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Abstract Immune checkpoint inhibitor (ICI) therapy is often associated with cutaneous immune‐related adverse events (irAEs). Drug eruptions stemming from concomitantly or consecutively administered medications are also frequent and tend to be severe. We herein present three cases of severe drug eruption in patients receiving antibiotics during ICI therapy in which hypotensive shock occurring during antibiotic administration was followed by generalized erythema and prolonged organ damage. Three patients received tazobactam/piperacillin (TAZ/PIPC) for an infection during ICI treatment. A high fever developed in all the patients after a switch was made to other antibiotics (Figures 2–4). Since no skin rash was observed at fever onset, a flare‐up of the infection was suspected, and TAZ/PIPC administration was resumed. Thereafter, the patients suddenly experienced hypotensive shock and respiratory failure requiring ICU management for generalized erythema and organ damage. Since anaphylaxis caused by TAZ/PIPC is rare, the patients’ clinical findings might be a manifestation of synergistic, complementary, immunomodulatory effects of ICI. In patients receiving ICI therapy, a fever occurring during antibiotic administration may indicate the onset of an immune hypersensitivity reaction to the drug. Resumption of antibiotic administration, especially TAZ/PIPC, during such a period may trigger an excessive inflammatory response, leading to an anaphylaxis‐like reaction and organ damage.

Abstract Background Circulating tumor DNA (ctDNA) is a biomarker with potential to reflect comprehensive genomic information and overcome intratumor heterogeneity. In contrast, carcinoembryonic antigen (CEA) is a conventional tumor marker for predicting recurrence, survival, and chemotherapeutic efficacy in patients with metastatic colorectal cancer (mCRC). However, the relationship between them remains unclear. Here, the relationship between plasma ctDNA and CEA levels was evaluated to clarify the advantages and disadvantages of their clinical use. Methods A total of 110 patients with mCRC underwent chemotherapy were enrolled. Amplicon‐based plasma genomic profiling of 14 genes that are commonly mutated in CRC by next‐generation sequencing was compared to the CEA level and tumor diameter using Spearman’s correlation coefficient. Results The overall concordance rate between the ctDNA and CEA levels was 75.5% (83/110). The correlation coefficient between the ctDNA and CEA levels was lower in the group of patients without liver and lymph node metastases (r = 0.18, p = 0.44) than in the group of patients with liver metastasis (r = 0.48, p

Abstract Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, a polymerase chain reaction (PCR)-based method, was the first tumor-agnostic companion diagnostic to detect MSI status in MSI-H solid tumors. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available; however, its real-world concordance with PCR-based testing of MSI-H/dMMR remains to be investigated. The co-primary end points included the positive and negative predictive values of MSI-H/dMMR. A retrospective analysis of 80 patients who had undergone both MSI testing and NGS between July 2015 and March 2021 was conducted. Five patients were confirmed to have MSI-H in both examinations. Among the 75 patients diagnosed as microsatellite stable (MSS) by PCR-based testing, one with pancreatic cancer was diagnosed as having MSI-H after NGS. One patient with pancreatic cancer was diagnosed as having MSS in both tests was found to have a mutation in MLH1 by NGS, which was confirmed as dMMR by IHC staining. NGS had positive and negative predictive values of 100% (5/5) and 98.7% (74/75), respectively, for MSI-H. The concordance between NGS and PCR-based testing was 98.8% (79/80). Thus, NGS can be useful for evaluating MSI/MMR status in clinical practice and can be an important alternative method for detecting MSI-H/dMMR in the future.

Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a “game changer,” the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.

Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis. Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract. Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis (p = 0.0455). No adverse events related to CCE-2 were observed. Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.

Purpose: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. Materials and Methods: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2- positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). Results: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. Conclusions: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients. [ABSTRACT FROM AUTHOR]