Cancer Chemotherapy and Pharmacology最新文献

{"title":"Risk factors for immune-related adverse events associated with pembrolizumab in patients with solid tumors.","authors":"Farah Shkakhwa, Farah Basbous, Dalia Shakhatreh, Kamal Al-Rabi, Nour Faqeer","doi":"10.1007/s00280-026-04968-9","DOIUrl":"https://doi.org/10.1007/s00280-026-04968-9","url":null,"abstract":"<p><strong>Purpose: </strong>Despite the widespread use of pembrolizumab, few real-world studies investigated risk factors for immune-related adverse events (irAEs). This study aimed to evaluate risk factors for irAEs associated with pembrolizumab treatment in patients with solid tumors.</p><p><strong>Methods: </strong>This retrospective single-center study included adult patients with solid tumors treated with pembrolizumab at King Hussein Cancer Center between January 2020 and June 2024. Patients' demographic, clinical, and laboratory data at baseline and after 1 month of pembrolizumab initiation, were collected. Multivariate logistic regression analysis was used to identify risk factors for irAEs at baseline and after 1 month of pembrolizumab therapy.</p><p><strong>Results: </strong>During the study period, 978 patients were included, with a median age of 60 years (range, 20-86 years). IrAEs occurred in 31.9% of patients, among whom lung cancer was the most common cancer type (46.5%). In the multivariate logistic regression analysis, baseline neutrophil-to-lymphocyte ratio (NLR) < 3 (odd ratio (OR) 1.58, p = 0.046) and higher programmed death-ligand 1 (PD-L1) expression (OR 1.009, p = 0.006) were identified as independent risk factors for irAEs. Elevated PD-L1 expression (OR 1.007, p = 0.028), and hemoglobin ≥ 10 g/dL (OR 1.90, p = 0.021) were identified as independent risk factors for irAEs after 1 month of pembrolizumab therapy.</p><p><strong>Conclusions: </strong>One-third of patients developed irAEs. An NLR < 3, higher PD-L1 expression, and hemoglobin ≥ 10 g/dL were identified as risk factors for irAEs. These factors may help in early risk stratification of patients receiving pembrolizumab.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond gastric acid: pharmacologic modulation of the tumor microenvironment by vonoprazan and its drug-interaction implications for chemotherapy and immunotherapy.","authors":"Ghassan Sonji, Nada Sonji, Afaf El Katerji","doi":"10.1007/s00280-026-04963-0","DOIUrl":"https://doi.org/10.1007/s00280-026-04963-0","url":null,"abstract":"<p><strong>Purpose: </strong>Vonoprazan, a potassium-competitive acid blocker, possesses distinct pharmacokinetic and pharmacodynamic properties, including a high pKa , prolonged systemic exposure, and sustained hypochlorhydria, that may have implications beyond gastric acid suppression for anticancer drug interactions and the tumor microenvironment.</p><p><strong>Methods: </strong>We critically reviewed preclinical and clinical literature to evaluate vonoprazan's potential effects across two proposed biological axes: the intracellular/organelle axis, involving potential lysosomal drug sequestration, pH regulation, autophagy, and apoptotic signaling, and the systemic microbiome axis, involving acid-suppression-associated microbial alterations and potential consequences for antitumor immunity.</p><p><strong>Results: </strong>Vonoprazan enhanced cisplatin cytotoxicity in MCF-7 breast cancer cells and attenuated cisplatin-associated nephrotoxicity in rats, while altering autophagy-related markers. Separate cancer-cell studies found no increase in VEGF expression under the tested conditions, in contrast to several proton pump inhibitors. Conversely, a retrospective NSCLC cohort associated vonoprazan exposure with higher hazards of progression and death during immune checkpoint inhibitor therapy, although causality was not established. A 2026 pharmacovigilance analysis also identified increased cholangitis reporting among immune checkpoint inhibitor-exposed reports with co-reported vonoprazan, although causality was not established. Clinical evidence for microbiome alterations is emerging, but their relevance to anticancer treatment outcomes remains uncertain.</p><p><strong>Conclusion: </strong>Available evidence supports a context-dependent pharmacologic framework rather than a uniform oncologic effect. Direct evidence for tumor-cell accumulation and vonoprazan-specific effects on V-ATPase activity in tumors remains limited. Prospective clinical and translational studies are needed to determine the clinical relevance of these potential interactions and to define appropriate use alongside anticancer therapies.