Clinical and Molecular Variables Associated With Early Progression to Checkpoint Inhibitors in MSI-High Metastatic Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND: About one third of patients with deficient mismatch repair/microsatellite instability-high metastatic colorectal cancer (dMMR/MSI-H mCRC) experience primary resistance or early progression on immune checkpoint inhibitors (ICI), while others benefit from exceptionally long-lasting responses. In this single-centre retrospective study, we aimed to identify variables associated with improved overall survival (OS) as well as early disease progression. METHODS: All dMMR/MSI-H mCRC patients treated with ICI between 2014 and 2022 were included. Baseline patient demographics, tumour characteristics as well response and outcome data were recorded. OS was estimated using the Kaplan-Meier method. Uni- and multivariate cox regression analysis was used to identify parameters associated with improved OS. Clinicopathological factors associated with early progression (≤ 12 months after treatment initiation) were assessed using uni- and multivariate logistic regression analysis. RESULTS: About 84 ICI-treated dMMR/MSI-H mCRC patients were included. Progressive disease occurred in 37 (44%) patients, but only in 11 (19%) patients with disease control at 12 months. Median OS was 80 months and improved outcome was associated with a lower neutrophile-to-lymphocyte ratio (NLR) (P = .004) and the presence of immune-related adverse events (irAEs) (P = .015). Early progression was associated with poor performance status (P = .036), a higher blood CRP level (P = .033) and absence of irAEs (P = .002). CONCLUSION: Disease progression in ICI-treated dMMR/MSI-H mCRC rarely occurs in patients experiencing disease control for at least 12 months. Performance status, presence of immune-related adverse events, CRP levels, CEA levels and NLR can be helpful to identify those patients that may benefit from ICI treatment, guiding clinicians in therapeutic decisions.

Fulminant ectopic Cushing's syndrome caused by metastatic small intestine neuroendocrine tumour - a case report and review of the literature.

Cushing's syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control.

A randomized controlled trial of hand/foot-cooling by hilotherapy to prevent oxaliplatin-related peripheral neuropathy in patients with malignancies of the digestive system.

BACKGROUND: Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin. PATIENTS AND METHODS: In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention. RESULTS: The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P = 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P = 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P = 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P = 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable. CONCLUSIONS: In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated.

Prevalence of microsatellite instable and Epstein-Barr Virus-driven gastroesophageal cancer in a large Belgian cohort.

Introduction: Patients with gastroesophageal adenocarcinoma (GEC) with microsatellite instability-high (MSI-H) or Epstein Barr Virus positivity (EBV+) might be good candidates for immunotherapy. Incidences of about 10% have been reported for both features, but are dependent on geographical region and disease stage. Aim: The aim is to study the prevalence of MSI-H and EBV+ in a Belgian single center cohort of patients with GEC. Methods: We retrospectively assessed the files of all patients with a newly diagnosed GEC between August, 1st 2018 and February, 29th 2020 at the University Hospitals Leuven, Belgium. Microsatellite instability (MSI) status was determined using immunohistochemistry (IHC) and polymerase chain reaction (PCR). EBV+ was assessed using in situ hybridization (ISH). A case report is provided to illustrate the importance of testing for MSI in GEC. Results: 247 gastroesophageal adenocarcinomas were included in this analysis. 62 (56% stage IV) of those were tested for EBV, but only 1 turned out to be EBV positive (1.6%). 116 patients (44.0% stage IV) were tested for MSI, of which 11 were MSI-H (9.5%). Half of the MSI-H tumors identified were at the gastroesophageal junction (GEJ). A patient with MSI-H metastatic GEC obtained a complete response with nivolumab, which persisted after discontinuation of treatment. Conclusion: While we confirm that about 10% of GECs are MSI-H, the incidence of EBV+ in our cohort (1.6%) is clearly lower than expected. Given the important prognostic and predictive implications, every gastroesophageal cancer should be tested for MSI.

Evaluating the accuracy of three international guidelines in identifying the risk of malignancy in pancreatic cysts: a retrospective analysis of a surgical treated population.

BACKGROUND AND STUDY AIMS: The international consensus Fukuoka guideline (Fukuoka ICG), The European evidence-based guideline on pancreatic cystic neoplasms (European EBG) and the American Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts (AGA IG) are 3 frequently cited guidelines for the risk stratification of neoplastic pancreatic cysts. The aim of this study was to assess the accuracy of detecting malignant cysts by strictly applying these guidelines retrospectively to a cohort of surgically resected pancreatic cysts. PATIENTS AND METHODS: 72 resected cysts were included in the analysis. Invasive carcinoma, high grade dysplasia and neuro-endocrine tumour were considered as "malignant cysts" for the purpose of the study. RESULTS: 32% of the resected cysts were malignant. The analysis showed that the Fukuoka ICG, European EBG and AGA IG had a sensitivity of 66,8%, 95,5%, 80%; a specificity of 26,8%, 11,3%, 43,8%; a positive predictive value of 31,8%, 35%, 47,1% and a negative predicted value of 61,1%, 83,3%, 77,8% respectively. The missed malignancy rate was respectively 11,3%, 1,5%, 7,7% and surgical overtreatment was respectively 48,4%, 59,1%, 34,6%. CONCLUSION: In this retrospective analysis, the European EBG had the lowest rate of missed malignancy at the expense of a high number of "unnecessary" resections. The Fukuoka ICG had the highest number of missed malignancy. The AGA IG showed the lowest rate of unnecessary surgery at the cost of a high number of missed malignancy. There is need to develop better biomarkers to predict the risk of malignancy.

Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

BACKGROUND: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). METHODS: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. RESULTS: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. CONCLUSIONS: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.