami, Miami, Florida
| | - Onofrio A Catalano
- Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Sara Lewis
- Department of Radiology, The Mount Sinai Hospital, New York, New York
| | | | - Kevin King
- Department of Radiology, University of Southern California, Los Angeles, California
| | - Lekha Sachdev
- Department of Radiology, Georgetown University, Washington, District of Columbia
| | - Edward W Lee
- Department of Radiology, University of California Los Angeles, Los Angeles, California
| | - Jill Bruno
- Department of Radiology, Virginia Commonwealth University, Richmond, Virginia
| | - Ihab Kamel
- Department of Radiology, Johns Hopkins University, Baltimore, Maryland
| | - Celestina Tolosa
- Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Karissa Kao
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Tarek Badawi
- Department of Internal Medicine, Henry Ford Health, Detroit, Michigan
| | - Eric M Przybyszewski
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Lisa Quirk
- Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas
| | - Piyush Nathani
- Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas
| | - Brandy Haydel
- Department of Internal Medicine, The Mount Sinai Hospital, New York, New York
| | - Emily Leven
- Department of Internal Medicine, The Mount Sinai Hospital, New York, New York
| | - Nicole Wong
- Department of Internal Medicine, Oregon Health Science University, Portland, Oregon
| | - Robert Albertian
- Department of Internal Medicine, University of Southern California, Los Angeles, California
| | - Ariana Chen
- Department of Internal Medicine, University of Southern California, Los Angeles, California
| | - Fuad Z Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Islam B Mohamed
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Ahmed Elkheshen
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Charles Marvil
- Department of Internal Medicine, Emory University, Atlanta, Georgia
| | - Gerard Issac
- Department of Internal Medicine, Emory University, Atlanta, Georgia
| | - Joseph W Clinton
- Department of Internal Medicine, Georgetown University, Washington, District of Columbia
| | - Stephanie M Woo
- Department of Internal Medicine, Georgetown University, Washington, District of Columbia
| | - Jung Yum
- Department of Internal Medicine, University of California Los Angeles, Los Angeles, California
| | - Erin Rieger
- Department of Internal Medicine, University of Chicago, Chicago, Illinois
| | - Alan L Hutchison
- Department of Internal Medicine, University of Chicago, Chicago, Illinois
| | - Don A Turner
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Manaf Alsudaney
- Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Perla Hernandez
- Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ziyi Xu
- Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Abdullah Khalid
- Department of Internal Medicine, Scripps Health, San Diego, California
| | - Bethany Barrick
- Department of Internal Medicine, Scripps Health, San Diego, California
| | - Bo Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Elliot B Tapper
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Wei Hao
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas
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Yin B, Luo W. Efficacy and safety of neoadjuvant bevacizumab plus chemotherapy in locally advanced gastric cancer patients: a retrospective, comparative study. World J Surg Oncol 2025; 23:26. [PMID: 39875999 PMCID: PMC11773743 DOI: 10.1186/s12957-024-03624-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 12/15/2024] [Indexed: 01/30/2025] Open
Abstract
OBJECTIVE The clinical benefits of neoadjuvant bevacizumab plus chemotherapy in locally advanced gastric cancer patients are controversial. This study intended to evaluate the efficacy and safety of neoadjuvant bevacizumab plus chemotherapy in these patients. METHODS In this retrospective study, 71 locally advanced gastric cancer patients receiving neoadjuvant bevacizumab plus chemotherapy or neoadjuvant chemotherapy alone were divided into bevacizumab plus chemo group (N = 23) and chemo group (N = 48). RESULTS Objective response rate (52.2% vs. 35.4%), disease control rate (91.3% vs. 81.3%), surgical resection rate (95.7% vs. 85.4%), R0 resection rate (87.0% vs. 75.0%), and the proportion of patients with tumor regression grade 0-1 (31.8% vs. 17.1%) tended to increase in bevacizumab plus chemo group versus chemo group, although there was no statistical significance. The 48-month progression-free survival (PFS) rates were 58.3% and 33.4% in bevacizumab plus chemo group and chemo group. The 48-month overall survival (OS) rates were 65.1% and 46.5% in bevacizumab plus chemo group and chemo group, respectively. PFS tended to ascend, but OS did not vary in bevacizumab plus chemo group versus chemo group. Bevacizumab plus chemo (vs. chemo) independently related to longer PFS [hazard ratio (HR) = 0.263, P = 0.015], but not OS (HR = 0.207, P = 0.056) in locally advanced gastric cancer patients. The incidence of grade 3-4 adverse events did not vary between groups (all P > 0.05). CONCLUSION Neoadjuvant bevacizumab plus chemotherapy achieves higher treatment response and longer survival to some extent, with tolerable adverse events versus neoadjuvant chemotherapy alone in locally advanced gastric cancer patients, but its application needs further verification.
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Affiliation(s)
- Bin Yin
- Gastroduodenal Pancreas Surgery Department, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, 410013, China
| | - Wei Luo
- Colorectal Surgery Department, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, No. 283 Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, China.
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Gayibov E, Karim AH. A Rapid Review of Adenocarcinoma and Pulmonary Tumor Thrombotic Microangiopathy: A Deadly Duo. Cureus 2025; 17:e76842. [PMID: 39897287 PMCID: PMC11787629 DOI: 10.7759/cureus.76842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2025] [Indexed: 02/04/2025] Open
Abstract
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM's poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.
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Affiliation(s)
- Emin Gayibov
- Third Faculty of Medicine, Charles University, Prague, CZE
| | - Amin H Karim
- Department of Cardiovascular Disease, Baylor College of Medicine, Houston, USA
- Department of Cardiovascular Disease, Weill Medical College of Cornell University, New York City, USA
- Department of Cardiovascular Disease, Methodist Academy of Medicine, Houston, USA
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6
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Moriguchi M, Okuda K, Horiguchi G, Kataoka S, Seko Y, Yamaguchi K, Nishimura T, Fujii H, Mitsumoto Y, Miyagawa M, Kirishima T, Okishio S, Hara T, Ishikawa H, Nagao Y, Jo M, Ishii M, Tanaka S, Yamauchi N, Mitsuyoshi H, Nakajima T, Taketani H, Yano K, Arai M, Umemura A, Itoh Y. Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma. Liver Int 2024; 44:1751-1761. [PMID: 38838097 DOI: 10.1111/liv.15918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/24/2024] [Accepted: 03/18/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND AND AIMS This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. METHODS Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. RESULTS The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. CONCLUSION Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.
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Affiliation(s)
- Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiichiro Okuda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Go Horiguchi
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Seita Kataoka
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Nishimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Yasuhide Mitsumoto
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Masami Miyagawa
- Department of Gastroenterology, Kyoto City Hospital, Kyoto, Japan
| | | | - Shinya Okishio
- Department of Gastroenterology, Fukuchiyama City Hospital, Kyoto, Japan
| | - Tasuku Hara
- Department of Gastroenterology, Fukuchiyama City Hospital, Kyoto, Japan
| | - Hiroki Ishikawa
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Omihachiman, Japan
| | - Yasuyuki Nagao
- Department of Gastroenterology, Matsushita Memorial Hospital, Osaka, Japan
| | - Masayasu Jo
- Department of Gastroenterology, Otsu City Hospital, Otsu, Japan
| | - Michiaki Ishii
- Department of Gastroenterology, Ayabe City Hospital, Kyoto, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | | | - Hironori Mitsuyoshi
- Department of Gastroenterology and Hepatology, Kyoto Chubu Medical Center, Kyoto, Japan
| | - Tomoki Nakajima
- Department of Gastroenterology, Saiseikai Kyoto Hospital, Kyoto, Japan
| | | | - Kota Yano
- Department of Gastroenterology and Hepatology, North Medical Center of Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Kyoto Yamashiro General Medical Center, Kyoto, Japan
| | - Atsushi Umemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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7
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Villeret F, Nahon P. Atezolizumab and bevacizumab with anticoagulant or antiplatelet therapy in hepatocellular carcinoma patients: Real-world data for informed clinical decision-making. Liver Int 2024; 44:1749-1750. [PMID: 39012158 DOI: 10.1111/liv.15954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 04/16/2024] [Indexed: 07/17/2024]
Affiliation(s)
- François Villeret
- Service d'Hépatologie, Institut d'Hépatologie de Lyon, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
- INSERM U1052, CNRS UMR 5286, Université de Lyon 1, Lyon, France
| | - Pierre Nahon
- AP-HP, Liver Unit, Hôpitaux Universitaires Paris Seine Saint-Denis, Bobigny, France
- Université Sorbonne Paris Nord, Bobigny, France
- Inserm, UMR-1138 "Functional Genomics of Solid Tumors", Centre de recherche des Cordeliers, Université de Paris, Paris, France
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Su M, Zhao L, Zhou J, Li X, Ding N. Celiac trunk aortic dissection induced by bevacizumab therapy for rectal cancer: A case report. Medicine (Baltimore) 2024; 103:e38882. [PMID: 38996149 PMCID: PMC11245218 DOI: 10.1097/md.0000000000038882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
RATIONALE Bevacizumab (Bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor A and is primarily used for the treatment of various solid tumors. Aortic dissection (AD) is a severe vascular disease caused by the tearing of the intimal layer of the aorta or bleeding within the aortic wall, resulting in the separation of different layers of the aortic wall. However, the pathogenesis is not fully understood. Some studies have suggested that Bev treatment is associated with the occurrence of AD. PATIENT CONCERNS A 67-year-old Chinese male was diagnosed with rectal cancer accompanied by liver and lung metastasis. Three days after starting combined chemotherapy with Bev, the patient developed persistent abdominal pain. Abdominal CT scan revealed celiac trunk AD in the abdominal aorta. DIAGNOSES The patient was diagnosed with rectal cancer accompanied by liver and lung metastases. Abdominal CT tomography revealed a celiac trunk AD. INTERVENTIONS Somatostatin combined with valsartan was used to control blood pressure. The patient was subsequently referred for vascular surgery and underwent an abdominal aortic angiography. Conservative treatment was continued. OUTCOMES Three months after the initiation of treatment, follow-up abdominal CT scans showed stability in the condition of celiac trunk AD, with no abdominal pain or hypertension. There were no signs of worsening dissection, aneurysm formation, or inadequate perfusion of end organs. LESSONS There may be a connection between Bev and elevated blood pressure as well as celiac trunk AD.