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Continuous infusion of granulocyte colony-stimulating factor is associated with an advantage in neutrophil recovery in pediatric oncologic disorders.","authors":"Yi-Lun Wang, Tsung-Yen Chang, Shih-Hsiang Chen, Yi-Wen Hsiao, Yu-Chuan Wen, Tang-Her Jaing","doi":"10.1007/s00280-026-04966-x","DOIUrl":"10.1007/s00280-026-04966-x","url":null,"abstract":"<p><strong>Introduction: </strong>The use of intensified chemotherapy has significantly improved overall survival (OS) and relapse-free survival (RFS) in cancer patients. However, it also increases the risk of chemotherapy-induced neutropenia (CIN). Granulocyte colony-stimulating factor (G-CSF) is commonly used to hasten neutrophil recovery, but limited research has focused on the superiority of different routes of G-CSF administration.</p><p><strong>Materials and methods: </strong>This was a randomized, prospective, single-institution study. Twenty-eight participants were enrolled and randomly assigned to experimental and control arms in a 1:1 ratio. At the end of the study, 20 cases were eligible for statistical analysis. The primary endpoint was the duration from the onset of neutropenia to steady neutrophil recovery. Secondary endpoints included the safety profile, 7-day emergency return rate, and the occurrence of infectious or febrile events.</p><p><strong>Results: </strong>The mean duration from CIN to neutrophil recovery was 6.2 days in the intravenous drip (IVD) group and 7.6 days in the intravenous injection (IVI) group (P = 0.0068). The mean difference between the two groups was 1.4 days. A significantly lower incidence of febrile neutropenia (FN) was observed in the IVD group compared to the IVI group (15% vs. 50%, P = 0.0407). Adverse effects (AEs) were comparable between the two groups.</p><p><strong>Conclusions: </strong>The IVD route of G-CSF administration leads to faster neutrophil recovery and reduces the risk of FN. All evaluable AEs are comparable between the two groups. These findings suggest that the IVD route may be a preferable option for optimizing supportive care in cancer patients with CIN.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of androgen deprivation therapy and acute kidney injury in patients with prostate cancer: a systematic review and meta-analysis of 72,980 patients.","authors":"Iago Zang Pires, Alexandre Yamada Fujimura, Marília Oberto da Silva Gobbo, Renan Yuji Ura Sudo, Tanize Louize Milbradt, Nilson Marquardt Filho, Gustavo Franco Carvalhal","doi":"10.1007/s00280-026-04962-1","DOIUrl":"10.1007/s00280-026-04962-1","url":null,"abstract":"<p><strong>Purpose: </strong>Androgen deprivation therapy (ADT) has been associated with increased cardiovascular and renal risks in prostate cancer patients. We performed a systematic review and meta-analysis of the currently available evidence to evaluate the rates of acute kidney injury (AKI) in prostate cancer patients under ADT.</p><p><strong>Materials and methods: </strong>PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to October 2024. Eligible observational studies comparing prostate cancer patients receiving ADT with those not receiving ADT were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed using I², τ², and 95% prediction intervals. Risk of bias and certainty of evidence were evaluated using the Newcastle-Ottawa Scale and GRADE framework, respectively. Statistical analyses were performed using R software version 4.3.1, and the study was reported according to PRISMA and MOOSE recommendations.</p><p><strong>Results: </strong>Four studies involving 72,980 patients were included. ADT was significantly associated with AKI occurrence when compared with the non-ADT control group (OR 1.34; 95% CI 1.29-1.40; p < 0.001; I2 = 68%). In a subgroup analysis, GnRH agonists demonstrated positive association with AKI risk (OR 1.49; 95% CI 1.02-2.17; p = 0.038; I2 83.1%). In contrast, orchiectomy was not associated with AKI (OR 1.1; 95% CI 0.85-1.42; p = 0.488; I2 = 0%). GnRH agonist ADT, compared to other ADT modalities, demonstrated negative association with AKI (OR 0.77; 95% CI 0.61-0.98; p = 0.035; I2 = 0%). The analysis of orchiectomy against GnRH agonist therapy suggests lower AKI rate in orchiectomized patients (OR 0.77; 95% CI 0.66-0.91; p = 0.001; I2 = 0%).