Immunological Checkpoint Blockade in Anal Squamous Cell Carcinoma: Dramatic Responses Tempered By Frequent Resistance.

PURPOSE OF REVIEW: Squamous cell carcinoma of the anus (SCCA) is an HPV-associated malignancy that has limited treatment options. Immunotherapy has expanded these options and here we review current and emerging immunotherapeutic approaches. RECENT FINDINGS: Multiple studies of single-agent anti-PD1/PD-L1 immunotherapy have demonstrated a modest response rate of approximately 10% to 15%. While a minority of patients (~5%) with SCCA experience durable complete responses, most advanced SCCAs are resistant to anti-PD1/PD-L1 monotherapy. Given the need for more broadly effective immunotherapies, novel strategies, such as adaptive cell therapies and therapeutic vaccination, are being explored. To reduce the recurrence risk of localized high-risk SCCA, strategies combining immunotherapy with chemoradiation are also being investigated. While a small subset of patients with SCCA have prolonged responses to PD1-directed immunotherapy, the majority do not derive clinical benefit, and new immunotherapeutic strategies are needed. Better understanding of the immune microenvironment and predictive biomarkers could accelerate therapeutic advances.

Outcomes of Fecal Microbiota Transplantation for C. difficile Infection in Inflammatory Bowel Disease : A Systematic Review and Meta-analysis.

BACKGROUND: Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridioides difficile infection (CDI). Data on FMT for CDI in patients with underlying inflammatory bowel disease (IBD) are emerging but conflicting. We performed a systematic review and meta-analysis to describe the efficacy and safety of FMT for CDI in IBD and its impact on IBD outcomes. METHODS: A systematic search of multiple databases including Embase, Scopus, and Web of Science was performed. Our primary analysis focused on pooled rate of CDI resolution after single and multiple FMTs in IBD patients. Additional analyses included rates of IBD-associated outcomes (flare, surgery, symptom improvement) after FMT. The random-effects model was used to calculate pooled rates. RESULTS: Among 457 adult patients, 363 had CDI resolution after first FMT with a pooled cure rate of 78% [95% confidence interval (CI): 73%-83%; I2 =39%]. Overall pooled rate cure rate with single and multiple FMTs was 88% (95% CI: 81%-94%; I2 =73%). The pooled rate of an IBD flare after FMT was 26.8% (95% CI: 22.5%-31.6%; I2 =9%) and of colectomy was 7.3% (95% CI: 4.7%-10.5%; I2 =56%). Among 141 pediatric patients, 106 had CDI resolution after first FMT with pooled cure rate of 78% (95% CI: 58%-93%; I2 =59%). Overall pooled cure rate with single and multiple FMTs was 77% (95% CI: 50%-96%; I2 =63%). The pooled rate of an IBD flare after FMT was 10.8% (95% CI: 5.7%-18.5% I2 =43%), and of colectomy was 10.3% (95% CI: 2.1%-30.2% I2 =23%). CONCLUSIONS: FMT appears to be a highly effective therapy for preventing recurrent CDI in patients with IBD. Patients who fail a single FMT may benefit from multiple FMTs.

Gut Microbiome-Colorectal Cancer Relationship.

Traditionally, the role of gut dysbiosis was thought to be limited to pathologies like Clostridioides difficile infection, but studies have shown its role in other intestinal and extraintestinal pathologies. Similarly, recent studies have surfaced showing the strong potential role of the gut microbiome in colorectal cancer, which was traditionally attributed mainly to sporadic or germline mutations. Given that it is the third most common cancer and the second most common cause of cancer-related mortality, 78 grants totaling more than USD 28 million have been granted to improve colon cancer management since 2019. Concerted efforts by several of these studies have identified specific bacterial consortia inducing a proinflammatory environment and promoting genotoxin production, causing the induction or progression of colorectal cancer. In addition, changes in the gut microbiome have also been shown to alter the response to cancer chemotherapy and immunotherapy, thus changing cancer prognosis. Certain bacteria have been identified as biomarkers to predict the efficacy of antineoplastic medications. Given these discoveries, efforts have been made to alter the gut microbiome to promote a favorable diversity to improve cancer progression and the response to therapy. In this review, we expand on the gut microbiome, its association with colorectal cancer, and antineoplastic medications. We also discuss the evolving paradigm of fecal microbiota transplantation in the context of colorectal cancer management.