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Affiliation(s)
- Mingming Su
- Department of Medical of Oncology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People’s Hospital, Wuxi, Jiangsu, China
| | - Lili Zhao
- Department of Medical of Oncology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People’s Hospital, Wuxi, Jiangsu, China
| | - Jing Zhou
- Department of Medical of Oncology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People’s Hospital, Wuxi, Jiangsu, China
| | - Xuan Li
- Department of Medical of Oncology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People’s Hospital, Wuxi, Jiangsu, China
| | - Ning Ding
- Department of Medical of Oncology, Affiliated Huishan Hospital of Xinglin College, Nantong University, Wuxi Huishan District People’s Hospital, Wuxi, Jiangsu, China
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9
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Vakilian S, Al-Hashmi S, Al-Kindi J, Al-Fahdi F, Al-Wahaibi N, Shalaby A, Al-Riyami H, Al-Harrasi A, Jamshidi-Adegani F. Avastin-Loaded 3D-Printed Alginate Scaffold as an Effective Antiadhesive Barrier to Prevent Postsurgical Adhesion Bands Formation. Macromol Biosci 2024; 24:e2300530. [PMID: 38319279 DOI: 10.1002/mabi.202300530] [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: 11/19/2023] [Revised: 01/18/2024] [Indexed: 02/07/2024]
Abstract
Postoperative adhesion can cause complications, such as pain and organ blockage, in the abdominal regions. To address this issue, surgical techniques and antiadhesive treatments are applied. Given the significant role of vascularization in adhesion band formation, Avastin (Ava) that targets vascular endothelial growth factor (VEGF) can be applied to prevent peritoneal adhesion bands. Moreover, Alginate (Alg), a natural polysaccharide, is a promising physical barrier to prevent adhesion bands. Incorporating Ava into Alg hydrogel in a form of 3D-printed scaffold (Alg/Ava) has potential to suppress inflammation and angiogenesis, leading to reduce peritoneal adhesion bands. Following physical, morphological, and biocompatibility evaluations, the efficacy of Alg and Ava alone and their combination in Alg/Ava on the formation of postsurgical adhesions is evaluated. Upon confirming physical stability and sustained release of Ava, the Alg/Ava scaffold effectively diminishes both the extent and strength of adhesion bands. Histopathological examination shows that the reduction in fibrosis and inflammation is responsible for preventing adhesion bands by the Alg/Ava scaffold. Additionally, the cytokine assessment reveals that this is due to the inhibition in the secretion of VEGF and Interleukin 6 suppressing vascularization and inflammatory pathways. This study suggests that a 3D-printed Alg/Ava scaffold has great potential to prevent the postsurgical adhesion bands.
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Affiliation(s)
- Saeid Vakilian
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
| | - Sulaiman Al-Hashmi
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
| | - Juhaina Al-Kindi
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
| | - Fahad Al-Fahdi
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
| | - Nasar Al-Wahaibi
- Department of Biomedical Science, College of Medicine & Health Sciences, Sultan Qaboos University, Alkoudh, 123, Oman
- Department of Pathology, College of Medicine & Health Sciences, Sultan Qaboos University, P. O. Box: 35, Alkoudh, 123, Oman
| | - Asem Shalaby
- Department of Pathology, College of Medicine & Health Sciences, Sultan Qaboos University, P. O. Box: 35, Alkoudh, 123, Oman
- Pathology Department, College of Medicine, Mansoura University, Mansoura, Dakahlia, 35516, Egypt
| | - Hamad Al-Riyami
- Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Alkoudh, PC 123, Oman
| | - Ahmed Al-Harrasi
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
| | - Fatemeh Jamshidi-Adegani
- Laboratory for Stem Cell & Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, PC 616, Oman
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10
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Santorsola M, Capuozzo M, Nasti G, Sabbatino F, Di Mauro A, Di Mauro G, Vanni G, Maiolino P, Correra M, Granata V, Gualillo O, Berretta M, Ottaiano A. Exploring the Spectrum of VEGF Inhibitors' Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice. Cancers (Basel) 2024; 16:350. [PMID: 38254839 PMCID: PMC10813960 DOI: 10.3390/cancers16020350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/11/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
The use of Vascular Endothelial Growth Factor inhibitors (VEGFi) has become prevalent in the field of medicine, given the high incidence of various pathological conditions necessitating VEGF inhibition within the general population. These conditions encompass a range of advanced neoplasms, such as colorectal cancer, non-small cell lung cancer, renal cancer, ovarian cancer, and others, along with ocular diseases. The utilization of VEGFi is not without potential risks and adverse effects, requiring healthcare providers to be well-prepared for identification and management. VEGFi can be broadly categorized into two groups: antibodies or chimeric proteins that specifically target VEGF (bevacizumab, ramucirumab, aflibercept, ranibizumab, and brolucizumab) and non-selective and selective small molecules (sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, etc.) designed to impede intracellular signaling of the VEGF receptor (RTKi, receptor tyrosine kinase inhibitors). The presentation and mechanisms of adverse effects resulting from VEGFi depend primarily on this distinction and the route of drug administration (systemic or intra-vitreal). This review provides a thorough examination of the causes, recognition, management, and preventive strategies for VEGFi toxicities with the goal of offering support to oncologists in both clinical practice and the design of clinical trials.
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Affiliation(s)
- Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | | | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Salerno, Italy;
| | - Annabella Di Mauro
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | - Giordana Di Mauro
- Department of Human Pathology “G. Barresi”, University of Messina, 98125 Messina, Italy;
| | - Gianluca Vanni
- Breast Unit, Department of Surgical Science, PTV Policlinico Tor Vergata University, 00133 Rome, Italy;
| | - Piera Maiolino
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | - Marco Correra
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude), NEIRID Laboratory (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), IDIS (Instituto de Investigación Sanitaria de Santiago), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, via M. Semmola, 80131 Naples, Italy; (M.S.); (G.N.); (A.D.M.); (P.M.); (M.C.); (V.G.)
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11
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Andrade MMDL, Tejada GL, Peruzzo J, Bonamigo RR. Pustular psoriasis triggered by therapy with atezolizumab and bevacizumab. An Bras Dermatol 2024; 99:153-155. [PMID: 37657959 DOI: 10.1016/j.abd.2023.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 09/03/2023] Open
Affiliation(s)
| | | | - Juliano Peruzzo
- Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
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12
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Pang FW, Chen B, Peng DT, He J, Zhao WC, Chen TT, Xie ZG, Deng HH. Massive bleeding from a gastric artery pseudoaneurysm in hepatocellular carcinoma treated with atezolizumab plus bevacizumab: A case report. World J Gastrointest Surg 2023; 15:1232-1239. [PMID: 37405100 PMCID: PMC10315107 DOI: 10.4240/wjgs.v15.i6.1232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/30/2023] [Accepted: 04/19/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND The combination of atezolizumab (ATZ) and bevacizumab (BVZ) was approved as first-line systemic therapy for advanced hepatocellular carcinoma (HCC) owing to its superior rates of response and patient survival. However, ATZ + BVZ is associated with increased risk of upper gastrointestinal (GI) bleeding, including arterial bleeding, which is rare and potentially fatal. We present a case of massive upper GI bleeding from a gastric pseudoaneurysm in a patient with advanced HCC who had been treated with ATZ + BVZ.
CASE SUMMARY A 67-year-old man presented with severe upper GI bleeding after atezolizumab (ATZ) + bevacizumab (BVZ) therapy for HCC. Endoscopy failed to detect the bleeding site. Digital subtraction angiography revealed a gastric artery pseudoaneurysm and contrast extravasation from the inferior splenic artery and a branch of the left gastric artery. Successful hemostasis was achieved with embolization.
CONCLUSION HCC patients who have been treated with ATZ + BVZ should be followed for 3 to 6 mo to monitor for development of massive GI bleeding. Diagnosis may require angiography. Embolization is an effective treatment.
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Affiliation(s)
- Fu-Wen Pang
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Bin Chen
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - De-Ti Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Jian He
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Cheng Zhao
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tuan-Tuan Chen
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Zong-Gui Xie
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Hui Deng
- Department of Interventional Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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13
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Shibutani Y, Suzuki S, Sagara A, Enokida T, Okano S, Fujisawa T, Sato F, Yumoto T, Sano M, Kawasaki T, Tahara M. Impact of lenvatinib-induced proteinuria and renal dysfunction in patients with thyroid cancer. Front Oncol 2023; 13:1154771. [PMID: 36998435 PMCID: PMC10043443 DOI: 10.3389/fonc.2023.1154771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 02/28/2023] [Indexed: 03/15/2023] Open
Abstract
BackgroundProteinuria is the most frequent adverse event of lenvatinib use. However, the association between lenvatinib-induced proteinuria and renal dysfunction remains unclear.MethodsWe retrospectively reviewed medical records of patients with thyroid cancer without proteinuria treated with lenvatinib as a first-line systemic therapy at the initiation of treatment to assess the association between lenvatinib-induced proteinuria and renal function and the risk factors for the development of ≥3+ proteinuria on a dipstick test. Proteinuria was assessed by the dipstick test throughout the treatment in all cases.ResultsOf the 76 patients, 39 developed ≤2+ proteinuria (low proteinuria group) and 37 developed ≥3+ proteinuria (high proteinuria group). There was no significant difference in estimated glomerular filtration rate (eGFR) between high and low proteinuria groups at each time point, but there was a trend toward a significant decrease in eGFR of -9.3 ml/min/1.73 m2 in all patients after 2 years of treatment. The percentage of change in eGFR (ΔeGFR) significantly decreased in the high proteinuria group compared to that in the low proteinuria group (ΔeGFR: -6.8% vs. -17.2%, p=0.04). However, there was no significant difference in development of severe renal dysfunction with eGFR <30 ml/min/1.73 m2 between the two groups. Moreover, no patients permanently discontinued treatment because of renal dysfunction in both groups. Furthermore, renal function after completion of lenvatinib was reversible.ConclusionsThere was no association between the degree of lenvatinib-induced proteinuria and renal function. Therefore, treatment should be continued with attention to renal function, regardless of the degree of proteinuria.
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Affiliation(s)
- Yuma Shibutani
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Shinya Suzuki
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
- *Correspondence: Shinya Suzuki,
| | - Atsunobu Sagara
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Tomohiro Enokida
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takao Fujisawa
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Fumiaki Sato
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Tetsuro Yumoto
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Motohiko Sano
- Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa, Tokyo, Japan
| | - Toshikatsu Kawasaki
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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14
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Taheri SL, Rezazadeh M, Hassanzadeh F, Akbari V, Dehghani A, Talebi A, Mostafavi SA. Preparation, physicochemical, and retinal anti-angiogenic evaluation of poloxamer hydrogel containing dexamethasone/avastin-loaded chitosan-N-acetyl-L-cysteine nanoparticles. Int J Biol Macromol 2022; 220:1605-1618. [PMID: 36116595 DOI: 10.1016/j.ijbiomac.2022.09.101] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/07/2022] [Accepted: 09/11/2022] [Indexed: 11/05/2022]
Abstract
This study was meant to describe a Poloxamer hydrogel combining Chitosan-N-acetyl-L-cysteine (CNAC) nanoparticles to increase loading and sustained intravitreal administration of Avastin macromolecule. To increase the drug's efficacy and reduce the interfacial fluid pressure in a formulation, dexamethasone was used. To do so, CNAC was synthesized. Then, Avastin- loaded CNAC nanoparticles were prepared and optimized. The resulting hydrogel's sol-gel transition time and viscosity were determined using poloxamer and hydroxypropylmethylcellulose (HPMC). In vitro and in vivo investigations of Avastin-loaded CNAC nanoparticles and hydrogel comprising dexamethasone/Avastin-loaded CNAC nanoparticles were determined. In vitro, the drug release profile of optimized hydrogel containing Avastin-loaded CNAC nanoparticles was sustained and controlled over 256 h. The obtained results point to poloxamer/HPMC (18 %/0.5 %) as the best formulations for this hydrogel to develop a sol-gel transition. About 97 % of dexamethasone was released from the hydrogel within 18 h. In vivo results indicated that the optimized formulation compared with free Avastin could improve Diabetic retinopathy (DR). Consequently, we infer that this new drug delivery method may enhance Avastin intravitreal administration, lowering the frequency, danger, and expense of heavy intravitreal injections and resulting in improved treatment of posterior eye segment neovascularization and concomitant vitreoretinal disorders.