</p><p><strong>Conclusion: </strong>ADT was associated with higher odds of AKI among patients with prostate cancer. The association was particularly evident among patients receiving GnRH agonist-based therapy. However, the findings should be interpreted in light of the observational nature of the available evidence and the methodological limitations related to the synthesis of effect estimates reported using different statistical approaches.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crossing the toxicity threshold: a repeated landmark analysis of early toxicities and treatment modification during first-line CDK4/6 inhibitor therapy.","authors":"Tuğba Önder, Öztürk Ateş, Mehmet Emin Yılmaz, Ayşe Ocak Duran","doi":"10.1007/s00280-026-04960-3","DOIUrl":"https://doi.org/10.1007/s00280-026-04960-3","url":null,"abstract":"<p><strong>Background: </strong>Whether early treatment-related toxicities during cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy reflect treatment activity or simply longer treatment exposure remains unclear. Previous studies have largely evaluated toxicities cumulatively, potentially introducing immortal time bias into toxicity-outcome associations. We evaluated the prognostic significance of early toxicities and treatment modifications using repeated landmark analyses in patients receiving first-line CDK4/6i therapy for HR+/HER2- metastatic breast cancer.</p><p><strong>Methods: </strong>This retrospective study included 404 patients receiving first-line CDK4/6i plus endocrine therapy. Repeated landmark analyses at 8, 12, and 24 weeks evaluated associations of early toxicities and treatment modifications with subsequent progression-free survival (PFS) and overall survival (OS).</p><p><strong>Results: </strong>During treatment, any-grade neutropenia occurred in 88.1% of patients, hepatotoxicity in 22.5%, QTc prolongation in 17.6%, and dose modification in 37.4%. At both the 8- and 12-week landmarks, grade 1-2 neutropenia was consistently associated with improved PFS and OS in multivariable analyses (all p<0.05; 8-week PFS: 33.2 vs. 22.1 months; OS: 90.6 vs. 40.8 months). Grade 3-4 neutropenia showed less consistent associations with survival but remained associated with improved OS at 12 weeks. Dose modification was independently associated with shorter PFS at the 12- and 24-week landmarks (all p<0.05). Associations between neutropenia and survival were attenuated at the 24-week landmark.</p><p><strong>Conclusion: </strong>Grade 1-2 neutropenia was the most consistent toxicity-based predictor of favorable survival and may represent a potential clinical marker of treatment activity. Associations with grade 3-4 neutropenia were less consistent. Dose modification was associated with shorter PFS, whereas hepatotoxicity and QTc prolongation showed no consistent independent prognostic associations.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic analysis of pirtobrutinib, a non-covalent BTK inhibitor, in patients with hematological malignancies from the Phase 1/2 BRUIN study.","authors":"Robert Bell, Lisa M O'Brien, Eunice Yuen, Dan Liu, Sonya C Chapman","doi":"10.1007/s00280-026-04951-4","DOIUrl":"10.1007/s00280-026-04951-4","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to characterize the pharmacokinetics (PK) of pirtobrutinib, a highly selective and noncovalent Bruton's tyrosine kinase (BTK) inhibitor, in adult patients with hematological malignancies using data from the Phase 1/2 BRUIN study (NCT03740529).</p><p><strong>Methods: </strong>Pirtobrutinib was administered as monotherapy at doses ranging from 25 to 300 mg once daily (QD). PK samples were collected at multiple time points, including intensive sampling on Cycle (C) 1 Day (D) 1, C1D8, C2D1, and C4D1 for Phase 1 dose-escalation, and sparse sampling on C1D8 and C4D1 for Phase 1 dose-expansion and Phase 2. Population PK (popPK) analysis used nonlinear mixed-effects modeling.</p><p><strong>Results: </strong>Overall, 4487 evaluable pirtobrutinib concentrations obtained from 595 patients were included in the popPK analysis. Pirtobrutinib PK was well characterized by a 2-compartment model with linear clearance and 4-transit compartments for absorption. The mean elimination half-life was estimated to be 18.8 h. At the recommended Phase 2 dose (200 mg QD), the steady-state mean maximum drug concentration was 6460ng/mL, the mean minimum was 2260ng/mL, and the mean area under the concentration-time curve was 91300ng*h/mL. Pirtobrutinib disposition was significantly affected by body weight, renal function, and serum albumin, but not by formulation, cancer type, age, sex, race, ethnicity, or mild hepatic impairment.