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BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., =2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as =10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.). [ABSTRACT FROM AUTHOR]

Background and aims: In gastric cancer (GC), HER2 was the first biomarker for guided therapy registered for clinical use. Considering the recent approvals of immune check‐point blockade (ICB) in gastro‐oesophageal cancers, testing for mismatch repair deficiency (dMMR), Epstein–Barr virus (EBV) and PD‐L1 combined positive score (CPS) is becoming increasingly important. Here we describe a real‐world cohort on biomarker assessment in GC patients. Methods: Patients diagnosed with GC between 2017 and 2021 were included. Biomarker results were retrieved from electronic patient files. PD‐L1 CPS was determined retrospectively on dMMR and EBV‐positive (EBV+) tumours. Data on genomic sequencing were analysed separately. Results: Of 363 patients identified, 45% had metastatic disease. In 335 patients (92%) at least one biomarker was tested. The prevalence of HER2+, dMMR and EBV+ tumours was 10% (32 of 319), 7% (20 of 294) and 1% (three of 235), respectively. Of the dMMR and EBV+ tumours, 95% had a PD‐L1 CPS ≥ 5. Therapeutic strategy was adjusted in 31 of 55 patients and consisted of anti‐HER2 therapies as well as ICB in clinical trials. Genomic alterations were found in 44 of 60 tested patients. TP53 (73%) and PIK3CA (20%) mutations were most common, followed by KRAS mutations (11%) and amplifications (11%). Conclusions: In this real‐world cohort, testing for HER2, dMMR and EBV status affected treatment decisions in 56% of the patients. Although most dMMR and EBV+ tumours had a PD‐L1 CPS ≥ 5, not all patients with a high probability of treatment response are identified. Based on these results, a stepwise diagnostic strategy is proposed. [ABSTRACT FROM AUTHOR]

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making. Leveraging the neoadjuvant treatment setting offers the ability to deeply interrogate longitudinal tissue in order to gain translatable, pan-malignancy insights into response and mechanisms of resistance to immunotherapy. Neoadjuvant immunotherapy across cancers was a focus of discussion at the virtual Immunotherapy Bridge meeting (December 1–2, 2021). Clinical, biomarker, and pathologic insights from prostate, breast, colon, and non-small-cell lung cancers, melanoma and non-melanoma skin cancers were discussed and are summarized in this report. [ABSTRACT FROM AUTHOR]

Aims: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. Methods and results: The prognostic significance of OAC‐associated CD3+, CD4+, CD8+, forkhead box protein 3 (FoxP3+) and programmed cell death ligand 1 (PD‐L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). Conclusion: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy. [ABSTRACT FROM AUTHOR]

Neoadjuvant treatment with immunotherapy using dostarlimab leads to impressive clinical responses and omission of surgery in patients with mismatch repair (MMR)-deficient rectal cancers, according to a study published in the New England Journal of Medicine. [ABSTRACT FROM AUTHOR]

Dishing out treatment recommendations: The number of treatment options for cancer patients keeps expanding, but it remains difficult to predict which tumors will be sensitive to which treatments. As a result, most patients receive treatment according to standardized protocols. With this approach, some patients respond to treatment, but others only experience side effects. To help address this situation, Ooft et al. developed a method of testing drugs in patient-derived organoids, biopsy-derived cells from individual patients grown in a dish. In a clinical study, the responses of organoids to irinotecan correlated with patients' responses to the drug, suggesting that organoids could help avoid giving irinotecan to patients who would not benefit. There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy. [ABSTRACT FROM AUTHOR]

Harnessing immune cells to target tumours is a growing trend. The results of a clinical trial combining such treatment with other standard therapies for gastric cancer have altered medical practice — and more changes are to come.Clinical trial results point to a new way to treat gastric cancer. [ABSTRACT FROM AUTHOR]

Because most patients with cancer do not benefit from immunotherapies such as anti-PD1, the identification of biomarkers to select patients for immunotherapy is crucial. The response rate to anti-PD1 in dMMR colorectal cancers was no less than 40%, and was even 70% in other GI and endometrial dMMR cancers, whereas it was 0% in MMR-proficient colorectal cancer.[1] Although not routinely tested, dMMR can be found in other cancer types outside GI and endometrial cancers, in a frequency of approximately 2% to 3%.[2] Breast cancer is an example of a tumor type in which dMMR is rare (frequency is 0% to 1%).[3] To our knowledge, this is the first report on response to checkpoint blockade in a dMMR tumor that is not typically associated with dMMR. [Extracted from the article]

Background: Catheter-related bloodstream infections (CRBSIs) can lead to increased morbidity and length of stay (LOS) in the intensive care unit (ICU). The purpose of this study was to analyse the incidence of catheter-related bloodstream infection associated with central venous catheters (CVCs) and arterial catheters (ACs) and to identify risk factors for CRBSIs in our ICU. Methods: This was a prospective observational study in a 17-bed medical-surgical ICU of a 715-bed university hospital. Patients admitted to the ICU for ≥ 24 h between 1 September 2007 and 30 April 2008, who received a CVC or AC, were included in the study. Results: A total of 219 patients with 258 CVCs and 336 ACs were included in the study and observed for a combined total of 3172 catheter-days. The CRBSI incidence density was 1.2 per 1000 catheter-days for CVCs and 2.1 per 1000 catheter-days for ACs. The mean LOS ( p = 0.003), the number of days a catheter remained in situ ( p = 0.001), and the length of pre-ICU in-hospital stay ( p = 0.031) were significantly higher in the CRBSI group. Risk factor analysis was not reliable due to the low number of CRBSIs. Conclusion: The incidence of AC- and CVC-related CRBSIs was comparable to the incidence reported in the literature. However, the incidence for ACs was higher than for CVCs. In addition to CVCs, ACs should be considered a possible cause of catheter-related infections and both should be replaced when CRBSI is suspected. [ABSTRACT FROM AUTHOR]