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Affiliation(s)
- Sayed Latif Taheri
- Department of Pharmaceutics, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahboubeh Rezazadeh
- Department of Pharmaceutics, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farshid Hassanzadeh
- Department of Medicinal Chemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Vajihe Akbari
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Dehghani
- Department of Ophthalmology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ardeshir Talebi
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sayed Abolfazl Mostafavi
- Department of Pharmaceutics, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
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15
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Molecular perspective on targeted therapy in breast cancer: a review of current status. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:149. [PMID: 35834030 PMCID: PMC9281252 DOI: 10.1007/s12032-022-01749-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Breast cancer is categorized at the molecular level according to the status of certain hormone and growth factor receptors, and this classification forms the basis of current diagnosis and treatment. The development of resistance to treatment and recurrence of the disease have led researchers to develop new therapies. In recent years, most of the research in the field of oncology has focused on the development of targeted therapies, which are treatment methods developed directly against molecular abnormalities. Promising advances have been made in clinical trials investigating the effect of these new treatment modalities and their combinations with existing therapeutic treatments in the treatment of breast cancer. Monoclonal antibodies, tyrosine kinase inhibitors, antibody–drug conjugates, PI3K/Akt/mTOR pathway inhibitors, cyclin-dependent kinase 4/6 inhibitors, anti-angiogenic drugs, PARP inhibitors are among the targeted therapies used in breast cancer treatment. In this review, we aim to present a molecular view of recently approved target agents used in breast cancer.
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16
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Rehman S, Ullah H, Nagarajan JS, Sukaina M, Ghafoor B, Shaik Masthan S, Shahrukh S, Min Allah H, Qureshi MH. Pneumothorax as a Complication of Bevacizumab-Containing Chemotherapy: A Systematic Review of Case Reports. Cureus 2022; 14:e27338. [PMID: 36043019 PMCID: PMC9414787 DOI: 10.7759/cureus.27338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2022] [Indexed: 12/21/2022] Open
Abstract
Bevacizumab is a monoclonal anti-vascular endothelial growth factor (VEGF) antibody that binds to and makes all of the VEGF isoforms inactive, and thus prevents angiogenesis, development, and the spread of the tumor. The most reported side effects after administering bevacizumab include bleeding, high blood pressure, heart failure, proteinuria, thrombosis, and gastrointestinal perforation. Pneumothorax has rarely been reported as a complication of bevacizumab, but with an unclear mechanism. This article aims to explore the occurrence of pneumothorax as a side effect after using bevacizumab through a systematic review of current case reports published on the topic. A literature search was conducted using PubMed, Google Scholar, ScienceDirect, and Directory of Open Access through the utilization of appropriate keywords, and case reports were selected based on predefined inclusion and exclusion criteria. Our results encompass five case reports that were further evaluated for demographic, clinical, and treatment parameters. This systematic review concludes that pneumothorax can occur after bevacizumab-containing chemotherapy although this side effect is relatively rare. Awareness regarding this possible side effect can assist clinicians during their practice in considering pneumothorax as a possible differential diagnosis when encountering patients presenting with pulmonary symptoms after starting bevacizumab-containing chemotherapy; hence, timely diagnosis and treatment can save a life.
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Affiliation(s)
- Shafi Rehman
- Internal Medicine, Lady Reading Hospital, Peshawar, PAK
| | - Hameed Ullah
- Internal Medicine, Hayatabad Medical Complex, Peshawar, Peshawar, PAK
| | | | | | - Bushra Ghafoor
- Research, University of Texas Southwestern Medical Center, Dallas, USA
- Graduate Medical Education, Dera Ghazi Khan Medical College, Dera Ghazi Khan, PAK
- Internal Medicine, Nishtar Medical University, Multan, PAK
| | | | - Shazmah Shahrukh
- Internal Medicine, Dow University of Health Sciences, Civil Hospital Karachi, Karachi, PAK
| | - Hassan Min Allah
- Internal Medicine, Multan Medical and Dental College, Multan, PAK
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17
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Jiménez-Fonseca P, Gallardo E, Arranz Arija F, Blanco JM, Callejo A, Lavin DC, Costa Rivas M, Mosquera J, Rodrigo A, Sánchez Morillas R, Vares Gonzaléz M, Muñoz A, Carmona-Bayonas A. Consensus on prevention and treatment of cancer-associated thrombosis (CAT) in controversial clinical situations with low levels of evidence. Eur J Intern Med 2022; 100:33-45. [PMID: 35227541 DOI: 10.1016/j.ejim.2022.02.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/23/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cancer patients suffer high risk of venous thromboembolism (VTE). Cancer-associated VTE (CAT) causes hospitalization, morbidity, delayed cancer treatment, and mortality; therefore, exceptional CAT prevention and management are imperative. METHODS This review offers practical recommendations and treatment algorithms for eight complex, clinically relevant situations posing great uncertainty regarding management and requiring an urgent decision: VTE prophylaxis in ambulatory cancer patients with pancreatic pancreas (1) or lung cancer with molecular alterations (2); optimal management of VTE during antineoplastic treatment with antiangiogenics (3) or chemotherapy (4); protracted VTE treatment, determinants; (5) drugs used (6), and optimal VTE management in situations of high bleeding risk (7) or recurrent VTE (8). RESULTS With the evidence available, primary thromboprophylaxis in patients with lung cancer harbouring ALK/ROS1 translocations or pancreatic cancer receiving ambulatory chemotherapy must be appraised. If antiangiogenic therapy can yield a clear benefit and the patient recovers from a grade 3 thrombotic event, it can be cautiously re-introduced in selected cases, provided that the person agrees to assume the risk after being duly informed. Anticoagulation maintenance beyond 6 months is recommended in individuals with metastatic tumours, on active treatment, or at high risk for recurrent VTE without bleeding risk. In such cases, LMWH and DOACs are safe, being mindful that the latter could entail a higher risk of bleeding; consequently, they should be used judiciously in more haemorrhagic tumours, such as gastrointestinal cancers. In cases of recurrent VTE, the presence of active cancer, infra-therapeutic dose, and anticoagulant treatment failure must be ruled out. In individuals with platelet counts of 25,000-50,000 and VTE liable to recur who need anticoagulation, full-dose LMWH and transfusion support can be contemplated to reach values of > 50,000. In CAT unlikely to recur, decreasing the LMWH dose by 25-50% is recommended. Renal impairment associated with thrombosis must be treated with LMWHs; there is no need to adjust the dose in patients with CrCl > 30; with CrCl = 15-30, dose adjustment is advised, and suspended when CrCl is < 15. CONCLUSION We provide useful advice for complex, clinically relevant situations that clinicians treating CAT must face devoid of any unequivocal, strong, evidence-based recommendations.
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Affiliation(s)
- Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Avenida Roma, Oviedo 33011, Spain.
| | - Enrique Gallardo
- Medical Oncology Department, Hospital Universitario Parc Tauli, Sabadell, Spain
| | - Fernando Arranz Arija
- Medical Oncology Department, Complejo Asistencial Universitario de Palencia, Palencia, Spain
| | - Jesús Manuel Blanco
- Medical Oncology Department, Hospital Universitario de Donosti, Donosti-San Sebastián, Spain
| | - Ana Callejo
- Medical Oncology Department, Hospital Universitario Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Diego Cacho Lavin
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | | | - Joaquín Mosquera
- Medical Oncology Department, Hospital Universitario de A Coruña, A Coruña, Spain
| | - Alberto Rodrigo
- Medical Oncology Department, Hospital Arnau de Vilanova, Lleida, Spain
| | | | - María Vares Gonzaléz
- Internal Medicine Department, Hospital Universitario de A Coruña, A Coruña, Spain
| | - Andrés Muñoz
- Medical Oncology Department, Hospital Universitario Gregorio Marañon, Madrid, Spain
| | - Alberto Carmona-Bayonas
- Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, UMU, IMIB, Murcia, Spain
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Suarez-Meade P, Marenco-Hillembrand L, Sherman WJ. Neuro-oncologic Emergencies. Curr Oncol Rep 2022; 24:975-984. [PMID: 35353348 DOI: 10.1007/s11912-022-01259-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Patients with brain and spine tumors are at high risk of presenting cancer-related complications at disease presentation or during active treatment and are usually related to the type and location of the lesion. Here, we discuss presentation and management of the most common emergencies affecting patients with central nervous system neoplastic lesions. RECENT FINDINGS Tumor-related emergencies encompass complications in patients with central nervous system neoplasms, as well as neurologic complications in patients with systemic malignancies. Brain tumor patients are at high risk of developing multiple complications such as intracranial hypertension, brain herniation, intracranial bleeding, spinal cord compression, and others. Neuro-oncologic emergencies require immediate attention and multi-disciplinary care. These emergent situations usually need rapid decision-making and management on an inpatient basis.
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Affiliation(s)
| | | | - Wendy J Sherman
- Department of Neurology and Neurosurgery, Mayo Clinic, Jacksonville, FL, USA.
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19
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Antitumor effect of isoquercetin on tissue vasohibin expression and colon cancer vasculature. Oncotarget 2022; 13:307-318. [PMID: 35145607 PMCID: PMC8823695 DOI: 10.18632/oncotarget.28181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/08/2021] [Indexed: 11/25/2022] Open
Abstract
Tumor cells trigger angiogenesis through the expression of angiogenic factors. Vasohibins (VASHs) are a family of peptides that regulate angiogenesis. Flavonoids have antiproliferative antitumor properties; however, few studies have highlighted their antiangiogenic potential. This study evaluated the flavonoid isoquercetin (Q3G) as an antitumor compound related to colon cancer vascularization and regulation of VASH1 and 2. Mice bearing xenogeneic colon cancer (n = 15) were divided into 3 groups: Q3G-treated (gavage, daily over a week), bevacizumab-treated (intraperitoneal, single dose), or untreated animals. Tumor growth, histological characteristics, blood vessel volume, and VASH1 and 2 expressions were analyzed. Q3G impaired tumor growth and vascularization, upregulated VASH1, and downregulated VASH2 in comparison to untreated animals. Mice treated with Q3G showed approximately 65% fewer blood vessels than untreated animals and 50% fewer blood vessels than mice treated with bevacizumab. Thus, we show that Q3G has antitumor activity, impairs vascularization, and differentially modulates VASH1 and 2 expressions in colon cancer.