</p><p><strong>Conclusion: </strong>With the proposed starting dose of 200 mg QD, most patients (96%) were expected to exceed 90% BTK inhibition, across the entire dosing interval, indicating extensive and durable engagement of the drug target. No dose adjustments based on body weight, serum albumin or renal function were recommended.</p><p><strong>Clinical trial registration: </strong>NCT03740529.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Evaluation of QTc interval prolongation in patients with advanced clear cell renal cell carcinoma treated with first line sunitinib.","authors":"Agata Sałek-Zań, Mirosława Püsküllüoğlu, Agnieszka Stąpór, Justyna Jaworska, Agnieszka Pietruszka, Aleksandra Grela-Wojewoda, Maciej Stąpór, Tomasz Banaś","doi":"10.1007/s00280-026-04945-2","DOIUrl":"10.1007/s00280-026-04945-2","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas.","authors":"Leire Balaguer-Lluna, Clàudia Resa-Parés, Lucas Brstilo, Alberto Gómez-Caballero, Mercè Baulenas-Farrés, Jacqueline Mohr, Yutian Hu, Rosario Aschero, Ana Rodríguez, Gaia Botteri, Eva Rodríguez, Lydia Li-Chen, Raúl Mañogil, Federica Marino, Nuria Martínez-Velasco, Alex Ruano, Ángela García-Pelayo, Auriane Giron, Jaume Mora, Cinzia Lavarino, Macarena Sánchez-Navarro, Meritxell Teixidó, Aida Ormazabal, Rafael Artuch, Nora Unceta, Paula Schaiquevich, Angel M Carcaboso","doi":"10.1007/s00280-026-04950-5","DOIUrl":"10.1007/s00280-026-04950-5","url":null,"abstract":"<p><strong>Purpose: </strong>Pediatric-type diffuse high-grade gliomas (pHGG) are aggressive, largely incurable malignancies often characterized by PI3K/AKT pathway activation. This study investigated whether the PI3K inhibitor inavolisib and the AKT inhibitor ipatasertib could achieve therapeutic concentrations in the central nervous system (CNS) and demonstrate efficacy against PIK3CA-mutated pHGG.</p><p><strong>Methods: </strong>A panel of 12 pHGG cell lines with diverse PI3K/AKT genetic aberrations was screened for sensitivity to inavolisib and ipatasertib. Pharmacokinetic (PK) modeling was performed in mice to determine brain-to-plasma exposure ratios following oral administration (50 mg/kg inavolisib and 100 mg/kg ipatasertib). Finally, the in vivo efficacy of both inhibitors was evaluated using intracranial PIK3CA-mutated pHGG xenograft models, with survival and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) levels as primary endpoints.</p><p><strong>Results: </strong>All 12 cell lines exhibited PI3K/AKT alterations. The PIK3CA H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC₅₀ = 0.016 µM for inavolisib; 0.52 µM for ipatasertib). PK modeling revealed geometric mean brain-to-plasma ratios of 0.07 for inavolisib and 0.20 for ipatasertib, with model-predicted maximum brain concentrations of 0.69 µM and 0.93 µM, respectively. In vivo, inavolisib significantly extended survival (P = 0.0070) and increased CSF ctDNA release (P = 0.0317). In contrast, ipatasertib did not demonstrate significant in vivo activity.</p><p><strong>Conclusion: </strong>These findings highlight the therapeutic potential of inavolisib for treating PIK3CA-mutated pHGG. Despite the blood-brain barrier, inavolisib achieved sufficient CNS exposure to prolong survival in preclinical models, whereas ipatasertib efficacy did not translate from in vitro to in vivo settings.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ALDH2 with Alda-1 to reverse cisplatin resistance in lung adenocarcinoma.","authors":"Meidong Zhou, Fengjuan Tang, Zhiling Qu, Nan Luo, Sailong Ma, Xizhen Xu","doi":"10.1007/s00280-026-04954-1","DOIUrl":"https://doi.org/10.1007/s00280-026-04954-1","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin resistance remains a major obstacle in lung adenocarcinoma (LUAD) treatment. The role of Aldehyde dehydrogenase 2 (ALDH2), a detoxifying enzyme, in LUAD prognosis and chemoresistance is poorly understood.</p><p><strong>Methods: </strong>We analyzed ALDH2's prognostic value using clinical cohorts, TCGA, and proteomic data. Cisplatin-resistant cell lines and xenograft models were used to assess the effect of the ALDH2 agonist Alda-1. Molecular mechanisms were investigated via gain/loss-of-function studies.