Understanding homologous recombination repair deficiency in biliary tract cancers: clinical implications and correlation with platinum sensitivity.

BACKGROUND: Biliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting. PATIENTS AND METHODS: We carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy. RESULTS: A total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35). CONCLUSIONS: Patients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors.

Lost gallstones during laparoscopic cholecystectomy as a common but underestimated complication-case report and review of the literature.

Introduction: Laparoscopic cholecystectomy (LC) represents one of the most commonly performed routine abdominal surgeries. Nevertheless, besides bile duct injury, problems caused by lost gallstones represent a heavily underestimated and underreported possible late complication after LC. Methods: Case report of a Clavien-Dindo IVb complication after supposedly straightforward LC and review of all published case reports on complications from lost gallstones from 2000-2022. Case Report: An 86-year-old patient developed a perihepatic abscess due to lost gallstones 6 months after LC. The patient had to undergo open surgery to successfully drain the abscess. Reactive pleural effusion needed additional drainage. Postoperative ICU stay was 13 days. The patient was finally discharged after 33 days on a geriatric remobilization ward and died 12 months later due to acute cardiac decompensation. Conclusion: Intraabdominal abscess formation due to spilled gallstones may present years after LC as a late complication. Surgical management in order to completely evacuate the abscess and remove all spilled gallstones may be required, which could be associated with high morbidity and mortality, especially in elderly patients. Regarding the overt underreporting of gallstone spillage in case of postoperative gallstone-related complications, focus need be put on precise reporting of even apparently innocuous complications during LC.

Bevacizumab mitigates codon-specific effects of trifluridine/tipiracil on efficacy outcome parameters in metastatic colorectal cancer.

BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.

Prognostic value of metastatic pattern in colorectal cancer: a multicenter retrospective analysis in a real-life cohort.

BACKGROUND: Metastatic patterns have been linked with prognosis in colorectal cancer. We aim to determine the distribution of metastases, their dynamics during disease and their prognostic impact for specific clinical treatment scenarios (resection of metastasis and/or systemic treatment, best supportive care). MATERIAL AND METHODS: 978 patients diagnosed with metastatic colorectal adenocarcinoma treated at three oncological centers from 2006 to 2018 were included. Overall survival was assessed depending on tumor load, distribution of metastases and treatment of the patients. RESULTS: Most patients had single site metastasis (n = 684; 69.9%): 398 patients had liver (n = 398; 40.7%) and 103 patients had lung only metastasis (10.6%). The number of organs involved in metastases at diagnosis was highly prognostic (HR 0.77; CI 0.65, 0.90), whereas the additional gain of metastases during progression of the disease was not. The majority of patients (62.9-74.2%) with initial lung, liver or both metastases retained their initial metastatic status. In the overall population, lung only metastases were associated with the most favorable outcome (HR 0.64; CI 0.50, 0.81). This was also observed in patients receiving best supportive care (HR 0.45; CI 0.27, 0.75). Resection of lung only metastases resulted in longer median survival (102.2 months). A relevant survival difference in patients treated by systemic therapy alone was not observed. Lung only metastasis was associated with rectal cancer (p < .001) and RAS-mutation (p = .01); both, lung and liver metastasis were associated with time from diagnosis to first metastasis (p < .001). CONCLUSION: The number of organs involved in metastasis at diagnosis but not the total cumulative number of involved organs is of prognostic relevance in colorectal adenocarcinoma. This prognostic relevant initial metastasis distribution remains unchanged in the majority of patients during the disease. However, the prognostic impact of the metastatic pattern is potentially altered by treatment modality.

Treatment of drug-induced agranulocytosis with recombinant granulocyte colony-stimulating factor (rh G-CSF).

Five patients with drug-induced agranulocytosis received 300 micrograms recombinant human granulocyte colony-stimulating factor (rh G-CSF) subcutaneously twice daily for 2-5 days. G-CSF therapy resulted in a steep increase of the neutrophil count, which was faster than that in patients with spontaneous recovery reported in the literature. In all four patients with infectious complications fever rapidly declined with the increase of granulocytes. G-CSF may be useful in the management of drug-induced agranulocytosis.