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20
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Yen CC, Yen CJ. Safety of ramucirumab treatment in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein. Expert Opin Drug Saf 2022; 21:157-166. [PMID: 34668832 DOI: 10.1080/14740338.2022.1995353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 10/15/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the second most common cause of cancer-induced deaths worldwide, and limited therapeutic options are available for patients with advanced disease. Ramucirumab, a monoclonal antibody that blocks the vascular endothelial growth factor (VEGF) receptor-2, is the first biomarker-selected systemic agent with therapeutic efficacy, tolerability, and favorable patient-reported outcomes in patients with advanced HCC and elevated serum α-fetoprotein levels ≥400 ng/mL, who are resistant or intolerant to sorafenib therapy. However, treatment-induced adverse events (AEs), such as hypertension, proteinuria, bleeding, thromboembolism, and gastrointestinal perforation remain challenging and potentially fatal concerns. AREAS COVERED This review discusses the published or ongoing studies and subgroup analyses on ramucirumab therapy in patients with advanced HCC. We present information on the risks of ramucirumab-induced common or rare AEs and their management. EXPERT OPINION Ramucirumab toxicity secondary to VEGF inhibition is similar to the AEs that are known to be associated with other VEGF-blocking antibodies. Common AEs can be safely treated using conventional measures; however, rare and potentially fatal AEs necessitate close monitoring. With regard to the safety profile, more promising ramucirumab-containing combination therapies are likely to pave the future path for effective HCC treatment.
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Affiliation(s)
- Chih-Chieh Yen
- Division of Hematology/ Oncology, Department of Internal Medicine, National Cheng Kung University Hospital Douliou Branch, Yunlin, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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21
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Chhabra N, Kennedy J. A Review of Cancer Immunotherapy Toxicity II: Adoptive Cellular Therapies, Kinase Inhibitors, Monoclonal Antibodies, and Oncolytic Viruses. J Med Toxicol 2022; 18:43-55. [PMID: 33821435 PMCID: PMC8021214 DOI: 10.1007/s13181-021-00835-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 12/14/2022] Open
Abstract
Immunotherapy for cancer has undergone a rapid expansion in classes, agents, and indications. By utilizing aspects of the body's innate immune system, immunotherapy has improved life expectancy and quality of life for patients with several types of cancer. Adoptive cellular therapies, including chimeric antigen receptor T (CAR T) cell therapy, involve the genetic engineering of patient T cells to allow for targeting of neoplastic cells. Monitoring of patients during the lymphodepletion prior to therapy and following CAR T cell infusion is necessary to detect toxicity of therapy. Specific toxicities include cytokine release syndrome and neurologic toxicity, both of which may be life-threatening. Tocilizumab and/or corticosteroids should be considered for moderate to severe toxicity. Kinase inhibitor toxicity can occur as "on target" effects or "off target" effects to multiple organ systems due to shared protein epitopes. Treatments are organ-specific. Infusion reactions are common during treatment with monoclonal antibodies and treatment is largely supportive. Clinical experience with oncolytic viruses is limited, but local reactions including cellulitis as well as systemic influenza-like syndromes have been seen but are typically mild. Although clinical experience with adverse effects due to newer immunotherapy agents is growing, an up-to-date understanding of their mechanisms and potential toxicities is critical.
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Affiliation(s)
- Neeraj Chhabra
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA.
- Toxikon Consortium, Chicago, IL, USA.
| | - Joseph Kennedy
- Department of Emergency Medicine, Division of Medical Toxicology, Cook County Health, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA
- Toxikon Consortium, Chicago, IL, USA
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22
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Jaiswal V, Jain E, Hitawala G, Loh H, Patel S, Thada P, Nandwana V, Pandey S, Quinonez J, Naz S, Stein JD, Cueva W. Bevacizumab and Sinus Venous Thrombosis: A Literature Review. Cureus 2021; 13:e19471. [PMID: 34912612 PMCID: PMC8665695 DOI: 10.7759/cureus.19471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2021] [Indexed: 11/05/2022] Open
Abstract
Pediatric glioma treatment can be confounded by eloquent anatomical location and pathologic and genetic characteristics. Current literature suggests that the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has been linked to enhancing disease control; however, its safety and effectiveness are unknown. Bevacizumab has been linked with an increased incidence of intratumoral hemorrhage as well as arterial and venous thromboembolism. A rare adverse effect of chemotherapeutic treatment with bevacizumab is sinus venous thrombosis (SVT), with only a few cases reported to date. This review highlights the pathophysiology of bevacizumab, its rare and life-threatening side effect of SVT, and future recommendations.
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Affiliation(s)
- Vikash Jaiswal
- Research and Academic Affairs, Larkin Community Hospital, South Miami, USA
| | - Esha Jain
- Medicine, American University of Antigua, St. John's, ATG
| | | | - Hanyou Loh
- Medicine, National University of Singapore, Singapore, SGP
| | - Suyog Patel
- Medicine, B J Medical College, Ahmedabad, IND
| | - Pawan Thada
- Research, Larkin Community Hospital, South Miami, USA
| | | | - Shreya Pandey
- Research, Larkin Community Hospital, South Miami, USA
| | - Jonathan Quinonez
- Neurology/Osteopathic Neuromuscular Medicine, Larkin Community Hospital, South Miami, USA
| | - Sidra Naz
- Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Joel D Stein
- Osteopathic Neuromusculoskeletal Manipulative Medicine, Family Medicine, Sports Medicine, Pain Medicine, Lake Erie College of Osteopathic Medicine Bradenton, Bradenton, USA.,Pain Mangement, Osteopathic Neuromusculoskeletal Manipulative Medicine, Sports Medicine, Larkin Community Hospital, South Miami, USA
| | - Wilson Cueva
- Neurology, Larkin Community Hospital, South Miami, USA
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Molecular Genetics and the Role of Molecularly Targeted Agents in Metastatic Colorectal Carcinoma. J Gastrointest Cancer 2021; 51:387-400. [PMID: 31273629 DOI: 10.1007/s12029-019-00272-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is the third most common malignancy and fourth leading cancer-related deaths worldwide. In the USA, CRC is the third most commonly diagnosed cancer in both men and women. It is caused by genetic components and potential environmental factors such as consumption of processed meat, red meat, animal fats, low fiber intake, and obesity. Despite the utilization of effective screening modalities and guidelines in the USA, a significant number of patients are diagnosed with advanced, metastatic disease at the time of presentation to the physician. Recent advances in the understanding of molecular medicine with subsequent development and incorporation of newer therapeutic agents into current chemotherapeutic regimens have improved outcomes; however, the management of metastatic CRC remains challenging, particularly for the treating oncologists. METHODS We conducted a literature search on CRC mainly related to molecular genetics, targeted biologic agents, and published clinical trials. We also searched and reviewed ongoing clinical trials from Clinicaltrials.gov. RESULTS AND CONCLUSIONS Alterations in several oncogenes are associated with CRC, among those RAS, BRAF, and HER2 are of current clinical importance. Chemotherapy drugs, along with vascular endothelial growth factor or epidermal growth factor receptor monoclonal antibodies, are proven to be efficient with manageable toxicity profiles in metastatic CRC. Additional researches on Her-2-directed therapy, BRAF-targeted agents, immunotherapeutic, and newer molecularly targeted agents are needed for further improvement in outcome.
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24
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Tiosano A, Hadad A, Yanculovic N. Risk factors for an atherothrombotic event in patients with diabetic macular edema treated with intravitreal injections of bevacizumab. Int J Ophthalmol 2020; 13:1411-1416. [PMID: 32953580 DOI: 10.18240/ijo.2020.09.12] [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: 09/20/2019] [Accepted: 06/22/2020] [Indexed: 11/23/2022] Open
Abstract
AIM To identify risk factors for an atherothrombotic event (ATE) among patients who were treated for diabetic macular edema (DME) with intravitreal bevacizumab injections. METHODS This retrospective study enrolled all consecutive patients with DME who were treated by intravitreal bevacizumab from 2009 through 2016 in a single center. They were divided into one group treated by bevacizumab and subsequently had an ATE and a second group also treated by bevacizumab and did not have an ATE. RESULTS A total of 455 patients with DME were enrolled. Seventy-two of the patients had an ATE. A multivariate model adjusted for age, gender, smoking, body mass index, hemoglobin A1c (HbA1c), duration of diabetes, creatinine, and blood pressure revealed an increased risk for ATE in the patients with diabetic duration of more than 13y, a systolic blood pressure over 153.5 mm Hg at first treatment, or having been treated by more than 4 intravitreal bevacizumab injections. Additionally, patients that had an ATE within 3mo from the last intravitreal treatment underwent more bevacizumab injections (5.2±3.4 vs 3.07±1.86; P<0.001). CONCLUSION The risk factors for an ATE identified in this study are systolic blood pressure >153.5 mm Hg, a history of diabetic mellitus for more than 13y, and treatment with more than 4 intravitreal bevacizumab injections. These factors need to be borne in mind when bevacizumab is being considered in the management of patients with DME.
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Affiliation(s)
- Alon Tiosano
- Department of Ophthalmology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva 84101, Israel
| | - Aviel Hadad
- Department of Ophthalmology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva 84101, Israel
| | - Noam Yanculovic
- Department of Ophthalmology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva 84101, Israel
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25
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Ozaki Y, Yoshimura A, Sawaki M, Hattori M, Gondo N, Kotani H, Adachi Y, Kataoka A, Sugino K, Horisawa N, Endo Y, Nozawa K, Sakamoto S, Iwata H. Mechanisms and anatomical risk factors of pneumothorax after Bevacizumab use: A case report. World J Clin Oncol 2020; 11:504-509. [PMID: 32821655 PMCID: PMC7407928 DOI: 10.5306/wjco.v11.i7.504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 06/02/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bevacizumab is an antiangiogenic agent, and that synergizes with chemotherapeutic drugs. When used in combination therapies, Bevacizumab is associated with adverse events such as hemorrhage, gastrointestinal perforation, delayed wound healing, and pneumothorax. However, the molecular mechanisms underlying these adverse events are not fully understood.