</p><p><strong>Results: </strong>High ALDH2 expression was significantly associated with improved survival in univariate analysis and correlated with a favorable genomic instability profile in LUAD. Pharmacological activation of ALDH2 with Alda-1 restored cisplatin sensitivity in resistant cells and potently enhanced cisplatin's efficacy in vivo. Mechanistically, ALDH2 activation upregulated PKC-ζ, leading to downregulation of the drug efflux pump MDR1. Proteomic analysis further linked low ALDH2 expression to a pro-chemoresistance signature.</p><p><strong>Conclusion: </strong>ALDH2 represents a potential prognostic biomarker associated with favorable outcomes in LUAD, particularly in patients receiving chemotherapy. Its activation via Alda-1 overcomes cisplatin resistance by targeting the PKC-ζ/MDR1 axis, presenting a novel therapeutic strategy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Main pulmonary artery enlargement during bevacizumab therapy in KRAS-mutant metastatic colon cancer.","authors":"Mehmet Fatih Ozbay, Fikret Atlım, Sertac Vurgun, Mehmet Hunur, Ayse Keven, Eren Sahin, Sema Sezgin Göksu, Mustafa Karaca","doi":"10.1007/s00280-026-04953-2","DOIUrl":"https://doi.org/10.1007/s00280-026-04953-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a cornerstone of metastatic colorectal cancer treatment. While systemic hypertension is a recognized complication of VEGF pathway inhibition, the effects of bevacizumab on the pulmonary vasculature remain poorly characterized, and the only longitudinal CT data to date derive from hepatocellular carcinoma patients receiving atezolizumab plus bevacizumab. In this exploratory study, we investigated whether serial thoracic computed tomography (CT) demonstrates progressive enlargement of the main pulmonary artery (mPA) during bevacizumab-based chemotherapy in colon cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this retrospective single-center study, 150 patients with KRAS-mutant colon cancer treated with bevacizumab between 2017 and 2025 were screened. Patients with a minimum of 3 months of bevacizumab exposure and at least two follow-up thoracic CT scans were included. The mPA diameter, ascending aorta (AAo) diameter, and mPA/AAo ratio were measured at baseline (T0) and at approximately 3 (T1), 6 (T2), and 9 (T3) months. The primary analysis employed a linear mixed-effects model (LMM) with a patient-level random intercept. Adjusted models, paired secondary analyses, and exploratory overall survival (OS) analyses were also performed. All analyses were conducted in R.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Seventy-four patients met inclusion criteria (median age 62.8 years; 71.6% male). The mPA increased significantly from 23.7 ± 3.3 mm at T0 to 25.9 ± 3.3 mm at T3. In the unadjusted LMM, the mPA increased by + 0.94 mm at T1 (p &lt; 0.001), + 1.45 mm at T2 (p &lt; 0.001), and + 2.22 mm at T3 (p &lt; 0.001) relative to baseline. The linear trend estimate was + 0.72 mm per 3-month interval (95% CI: 0.61-0.83; p &lt; 0.001). Time effects remained significant after covariate adjustment. The mPA/AAo ratio also increased over time (p &lt; 0.001 at all timepoints). No cases of probable pulmonary hypertension (mPA ≥ 33 mm) were identified at any assessment. Exploratory Cox regression showed no significant association between early mPA change and OS (HR 0.92; 95% CI: 0.70-1.19; p = 0.508). Progression-free survival could not be analyzed because the dataset lacked a progression variable. Sensitivity analyses consistently confirmed the robustness of the longitudinal mPA increase.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Serial thoracic CT imaging demonstrated a statistically significant but small, progressive increase in mPA diameter during bevacizumab-based chemotherapy in this selected cohort. The change remained within the normal range, no patient crossed the threshold for probable pulmonary hypertension, and no association with OS was observed. In the absence of a non-bevacizumab comparator and of hemodynamic correlation, these changes cannot be attributed to bevacizumab; whether they carry clinical significance requires prospective validation with hemodynamic and echocar","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}