Safety of fecal microbiota transplantation for Clostridioides difficile infection focusing on pathobionts and SARS-CoV-2.

Clostridioides difficile infection (CDI) is a consequence of flagrant use of antibiotics, an aging population with increasing comorbidities, and increased hospitalizations. The treatment of choice for CDI is antibiotics (vancomycin or fidaxomicin), with a possibility of recurrent CDI despite lack of additional risk factors for CDI. For the last 10 years, fecal microbiota transplantation (FMT) has emerged as a promising therapy for recurrent CDI, with success rates of over 85% compared with less than 50% with antibiotics for multiple recurrent CDI. Along with the success of FMT, several adverse and serious adverse events with FMT have been reported. These range from self-limiting abdominal pain to death due to severe sepsis. This review focuses on the safety of FMT, emphasizing the reports of transmission of pathobionts like extended-spectrum beta lactamase Escherichia coli and Shiga toxin-producing E. coli. The severe acute respiratory syndrome coronavirus-2 is a potential pathogen that could be transmitted via FMT during the COVID-19 pandemic. The challenges faced by clinicians for donor screening, clinical trials, and other aspects of FMT during the pandemic are discussed.

The interplay of Clostridioides difficile infection and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease of the intestinal tract that commonly presents with diarrhea. Clostridioides difficile infection (CDI) is one of the most common complications associated with IBD that lead to flare-ups of underlying IBD. The pathophysiology of CDI includes perturbations of the gut microbiota, which makes IBD a risk factor due to the gut microbial alterations that occur in IBD, predisposing patients CDI even in the absence of antibiotics. Superimposed CDI not only worsens IBD symptoms but also leads to adverse outcomes, including treatment failure and an increased risk of hospitalization, surgery, and mortality. Due to the overlapping symptoms and concerns with false-positive molecular tests for CDI, diagnosing CDI in patients with IBD remains a clinical challenge. It is crucial to have a high index of suspicion for CDI in patients who seem to be experiencing an exacerbation of IBD symptoms. Vancomycin and fidaxomicin are the first-line treatments for the management of CDI in IBD. Microbiota restoration therapies effectively prevent recurrent CDI in IBD patients. Immunosuppression for IBD in IBD patients with CDI should be managed individually, based on a thorough clinical assessment and after weighing the pros and cons of escalation of therapy. This review summarizes the epidemiology, pathophysiology, the diagnosis of CDI in IBD, and outlines the principles of management of both CDI and IBD in IBD patients with CDI.

Kinetics of polymerase chain reaction positivity in patients with Clostridioides difficile infection.

BACKGROUND: Polymerase chain reaction (PCR) is a sensitive test for diagnosing Clostridioides difficile infection (CDI) and could remain positive following resolution of CDI. The kinetics of PCR positivity following antibiotics for CDI is unknown. We studied this and whether it predicted CDI recurrence. METHODS: Adults with CDI from October 2009 to May 2017 were included. Serial stool samples within 60 days of treatment were collected. Recurrent CDI was defined as diarrhea after interim symptom resolution with positive stool PCR within 56 or 90 days of treatment completion. Contingency table analysis was used to assess the risk of recurrence. RESULTS: Fifty patients were included [median age: 51 (range = 20-86) years, 66% women]. Treatment given was metronidazole, 50% (25); vancomycin, 44% (22); both, 4% (2); and fidaxomicin, 2% (1). Median duration of treatment for all 50 patients was 14 (range = 8-60) days. The median duration of treatment in patients who got prolonged therapy (>14 days) (n = 10) was 47 (range = 18-60) days. Median time to negative PCR was 9 (95% CI, 7-14) days from treatment initiation, which did not differ by antibiotics given (p = 0.5). A positive PCR during or after treatment was associated with a higher risk of recurrence at 56 days (p = 0.02) and at 90 days (p = 0.009). CONCLUSION: The median time to negative PCR in CDI was 9 days from treatment initiation. The PCR positivity during or after treatment may be useful for recurrence prediction; larger studies are needed to validate these results.