CASE SUMMARY A 45-year-old female with multiple lung metastases that were derived from primary breast cancer, was placed on Bevacizumab + paclitaxel therapy, since this combination has a potent antitumor effect. She reported dyspnea before cycle 3, day 1 and we therefore ran a chest X-ray, which detected a right pneumothorax. The coronal plane computed tomography revealed that one solid mass rapidly necrosed and was replaced by a cavity that passed through the bronchus in the right lower lobe. The cavity eventually ruptured the pleura and made the bronchopleural fistula that led to this pneumothorax. Thoracic cavity drainage using an intercostal catheter was performed. On the 7th day of drainage, the patient was discharged from our hospital on recovery. Recurrence of pneumothorax was not reported, and continuation of chemotherapy was made possible by changing the regimen.
CONCLUSION Patients with lung metastases surrounding the bronchi and on the pleura should be monitored for pneumothorax by Bevacizumab-containing chemotherapies.
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Affiliation(s)
- Yuri Ozaki
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Akiyo Yoshimura
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Masataka Sawaki
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Masaya Hattori
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Naomi Gondo
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Haruru Kotani
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Yayoi Adachi
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Ayumi Kataoka
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Kayoko Sugino
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Nanae Horisawa
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Yuka Endo
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Kazuki Nozawa
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Shoko Sakamoto
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
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26
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Faiza B, Shah SQ. Synthesis of 99mTc-p-SCN-Bzl-TCMC-bevacizumab for vascular endothelial growth factor (VEGF) receptor imaging using ovarian cancer model. J Radioanal Nucl Chem 2020. [DOI: 10.1007/s10967-020-07202-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Pervaiz S, Homsy S, Narula N, Ngu S, Elsayegh D. Bevacizumab-Induced Pneumonitis in a Patient With Metastatic Colon Cancer: A Case Report. CLINICAL MEDICINE INSIGHTS-CIRCULATORY RESPIRATORY AND PULMONARY MEDICINE 2020; 14:1179548420929285. [PMID: 32595283 PMCID: PMC7297475 DOI: 10.1177/1179548420929285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 04/28/2020] [Indexed: 11/29/2022]
Abstract
Bevacizumab is a vascular endothelial growth factor–directed humanized monoclonal antibody used to treat many types of cancer and some eye diseases. Due to inhibition of angiogenesis, many adverse reactions such as bowel necrosis, nasal septal perforation, and renal thrombotic microangiopathy have been described. However, its association with interstitial pneumonitis is scarcely reported in the literature. We report a case of a 79-year-old woman with metastatic colon cancer who presented with cough and dyspnea on exertion the day after initiation of bevacizumab. She was found to have bilateral airspace opacities on imaging. Infectious and cardiogenic etiologies of dyspnea were ruled out. Due to the temporal relationship with the initiation of chemotherapy, she was suspected to have developed bevacizumab-induced interstitial pneumonitis. She improved rapidly with high-dose steroids. Follow-up imaging showed resolution of infiltrates. This is the first reported case in the literature that directly links bevacizumab to interstitial pneumonitis.
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Affiliation(s)
- Sami Pervaiz
- Department of Internal Medicine, Staten Island University Hospital-Northwell Health, New York, NY, USA
| | - Sylvester Homsy
- Department of Internal Medicine, Staten Island University Hospital-Northwell Health, New York, NY, USA
| | - Naureen Narula
- Department of Internal Medicine, Staten Island University Hospital-Northwell Health, New York, NY, USA
| | - Sam Ngu
- Department of Internal Medicine, Staten Island University Hospital-Northwell Health, New York, NY, USA
| | - Dany Elsayegh
- Department of Internal Medicine, Staten Island University Hospital-Northwell Health, New York, NY, USA
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Santos MLC, Brito BBD, da Silva FAF, Botelho ACDS, Melo FFD. Nephrotoxicity in cancer treatment: An overview. World J Clin Oncol 2020; 11:190-204. [PMID: 32355641 PMCID: PMC7186234 DOI: 10.5306/wjco.v11.i4.190] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 01/24/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment. The kidney is an important elimination pathway for many antineoplastic drugs and their metabolites, which occurs by glomerular filtration and tubular secretion. Chemotherapeutic agents, both conventional cytotoxic agents and molecularly targeted agents, can affect any segment of the nephron including its microvasculature, leading to many clinical manifestations such as proteinuria, hypertension, electrolyte disturbances, glomerulopathy, acute and chronic interstitial nephritis, acute kidney injury and at times chronic kidney disease. The clinician should be alert to recognize several factors that may maximize renal dysfunction and contribute to the increased incidence of nephrotoxicity associated with these drugs, such as intravascular volume depletion, the associated use of nonchemotherapeutic nephrotoxic drugs (analgesics, antibiotics, proton pump inhibitors, and bone-targeted therapies), radiographic ionic contrast media or radiation therapy, urinary tract obstruction, and intrinsic renal disease. Identification of patients at higher risk for nephrotoxicity may allow the prevention or at least reduction in the development and severity of this adverse effect. Therefore, the aim of this brief review is to provide currently available evidences on oncologic drug-related nephrotoxicity.
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Affiliation(s)
- Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Bahia, Brazil
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Lam SY, Lee CS, Sharma S, Cheng K. Bevacizumab-induced dysphonia: A case report with brief review of literature. J Oncol Pharm Pract 2019; 26:1032-1036. [PMID: 31771464 DOI: 10.1177/1078155219889388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Anti-angiogenic treatment in adjunct with chemotherapy is widely used for the treatment of various cancers. These agents inhibit vascular endothelial growth factor (VEGF) signaling thereby inhibiting tumor proliferation and invasion. Dysphonia, or voice changes, has been documented, but is an underreported side effect of anti-angiogenic agents. We report a case of intermittent dysphonia in a patient with metastatic, platinum-refractory ovarian cancer treated with bevacizumab. CASE REPORT A 48-year-old female with high grade mixed type ovarian adenocarcinoma and concurrent left sided breast cancer was transitioned to palliative therapy with gemcitabine-bevacizumab for her ovarian cancer. At a follow-up visit after three cycles of the new therapy, the patient complained of intermittent changes in her voice, describing periods of hoarseness or softness in her voice after the chemotherapy-sometimes to the point that her voice was inaudible. Management and outcome: A new pelvic thrombus was discovered upon assessment of the patient's disease. Bevacizumab was held and she was referred to ear, nose, and throat evaluation for dysphonia. Laryngoscopic examination showed normal vocal cord, with normal movements and no lesion or necrosis. During subsequent follow-up, the patient reported improvement in her voice with no additional dysphonia. DISCUSSION Vocal adverse effects of anti-VEGF agents have been documented in landmark trials and case reports; however, clinicians are often unaware of this rare side effect. Although VEGF-induced dysphonia may be rare and may not impede the patient's quality of life in some cases, it is critical to acknowledge and not underestimate this adverse effect.
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Affiliation(s)
- So Yi Lam
- St. John's University, New York, NY, USA
| | - Chung-Shien Lee
- Department of Clinical Health Professions, St. John's University College of Pharmacy and Health Sciences, New York, NY, USA
| | | | - Kit Cheng
- Monter Cancer Center of Northwell Health, New York, NY, USA
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Plummer C, Michael A, Shaikh G, Stewart M, Buckley L, Miles T, Ograbek A, McCormack T. Expert recommendations on the management of hypertension in patients with ovarian and cervical cancer receiving bevacizumab in the UK. Br J Cancer 2019; 121:109-116. [PMID: 31182765 PMCID: PMC6738076 DOI: 10.1038/s41416-019-0481-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 03/15/2019] [Accepted: 05/02/2019] [Indexed: 01/09/2023] Open
Abstract
Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody that may prolong survival in ovarian and cervical cancer when given in combination with chemotherapy. It works by blocking the signalling pathways that are required for tumour angiogenesis, potentially limiting the cancer’s ability to grow and spread. Hypertension is a known side effect of all angiogenesis inhibitors and could lead to interruption or premature discontinuation of effective anti-cancer treatment. Hypertension may also act as a barrier to the initiation of such treatment. In this review, we aim to present clear and practical recommendations on the management of blood pressure in ovarian and cervical cancer patients before, during and after bevacizumab treatment. This guidance covers considerations before initiating bevacizumab therapy and recommendations on the management of patients who develop hypertension, or who experience worsening of pre-existing hypertension, during bevacizumab treatment, and once the course of bevacizumab has been completed. These recommendations were developed collaboratively by a group of clinicians, comprising cardiologists, oncologists, a general practitioner and specialist oncology nurses, with expertise and practical experience in either oncology or hypertension. The aim of these recommendations is to support oncologists with hypertension assessment and management to facilitate starting or continuing bevacizumab.
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Affiliation(s)
| | - Agnieszka Michael
- St Luke's Cancer Centre, Royal Surrey County Hospital, Guildford, UK
| | - Ghazia Shaikh
- Northern Centre for Cancer Care, Newcastle upon Tyne, UK
| | | | - Lynn Buckley
- Hull and East Yorkshire Hospitals NHS Trust, Cottingham, UK
| | - Tracie Miles
- Royal United Hospitals Bath NHS Foundation Trust, Bath, UK
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Zheng W, Cao L, Xu Z, Ma Y, Liang X. Anti-Angiogenic Alternative and Complementary Medicines for the Treatment of Endometriosis: A Review of Potential Molecular Mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:4128984. [PMID: 30402122 PMCID: PMC6191968 DOI: 10.1155/2018/4128984] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/15/2018] [Accepted: 08/29/2018] [Indexed: 12/16/2022]
Abstract
Endometriosis is caused by the growth or infiltration of endometrial tissues outside of the endometrium and myometrium. Symptoms include pain and infertility. Surgery and hormonal therapy are widely used in Western medicine for the treatment of endometriosis; however, the side effects associated with this practice include disease recurrence and menopause, which can severely influence quality of life. Angiogenesis is the main biological mechanism underlying the development of endometriosis. Numerous natural products and Chinese medicines with potent anti-angiogenic effects have been investigated, and the molecular basis underlying their therapeutic effects in endometriosis has been explored. This review aims to describe natural products and compounds that suppress angiogenesis associated with endometriosis and to assess their diverse molecular mechanisms of action. Furthermore, this review provides a source of information relating to alternative and complementary therapeutic products that mediate anti-angiogenesis. An extensive review of the literature and electronic databases, such as the China National Knowledge Infrastructure, PubMed, and Embase, was conducted using the keywords 'endometriosis,' 'traditional Chinese medicine,' 'Chinese herbal medicine,' 'natural compounds,' and 'anti-angiogenic' therapy. Anti-angiogenic therapy is an emerging strategy for the treatment of endometriosis. Natural anti-angiogenic products and Chinese medicines provide several beneficial clinical effects, including pain relief. In this review, we summarize clinical trials and experimental studies of endometriosis using natural products and Chinese medicines. In particular, we focus on anti-angiogenic products and alternative and complementary medicines for the treatment of endometriosis and additionally examine their therapeutic efficacy and mechanisms of action. Anti-angiogenic natural products and/or compounds provide a new approach for the treatment of endometriosis. Future work will require randomized trials with larger numbers of subjects, as well as long-term follow-up to confirm the findings described here.
