Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in β2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

Immunotherapy with PD-1 blockade has achieved a great success in colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR), and has become the first-line therapy in metastatic setting. Studies of neoadjuvant immunotherapy also report exciting results, showing high rates of clinical complete response (cCR) and pathological complete response. The high efficacy and long duration of response of immunotherapy has prompt attempts to adopt watch-and-wait strategy for patients achieving cCR following the treatment. Thankfully, the watch-and-wait approach has been proposed for nearly 20 years for patients undergoing chemoradiotherapy and has gained ground among patients as well as clinicians. In this narrative review, we combed through the available information on immunotherapy for CRC and on the watch-and-wait strategy in chemoradiotherapy, and looked forward to a future where neoadjuvant immunotherapy as a curative therapy would play a big part in the treatment of MSI-H/dMMR CRC.

An 86-year-old woman with a subcutaneous nodule in her left axilla visited our hospital. She had no gastrointestinal symptoms, but contrast-enhanced computed tomography revealed a cecal mass and systemic metastasis, including cutaneous, bone, peritoneal dissemination and ascites. Colonoscopy revealed a circumferential, elevated cecal lesion. She underwent right hemicolectomy to prevent colon obstruction. The pathological diagnosis was poorly differentiated adenocarcinoma (por1>tub2>muc) arising from the appendix with a BRAFV600E mutation and microsatellite instability-high. Chemotherapy was administered, and she is currently still alive and undergoing chemotherapy. We describe a rare case of advanced appendiceal cancer without gastrointestinal symptoms diagnosed due to cutaneous metastasis.

Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.

Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

Perioperative chemotherapy is standard treatment for patients with early high-risk gastroesophageal adenocarcinoma independent of molecular subtype. Approximately 8% of gastroesophageal cancers have a microsatellite instable phenotype (MSI-H), and retrospective analyses of neoadjuvant/adjuvant chemotherapy trials suggests no survival benefit in this patient population compared with surgery alone. Patients with advanced MSI-H malignancies obtain durable responses with immunotherapy using anti-programmed cell death protein 1 (PD-1) checkpoint blockade. We describe a case of a patient with an early MSI-H gastroesophageal adenocarcinoma who progressed on neoadjuvant chemotherapy precluding subsequent surgical resection. The patient was subsequently treated with immunotherapy using the anti-PD-1 antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab leading to a complete remission with biopsies of the residual tumor mass and regional lymph nodes revealing no residual tumor. This case highlights the lack of benefit from neoadjuvant chemotherapy in patients with MSI-H gastroesophageal cancers and suggests that perioperative anti-PD-1-based immunotherapy should be further investigated in this patient population. KEY POINTS: This report describes the successful salvage treatment of a patient with an early high-risk MSI-H gastroesophageal carcinoma who progressed through neoadjuvant chemotherapy using combination immunotherapy of the anti-programmed cell death protein 1 (PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab, leading to an ongoing complete remission. The case is in keeping with retrospective analyses of perioperative treatment trials demonstrating a lack of chemotherapy benefit in patients with MSI-H gastroesophageal carcinoma and supports the further investigation of anti-PD-1-based immunotherapy as a treatment modality in this patient population. The case highlights the potential difficulties that may be encountered in the surgical management of patients treated with neoadjuvant immunotherapy with reactive dense fibrotic changes precluding surgical resection.

Metastatic colorectal cancer with BRAF mutation is a type of highly invasive malignant tumor with poor prognosis and few treatment options. Here, we report a case of a BRAF-mutant and DNA mismatch-repair deficiency colorectal cancer patient with postoperative recurrence as well as abdominal cavity and pelvic metastasis, whose condition was relieved continuously after treatment with a new anti-PD-1 antibody, BGB-A317.

Deficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). The impact of MSI on survival in metastatic colorectal cancer (mCRC) is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era.
A total of 75 MSI-high (MSI-H) mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous/synchronous) microsatellite-stable (MSS) mCRC pts were identified from 1,268 mCRC pts who had MSI/mismatch repair test results at Mayo Clinic Rochester between January 1992 and July 2016. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazards models.
The MSS group was well matched to the MSI-H group based on age, gender, location, and chronicity of metastatic disease. MSI-H mCRC pts had earlier disease recurrence (median time from initial diagnosis to metastatic disease diagnosis, MSI-H group 12.9 vs. MSS group 20.9 months, p = .034). Median overall survival (OS) was 28.1 and 37.4 months for MSI-H and MSS pts, respectively (p = .99). In total, 94.7% of MSI-H pts and 98.7% of MSS pts had fluoropyrimidine-based chemotherapy for metastatic disease, and there was no difference in OS between these two groups (32.3 vs. 37.4 months, p = .91). Forty-three MSI-H and thirty-nine MSS pts had metastasectomy and/or ablation of metastases (p = .51) with longer median OS compared with pts without metastasectomy (MSI-H: 82.0 vs. 13.9, p < .001; MSS: 69.9 vs. 19.7, p < .001). Age <65 years, BRAF wild type, and metastasectomy were associated with better OS in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis (p < .001).
In mCRC, patients with MSI-H tumors have similar, but numerically shorter, median overall survival compared with those with MSS tumors. In both groups, metastasectomy and ablation of metastatic disease should be considered to optimize OS.
This study clearly demonstrated the survival benefits that aggressive metastasectomy provides in selected microsatellite instability-high metastatic colorectal cancer patients. This could be meaningful practice-changing information that has been long awaited.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor\'s invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

Endometrial dedifferentiated carcinoma consists of a combination of undifferentiated and differentiated carcinomas. To date, clear cell carcinoma components in endometrial dedifferentiated carcinoma have not been reported. We report the first case of endometrial dedifferentiated carcinoma with clear cell carcinoma in a 58-year-old woman. The uterine corpus was completely replaced and enlarged by a heterogeneous mass. The endometrial cut surface showed a yellowish papillary growing mass involving endometrium and deeper myometrium. Microscopically, the three components (endometrioid carcinoma, FIGO grade 1, clear cell carcinoma and undifferentiated carcinoma) were noted with differentiated carcinoma components lining the endometrial cavity, while undifferentiated carcinoma components were identified in deeper endometrium and myometrium. Our histologic diagnosis was supported by the pattern of immunoreactivity. Tumor cells showed loss of expression of MLH1/PMS2 protein and displayed high microsatellite-instability in all three components. Furthermore, all three components including clear cell carcinoma had loss of PTEN and ARID1A expression. Our observations suggest that the three components derived from a monoclonal origin, as the three components had in common specific genetic alterations.