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Affiliation(s)
| | - Lixing Cao
- Team of Application of Chinese Medicine in Perioperative Period, Guangdong Provincial Hospital of Chinese Medicine, China
| | - Zheng Xu
- Guangzhou University of Chinese Medicine, China
| | - Yuanyuan Ma
- Department of Gynecology, Anyang Hospital of Traditional Chinese Medicine, China
| | - Xuefang Liang
- Department of Gynecology, Guangdong Provincial Hospital of Chinese Medicine, China
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Wu YS, Shui L, Shen D, Chen X. Bevacizumab combined with chemotherapy for ovarian cancer: an updated systematic review and meta-analysis of randomized controlled trials. Oncotarget 2018; 8:10703-10713. [PMID: 27793044 PMCID: PMC5354693 DOI: 10.18632/oncotarget.12926] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 10/21/2016] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND This meta-analysis was updated with results from a new trial and final data to reassess the efficacy and safety of bevacizumab combined with chemotherapy in ovarian cancer (OC). METHODS Randomized controlled trials (RCTs) were searched in PubMed, EMBASE, Cochrane clinical trials, Web of Science and clinicaltrial.gov databases. Outcomes included the progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and common adverse events. The hazard ratio (HR), risk ratio (RR) and odds ratio (OR) were pooled when the meta-analysis was performed. RESULTS Five RCTs with 4994 patients were included. In overall newly diagnosed OC, bevacizumab combined with chemotherapy did not significantly improve PFS (HR 0.85, 95%CI 0.70-1.02) or OS (HR 0.94, 95%CI 0.84-1.05). In the high-risk progression subgroup, the addition of bevacizumab significantly improved PFS (HR 0.76, 95%CI 0.68-0.84) and OS (HR 0.85, 95%CI 0.74-0.96). In recurrent OC, the addition of bevacizumab to chemotherapy significantly extended PFS (HR 0.53, 95%CI 0.45-0.63) and OS (HR 0.87, 95%CI 0.77-0.99). The ORR was improved (OR 2.37, 95%CI 1.99-2.82) in the overall population. Bevacizumab increased the incidence of hypertension (RR 21.27, 95%CI 9.42-48.02), proteinuria (RR 4.77, 95%CI 2.15-10.61), bleeding (RR 3.16, 95%CI 1.59-6.30), GI perforations (RR 2.76, 95%CI 1.51-5.03), arterial thrombosis events (RR 2.39, 95%CI 1.39-4.10) and venous thrombosis events (RR 1.43, 95%CI 1.04-1.96). CONCLUSIONS Bevacizumab combined with chemotherapy significantly improved PFS and OS in both patients with high-risk of progression and patients with recurrent OC, with an increased incidence of common adverse events. However, no statistically significant survival benefit was identified in the front-line settings.
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Affiliation(s)
- Yu Shen Wu
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Lin Shui
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Dan Shen
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Xiaopin Chen
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
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Malyszko J, Kozlowska K, Kozlowski L, Malyszko J. Nephrotoxicity of anticancer treatment. Nephrol Dial Transplant 2018; 32:924-936. [PMID: 28339935 DOI: 10.1093/ndt/gfw338] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 08/10/2016] [Indexed: 12/12/2022] Open
Abstract
Severe adverse systemic drug events occur commonly as a result of treatment of cancer patients. Nephrotoxicity of chemotherapeutic agents remains a significant complication limiting the efficacy of the treatment. A variety of renal disease and electrolyte disorders can result from the drugs that are used to treat malignant disease. The kidneys are a major elimination pathway for many antineoplastic drugs and their metabolites. Tumour lysis syndrome, an emergency in haematooncology, occurs most often after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukaemia. Chemotherapeutic agents can affect the glomerulus, tubules, interstitium and renal microvasculature, with clinical manifestations that range from asymptomatic elevation of serum creatinine to acute renal failure requiring dialysis. Some factors such as intravascular volume depletion, as well as concomitant use of other drugs or radiographic ionic contrast media, can potentiate or contribute to the nephrotoxicity. Cytotoxic agents can cause nephrotoxicity by a variety of mechanisms. The most nephrotoxic chemotherapeutic drug is cisplatin, which is often associated with acute kidney injury. Many other drugs such as alkylating agents, antimetabolites, vascular endothelial growth factor pathway inhibitors and epidermal growth factor receptor pathway inhibitors may have toxic effects on the kidneys. The aim of this review is to discuss the issue of nephrotoxicity associated with chemotherapy. In routine clinical practice, monitoring of kidney function is mandatory in order to identify nephrotoxicity early, allowing dosage adjustments or withdrawal of the offending drug.
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Affiliation(s)
- Jolanta Malyszko
- 2nd Department ofNephrology and Hypertension with Dialysis Unit, Medical University in Bialystok
| | - Klaudia Kozlowska
- 2nd Department ofNephrology and Hypertension with Dialysis Unit, Medical University in Bialystok
| | - Leszek Kozlowski
- Department of Oncological Surgery, Ministry of Interior Affairs Hospital, Bialystok, Poland
| | - Jacek Malyszko
- 1st Department of Nephrology and Transplantology with Dialysis Unit, Medical University in Bialystok, Bialystok, Poland
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Noh K, Mangala LS, Han HD, Zhang N, Pradeep S, Wu SY, Ma S, Mora E, Rupaimoole R, Jiang D, Wen Y, Shahzad MMK, Lyons Y, Cho M, Hu W, Nagaraja AS, Haemmerle M, Mak CSL, Chen X, Gharpure KM, Deng H, Xiong W, Kingsley CV, Liu J, Jennings N, Birrer MJ, Bouchard RR, Lopez-Berestein G, Coleman RL, An Z, Sood AK. Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis. Cell Rep 2017; 21:2785-2795. [PMID: 29212026 PMCID: PMC5749980 DOI: 10.1016/j.celrep.2017.11.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 09/18/2017] [Accepted: 11/02/2017] [Indexed: 11/25/2022] Open
Abstract
Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies.
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Affiliation(s)
- Kyunghee Noh
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Lingegowda S Mangala
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hee-Dong Han
- Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, South Korea
| | - Ningyan Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Sunila Pradeep
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sherry Y Wu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shaolin Ma
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Edna Mora
- Department of Surgery, University of Puerto Rico, San Juan 00936, Puerto Rico; University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA
| | - Rajesha Rupaimoole
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Dahai Jiang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yunfei Wen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mian M K Shahzad
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yasmin Lyons
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - MinSoon Cho
- Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Archana S Nagaraja
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Monika Haemmerle
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Celia S L Mak
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiuhui Chen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kshipra M Gharpure
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hui Deng
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Wei Xiong
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Charles V Kingsley
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nicholas Jennings
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael J Birrer
- University of Alabama Comprehensive Cancer Center, Birmingham, AL 35294, USA
| | - Richard R Bouchard
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Lopez-Berestein
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert L Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Williams SJ, Khokhar A, Gharib A. Successful rapid desensitization to intravenous bevacizumab using a 14-step protocol: Case report. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2017; 5:1746-1747. [DOI: 10.1016/j.jaip.2017.04.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/24/2017] [Accepted: 04/20/2017] [Indexed: 11/25/2022]
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Rodriguez CA, Martin T, Lozano R, Gomez A, Cruz JJ. Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer. Breast J 2017; 23:745-746. [PMID: 28845572 DOI: 10.1111/tbj.12913] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 11/18/2016] [Indexed: 11/29/2022]
Abstract
Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone-sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab.
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Affiliation(s)
- Cesar A Rodriguez
- Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Teresa Martin
- Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Rebeca Lozano
- Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Amalia Gomez
- Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Juan J Cruz
- Medical Oncology Dept, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
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Gross ME, Dorff TB, Quinn DI, Diaz PM, Castellanos OO, Agus DB. Safety and Efficacy of Docetaxel, Bevacizumab, and Everolimus for Castration-resistant Prostate Cancer (CRPC). Clin Genitourin Cancer 2017; 16:S1558-7673(17)30200-8. [PMID: 28826933 PMCID: PMC7444943 DOI: 10.1016/j.clgc.2017.07.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 06/16/2017] [Accepted: 07/09/2017] [Indexed: 11/17/2022]
Abstract
BACKGROUND Previous data suggests that co-targeting mammalian target of rapamycin and angiogenic pathways may potentiate effects of cytotoxic chemotherapy. We studied combining mammalian target of rapamycin and vascular endothelial growth factor inhibition with docetaxel in castrate-resistant prostate cancer (CRPC). METHODS Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Docetaxel and bevacizumab were given intravenously day 1 with everolimus orally daily on a 21-day cycle across 3 dose levels (75:15:2.5, 75:15:5, and 65:15:5; docetaxel mg/m2, mg/kg bevacizumab, and mg everolimus, respectively). Maintenance therapy with bevacizumab/everolimus without docetaxel was allowed after ≥ 6 cycles. RESULTS Forty-three subjects were treated across all dose levels. Maximal tolerated doses for the combined therapies observed in the phase 1B portion of the trial were: docetaxel 75 mg/m2, bevacizumab 15 mg/kg, and everolimus 2.5 mg. Maximal prostate-specific antigen decline ≥ 30% and ≥ 50% was achieved in 33 (79%) and 31 (74%) of patients, respectively. Best response by modified Response Evaluation Criteria In Solid Tumors criteria in 25 subjects with measurable disease at baseline included complete or partial response in 20 (80%) patients. The median progression-free and overall survival were 8.9 months (95% confidence interval, 7.4-10.6 months) and 21.9 months (95% confidence interval, 18.4-30.3 months), respectively. Hematologic toxicities were the most common treatment-related grade ≥ 3 adverse events including: febrile neutropenia (12; 28%), lymphopenia (12; 28%), leukocytes (10; 23%), neutrophils (9; 21%), and hemoglobin (2; 5%). Nonhematologic grade ≥ 3 adverse events included: hypertension (8; 19%), fatigue (3; 7%), pneumonia (3; 7%), and mucositis (4; 5%). There was 1 treatment-related death owing to neutropenic fever and pneumonia in a patient treated at dose level 3 despite dose modifications and prophylactic growth factor support. CONCLUSIONS Docetaxel, bevacizumab, and everolimus can be safely administered in CRPC and demonstrate a significant level of anticancer activity, meeting the predetermined response criteria. However, any potential benefit of combined therapy must be balanced against increased risk for toxicities. Our results do not support the hypothesis that this combination of agents improves upon the results obtained with docetaxel monotherapy in an unselected population of chemotherapy-naive patients with CRPC.
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Affiliation(s)
- Mitchell E Gross
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA; Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
| | - Tanya B Dorff
- Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - David I Quinn
- Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA; USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Patricia M Diaz
- Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Olga O Castellanos
- Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - David B Agus
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA; Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Hwang YS, Liu CH, Huang YC, Chen CS, Chen TL, Wang NK, Chen YP, Chen KJ, Lai CC, Wu WC. Systemic effects after intravitreal injection of bevacizumab in new born rabbit eyes. Cutan Ocul Toxicol 2017; 37:41-51. [PMID: 28614955 DOI: 10.1080/15569527.2017.1331356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
PURPOSE To determine the systemic impact of intravitreal injection of bevacizumab (IVB), an anti-vascular endothelium growth factor antibody, in newborn rabbits. MATERIALS AND METHODS We used four groups of rabbits. Group 1 rabbits received a single injection of IVB starting from the age of 6 weeks. Group 2 rabbits received a single injection of balanced salt solution (BSS, 0.025 ml) and served as controls for group 1. Group 3 rabbits received two consecutive injections of IVB at the ages of 6 and 10 weeks. Group 4 rabbits received two consecutive injections of BSS at the ages of 6 and 10 weeks and served as controls for group 3. During the experiment, a complete blood count (CBC), clinical biochemistry, weight gain, food intake, body temperature, blood pressure, pulse, and mortality were measured in the animals. Two months after IVB injection, the animals were sacrificed, and histology of the major organs was checked. Immunohistochemistry was assessed to explore the neurons in the central nervous system (CNS). RESULTS We found there were no morphological or functional changes in the eyes following IVB injection. Furthermore, there were no differences in CBC, biochemistry, or other measured parameters among the four groups of animals. We checked the histology of the major organs and neurons in the CNS and they did not reveal significant differences among the four groups of animals. CONCLUSIONS Conclusively, IVB of either one or two injections (0.625 mg) in newborn rabbit eyes is well tolerated and does not cause noticeable systemic organ pathology.
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Affiliation(s)
- Yih-Shiou Hwang
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Chi-Hsien Liu
- c Graduate Institute of Biochemical and Biomedical Engineering , Chang Gung University , Taoyuan , Taiwan
| | - Yin-Cheng Huang
- b College of Medicine , Chang Gung University , Taoyuan , Taiwan.,d Department of Neurosurgery , Chang Gung Memorial Hospital , Taoyuan , Taiwan
| | - Chih-Shan Chen
- e Laboratory Animal Center , Chang Gung Memorial Hospital , Taoyuan , Taiwan
| | - Tun-Lu Chen
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Nan-Kai Wang
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Yen-Po Chen
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Kwan-Jen Chen
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Chi-Chun Lai
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Wei-Chi Wu
- a Department of Ophthalmology , Chang Gung Memorial Hospital , Taoyuan , Taiwan.,b College of Medicine , Chang Gung University , Taoyuan , Taiwan
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Lee CS, Alwan LM, Sun X, McLean KA, Urban RR. Routine proteinuria monitoring for bevacizumab in patients with gynecologic malignancies. J Oncol Pharm Pract 2016; 22:771-776. [PMID: 26447100 DOI: 10.1177/1078155215609987] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Proteinuria leading to nephrotic syndrome is a rare adverse event arising from treatment with bevacizumab. There is limited evidence to guide the frequency and appropriate test for monitoring for proteinuria. The purpose of this study was to determine the prevalence and severity of proteinuria during bevacizumab administration to patients with gynecologic malignancies, and to evaluate risk factors associated with this toxicity; a secondary objective was to evaluate the cost of routine proteinuria monitoring to assess for opportunities of cost containment that could change clinical practice. METHODS A retrospective chart review was performed at an academic gynecologic oncology clinic. Women over 18 years of age with a diagnosed gynecologic malignancy were evaluated for the development of proteinuria while receiving bevacizumab treatment as measured by a urine protein-to-creatinine ratio. Patient and disease-specific risk factors were evaluated using logistic regression to determine correlations of risk factors to development of proteinuria. Cost assessment was performed using institution-specific data for urine laboratory tests. RESULTS Eighty-nine patients were identified, and the overall prevalence of proteinuria of any grade was 35%. The mean number of bevacizumab cycles was 13 (2-64 cycles). The majority of patients experienced grade 1 proteinuria (70%, 62 patients). Grade 3 proteinuria was observed in two patients (2%). There was a trend toward increased bevacizumab cycles associated with increased grade proteinuria (p = 0.053), however there were no factors significantly associated with the development of proteinuria as measured by urine protein-to-creatinine ratio. CONCLUSION Monitoring of urine protein-to-creatinine ratios with each cycle may be unnecessary due to the low prevalence of grade 3 proteinuria observed. Additionally, urine protein-to-creatinine ratios may not provide adequate assessment of proteinuria toxicity associated with bevacizumab therapy. Potential cost savings opportunities for the institution can be realized with a cost-reductive monitoring algorithm that will utilize less costly laboratory techniques for patients at high risk of developing proteinuria.
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Affiliation(s)
- Catherine S Lee
- Department of Pharmacy, University of Washington Medical Center, Seattle, WA, USA
| | - Laura M Alwan
- Department of Pharmacy, University of Washington Medical Center, Seattle, WA, USA
| | | | - Katherine A McLean
- Division of Gynecologic Oncology, University of Washington Medical Center, Seattle, WA, USA
| | - Renata R Urban
- Division of Gynecologic Oncology, University of Washington Medical Center, Seattle, WA, USA
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Goff LW, Cohen RB, Berlin JD, de Braud FG, Lyshchik A, Noberasco C, Bertolini F, Carpentieri M, Stampino CG, Abbattista A, Wang E, Borghaei H. A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors. Clin Cancer Res 2016; 22:2146-54. [PMID: 26655846 PMCID: PMC7328801 DOI: 10.1158/1078-0432.ccr-15-1622] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 11/18/2015] [Indexed: 02/05/2023]
Abstract
PURPOSE Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. EXPERIMENTAL DESIGN This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. RESULTS Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. CONCLUSIONS The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.
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Affiliation(s)
- Laura W Goff
- Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
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Efficacy and Toxicity Assessment of Different Antibody Based Antiangiogenic Drugs by Computational Docking Method. Adv Bioinformatics 2016; 2016:7053712. [PMID: 27047544 PMCID: PMC4800073 DOI: 10.1155/2016/7053712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/21/2016] [Indexed: 11/17/2022] Open
Abstract
Bevacizumab and trastuzumab are two antibody based antiangiogenic drugs that are in clinical practice for the treatment of different cancers. Presently applications of these drugs are based on the empirical choice of clinical experts that follow towards population based clinical trials and, hence, their molecular efficacies in terms of quantitative estimates are not being explored. Moreover, different clinical trials with these drugs showed different toxicity symptoms in patients. Here, using molecular docking study, we made an attempt to reveal the molecular rationale regarding their efficacy and off-target toxicity. Though our study reinforces their antiangiogenic potentiality and, among the two, trastuzumab has much higher efficacy; however, this study also reveals that compared to bevacizumab, trastuzumab has higher toxicity effect, specially on the cardiovascular system. This study also reveals the molecular rationale of ocular dysfunction by antiangiogenic drugs. The molecular rationale of toxicity as revealed in this study may help in the judicious choice as well as therapeutic scheduling of these drugs in different cancers.
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Iida T, Yabana T, Nakagaki S, Adachi T, Kondo Y. A Rupture of a Lung Metastatic Lesion of Colon Cancer, Leading to Pneumothorax Caused by Bevacizumab. Intern Med 2016; 55:3125-3129. [PMID: 27803405 PMCID: PMC5140860 DOI: 10.2169/internalmedicine.55.7155] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The patient was a 57-year-old man who was diagnosed with multiple lung metastases of sigmoid colon cancer. The patient developed progressive disease after 8 courses of bevacizumab + capecitabine and oxaliplatin therapy, therefore, bevacizumab + irinotecan, leucovorin, and 5-fluorouracil therapy was started. During the fifth course, he experienced pain on the left side of his chest. On computed tomography, bleeding from the pulmonary metastatic lesions was suspected. Two days later, a pneumothorax was detected. Although several cases of pneumothorax induced by bevacizumab have been reported, this case is the first documentation that bevacizumab caused a rupture of the lung metastatic lesion, leading to a pneumothorax.
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Affiliation(s)
- Tomoya Iida
- Department of Gastroenterology, Otaru City General Hospital, Japan
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Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2. J Neurooncol 2015; 124:229-36. [PMID: 26022982 DOI: 10.1007/s11060-015-1828-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 05/25/2015] [Indexed: 12/22/2022]
Abstract
Vestibular schwannoma (VS) growth in neurofibromatosis type 2 (NF2) can be responsible for brainstem compression and hearing loss. Surgical removal remains the standard therapy despite potential morbidity. Previous studies suggested that the inhibition of the VEGF-pathway with bevacizumab could result in hearing improvement, reduction of the tumor volume or both in adults. We retrospectively describe the French experience of bevacizumab treatment delivered for progressive VS in pediatric NF2 patients. Patients received Bevacizumab 5 or 10 mg/kg every 2 weeks according to the physician's choice. Follow-up included clinical assessment, audiometry and volumetric MRI every 3-6 months. Seven patients harboring 11 VS were included. The median age at inclusion was 15 years (11.4-18.8), and the median treatment duration was 11.3 months (3.2-55.6). At baseline, the median tumor volume was 1.2 cm(3) (0.52-13.5) and the median word recognition score was 90 % (0-100). We observed one major response, two minor responses and a decrease in the rate of tumor growth for the 4 other patients. The median annual growth rate before treatment was significantly higher than after 1 year of treatment (138 vs. 36 %, n = 5, p = 0.043). We noted one hearing improvement over the course of 1 year under treatment (hearing response rate was 14 %). Overall, the treatment was well tolerated. Our study supports that bevacizumab is an attractive therapeutic option for pediatric NF2 patients with growing VS. Thorough multidisciplinary evaluation is necessary to identify the best candidates prior to treatment. It is likely that a better functional outcome would be expected if targeted therapies were discussed early in the management of the disease.
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Manso L, Moreno F, Márquez R, Castelo B, Arcediano A, Arroyo M, Ballesteros AI, Calvo I, Echarri MJ, Enrech S, Gómez A, González Del Val R, López-Miranda E, Martín-Angulo M, Martínez-Jañez N, Olier C, Zamora P. Use of bevacizumab as a first-line treatment for metastatic breast cancer. ACTA ACUST UNITED AC 2015; 22:e51-60. [PMID: 25908921 DOI: 10.3747/co.22.2210] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.
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Affiliation(s)
- L Manso
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | - F Moreno
- Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - R Márquez
- MD Anderson Cancer Center, Madrid, Spain
| | - B Castelo
- Hospital Universitario La Paz, Madrid, Spain
| | - A Arcediano
- Hospital General Universitario de Guadalajara, Guadalajara, Mexico
| | - M Arroyo
- Hospital Príncipe de Asturias, Alcalá de Henares, Spain
| | | | - I Calvo
- Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - M J Echarri
- Hospital Universitario Severo Ochoa, Leganés, Spain
| | - S Enrech
- Hospital Universitario de Getafe, Getafe, Spain
| | - A Gómez
- Hospital Universitario de Salamanca, Salamanca, Spain
| | | | | | | | | | - C Olier
- Hospital Universitario Fundación Alcorcón, Alcorcón, Spain
| | - P Zamora
- Hospital Universitario La Paz, Madrid, Spain
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Abstract
Our aim was to investigate the effects of anti-vascular endothelial growth factor (anti-VEGF) antibody Bevacizumab on endometrial explants and on apoptotic gene expression levels in the rat endometriosis model. Endometriotic implants were surgically formed, and rats treated with (i) 1 mg/kg single subcutaneous injection of depot leuprolide acetate; (ii) 2.5 mg/kg of single intaperitoneal injection of bevacizumab; (iii) intraperitoneal injection of saline. Histopathologic scores and adhesion scores of endometriotic foci and levels of Bcl-2-associated X protein (Bax), Cytochrome c (Cyt-c), B-cell lymphoma/leukemia 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) mRNA gene expressions of endometriotic foci. Bevacizumab treatment decreased the endometriotic explant size compared with control. Bevacizumab-treated rats had lower total adhesion scores when compared with the control group. Semi-quantitative evaluation of the persistence of endometrial epithelial cells in the explants showed a lower score in gonadotropin-releasing hormone (GnRH) agonist-treated rats compared with control rats. In Bevacizumab increased expression of Bax 3.1-fold, Cyt-c 1.3-fold and decreased expression of Bcl-2 0.4-fold, Bcl-xl 0.8-fold compared with the control group. The GnRH agonist increased expression of Bax 3.0 fold, Cyt-c 1.3 fold and decreased expression of Bcl-2 0.4-fold, Bcl-xl 0.8-fold, compared with the control group. This study suggests that a novel angiogenesis inhibitor, anti-VEGF antibody bevacizumab is as effective as GnRH agonist in the regression of the endometriotic lesions in rat endometriosis model. One possible mechanism of this effect is the induction of apoptosis.
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Datta-Mitra A, Riar NK, Raychaudhuri SP. Remission of psoriasis and psoriatic arthritis during bevacizumab therapy for renal cell cancer. Indian J Dermatol 2014; 59:632. [PMID: 25484418 PMCID: PMC4248526 DOI: 10.4103/0019-5154.143574] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is employed for treatment of several cancers and retinopathies. Although previous reports of remission of psoriasis with bevacizumab do exist, but its current experience for psoriatic arthritis (PsA) is still limited. In this report, we describe a patient with metastatic renal cell cancer, psoriasis and PsA, who experienced a complete remission of psoriasis and PsA during bevacizumab therapy without any other management for psoriasis and PsA. We also found a flare up of his psoriatic disease after switching to other kinase inhibitors like sorafenib or sunitinib. This suggests that bevacizumab might have a promising future in the treatment of psoriasis and PsA.
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Affiliation(s)
- Ananaya Datta-Mitra
- Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA 95616, USA ; Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, VA Medical Centre Sacramento, Mather, CA 95655, USA
| | - Navdeep K Riar
- Department of Internal Medicine, Division of Hospital Medicine, University of California Davis, School of Medicine, Sacramento, CA 95817, USA
| | - Siba P Raychaudhuri
- Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA 95616, USA ; Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, VA Medical Centre Sacramento, Mather, CA 95655, USA
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Shi C, Gao F, Gao X, Liu Y. A novel anti-VEGF165 monoclonal antibody-conjugated liposomal nanocarrier system: physical characterization and cellular uptake evaluation in vitro and in vivo. Biomed Pharmacother 2014; 69:191-200. [PMID: 25661357 DOI: 10.1016/j.biopha.2014.11.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 11/12/2014] [Indexed: 01/18/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) is an important target for cancer therapy. In the present study, we conjugated the novel fully-human anti-VEGF165 monoclonal antibody, mAb165, with a PEGylated liposome (lip) to produce a monoclonal antibody-conjugated PEGylated liposome (mAb-lip). Physical characterization of mAb-lips showed an average particle size of 108nm. Using a bicinchoninic acid (BCA) assay, the coupling efficiency of mAb165 conjugated to the liposome was 69.8±0.5μg mAb/μmol phospholipid. In addition, we confirmed that conjugation between mAb165 and the liposome did not affect the structure and VEGF binding affinity of the antibody. Cell uptake of mAb-lips was assessed in four cell lines: MCF-7, HepG-2, SGC-7901, and L02 cells. Confocal microscopy and flow cytometry demonstrated that there was no significant difference in cell uptake between mAb-lips and mAb-free liposome either in VEGF-expressing tumor cells or normal cells. Moreover, the cytotoxicity of paclitaxel encapsulated in mAb-lips was not increased in the four cell lines. However, in BALB/c nude mice bearing MCF-7 xenografts, mAb-lips showed superior targeting activity to tumor tissues when compared with the unmodified liposome, which was demonstrated by the fact that rhodamine-labeled mAb-lips exhibited higher fluorescence intensity in tumor tissues than the unmodified liposome. Thus, our study indicated that mAb-lips may have the potential to enhance the therapeutic index of anticancer agents through targeted delivery to tumor cells in vivo.
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Affiliation(s)
- Chenyang Shi
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Fei Gao
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiangdong Gao
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yu Liu
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
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Gubbi A, Kendrick JE, Finkler NJ. The role of bevacizumab in recurrent, platinum-sensitive ovarian cancer. Expert Rev Anticancer Ther 2014; 14:1105-13. [PMID: 25189201 DOI: 10.1586/14737140.2014.956095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The majority of women with ovarian cancer will experience a recurrence of their disease despite aggressive primary cytoreduction and adjuvant cytotoxic chemotherapy. Notwithstanding the high rate of recurrence, targeted and biologic agents have helped to decrease the dependence on cytotoxic chemotherapy. Bevacizumab, a vascular endothelial growth factor inhibitor, has been shown to cause regression in tumor vasculature, inhibition of angiogenesis and prevention of progenitor cell recruitment. Phase III clinical trials of bevacizumab in patients with primary epithelial ovarian cancer and in patients with platinum-sensitive ovarian cancer have shown an improvement in progression free survival without an appreciable difference in overall survival. The addition of bevacizumab to standard cytotoxic chemotherapy regimens has demonstrated improved response rates, and improved progression free survival. These results have stimulated research in additional angiogenesis inhibitors and trials to further incorporate bevacizumab into the treatment schema for patients with recurrent ovarian cancer.
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Affiliation(s)
- Ajit Gubbi
- Florida Hospital Cancer Institute - Gynecologic Oncology, 2501 North Orange Ave, Orlando, Florida 32804, USA
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Kunos CA, Sherertz TM. Long-Term Disease Control with Triapine-Based Radiochemotherapy for Patients with Stage IB2-IIIB Cervical Cancer. Front Oncol 2014; 4:184. [PMID: 25105092 PMCID: PMC4109518 DOI: 10.3389/fonc.2014.00184] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 06/30/2014] [Indexed: 01/27/2023] Open
Abstract
Background: National Cancer Institute phase I #7336 and phase II #8327 clinical trials explored the safety and efficacy of triapine (NSC #663249) added to cisplatin radiochemotherapy in untreated patients with advanced-stage cervical cancer. Triapine inhibits ribonucleotide reductase, the rate-limiting enzyme responsible for DNA-building deoxyribonucleotides, and thereby, enhances radiochemosensitivity by prolonging DNA repair time. Here, we report 3-year efficacy endpoints of pelvic locoregional relapse rate, disease-free, and overall survivals. Methods: Eligible patients with bulky IB–IIIB cervical cancer underwent three-times weekly triapine (25 or 50 mg/m2), once-weekly cisplatin (40 mg/m2), and conventional daily pelvic radiation followed by brachytherapy. A cumulative incidence method estimated pelvic locoregional relapse rates. Disease-free survival was measured from radiochemotherapy start date to the date of first relapse or cancer-related death. Overall survival was measured from radiochemotherapy start date to the date of any-cause death. The Kaplan–Meier method estimated survivals. Findings: Between 2006 and 2011, 24 untreated patients with cervical cancer met criteria for reporting in this study. A median 3.4 years of follow-up time (range, 0.3–7.6 years) has been observed. All had squamous cancers and the majority had either node-positive stage IB–IIA (33%) or stage IIIB (42%) disease. The 3-year pelvic locoregional relapse rate, disease-free survival, and overall survival were 4% [95% confidence interval (CI), 0–20%], 80% (95% CI: 71–89%), and 82% (95% CI: 74–90%), respectively. Interpretation: Triapine radiochemotherapy was safe, active, and effective in patients with untreated advanced-stage cervical cancer, worthy of randomized clinical trial study.
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Affiliation(s)
- Charles A Kunos
- Department of Radiation Oncology, Summa Cancer Institute, Summa Health System , Akron, OH , USA
| | - Tracy M Sherertz
- Department of Radiation Oncology, CASE Comprehensive Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine , Cleveland, OH , USA
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Elstner KE, Clarke FK, Turner SJ. Case report: management of persistent dural anastomotic dehiscence in a patient treated with bevacizumab. Ann Plast Surg 2014; 71:652-3. [PMID: 23241766 DOI: 10.1097/sap.0b013e3182583ee6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
A 55-year-old woman with recurrent glioblastoma multiforme on palliative chemotherapy including Avastin, an angiogenesis inhibitor, presents with several episodes of bacterial meningitis secondary to a persistent cerebrospinal fluid (CSF) leak. Anastomotic dehiscence of the dura mater in the region of the previous craniotomy sites was evident. Attempts to repair the cranial CSF leak with external ventricular drain and ventriculoperitoneal shunt were unsuccessful. This patient underwent repair of the dural defects with a radial forearm free fascial flap, with consequent resolution of the CSF leak.A literature search was performed, and the available data on angiogenesis inhibitors and anastomotic dehiscence was reviewed, specifically focusing on delayed anastomotic dehiscence in patients receiving Avastin (bevacizumab). Although the potential complications of anastomotic dehiscence in patients receiving angiogenesis inhibitors are well documented, there is comparatively little documentation in the literature regarding delayed wound or anastomotic dehiscence. Twenty such cases were found cited in the literature; however, only one study was found which specifically considered angiogenesis inhibitors within the context of central nervous system malignancies.
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Affiliation(s)
- Kristen E Elstner
- From the Department of Plastics and Reconstructive Surgery, Prince of Wales Hospital, Randwick, New South Wales, Australia
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