Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial)

Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by <8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (>12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507

COVID-19 atypical Parsonage-Turner syndrome: a case report

Background Neurological manifestations of Sars-CoV-2 infection have been described since March 2020 and include both central and peripheral nervous system manifestations. Neurological symptoms, such as headache or persistent loss of smell and taste, have also been documented in COVID-19 long-haulers. Moreover, long lasting fatigue, mild cognitive impairment and sleep disorders appear to be frequent long term neurological manifestations after hospitalization due to COVID-19. Less is known in relation to peripheral nerve injury related to Sars-CoV-2 infection. Case presentation We report the case of a 47-year-old female presenting with a unilateral chest pain radiating to the left arm lasting for more than two months after recovery from Sars-CoV-2 infection. After referral to our post-acute outpatient service for COVID-19 long haulers, she was diagnosed with a unilateral, atypical, pure sensory brachial plexus neuritis potentially related to COVID-19, which occurred during the acute phase of a mild Sars-CoV-2 infection and persisted for months after resolution of the infection. Conclusions We presented a case of atypical Parsonage-Turner syndrome potentially triggered by Sars-CoV-2 infection, with symptoms and repercussion lasting after viral clearance. A direct involvement of the virus remains uncertain, and the physiopathology is unclear. The treatment of COVID-19 and its long-term consequences represents a relatively new challenge for clinicians and health care providers. A multidisciplinary approach to following-up COVID-19 survivors is strongly advised

Role of gut microbiome on immunotherapy efficacy in melanoma

The gut microbiota is considered a key component in many aspects of cancer pathophysiology and response to therapy. In particular, in recent years intriguing evidences has been emerging regarding the role of the intestinal microbiota in the response to immunotherapy and in promoting the development of adverse events, such as colitis. For this reason, studies are being carried out both on pre-clinical models and on humans to study how to predict the response to immunotherapy through the study of the microbiota or how to improve its clinical response through modulation. Promising data have recently been reported through modulation by probiotics or prebiotics, and in particular by fecal microbiota transplantation. The aim of this review is to analyze the evidence regarding the role of the microbiota in immunotherapy with a particular focus on melanoma

Microbiota Composition in Diverticular Disease: Implications for Therapy

Gut microbiota (GM) composition and its imbalance are crucial in the pathogenesis of several diseases, mainly those affecting the gastrointestinal tract. Colon diverticulosis and its clinical manifestations (diverticular disease, DD) are among the most common digestive disorders in developed countries. In recent literature, the role of GM imbalance in the onset of the different manifestations within the clinical spectrum of DD has been highlighted. This narrative review aims to summarize and critically analyze the current knowledge on GM dysbiosis in diverticulosis and DD by comparing the available data with those found in inflammatory bowel disease (IBD). The rationale for using probiotics to rebalance dysbiosis in DD is also discussed

Role of gut microbiome on immunotherapy efficacy in melanoma

The gut microbiota is considered a key component in many aspects of cancer pathophysiology and response to therapy. In particular, in recent years intriguing evidences has been emerging regarding the role of the intestinal microbiota in the response to immunotherapy and in promoting the development of adverse events, such as colitis. For this reason, studies are being carried out both on pre-clinical models and on humans to study how to predict the response to immunotherapy through the study of the microbiota or how to improve its clinical response through modulation. Promising data have recently been reported through modulation by probiotics or prebiotics, and in particular by fecal microbiota transplantation. The aim of this review is to analyze the evidence regarding the role of the microbiota in immunotherapy with a particular focus on melanoma

From Regular Catharsis with Castor Oil to Recognizing the Importance of the Intestinal Microbiota

The need to shed light on the unknown aspects of pathophysiology of common disorders, such as gastrointestinal ones, has led researchers through last decades to study and define the role of microorganisms within the human intestine and their interactions with the host. The progress of technology has permitted the overcoming of culture-based methods to study microbes and paved the way to molecular techniques, which allow the analysis of microbial genome, microbial functions, and metabolism. These progresses opened a window on the world of microbiology and permitted to deepen into the key role played by gut microbiota and dysbiosis in health status and diseases, both gastrointestinal and extraintestinal. So, scientists focused their attention in developing new strategies to restore eubiosis and to manipulate gut microbes by modifying dietary habits, administrating antibiotics, probiotics, and prebiotics and using fecal microbiota transplantation as treatment of gastrointestinal, infectious, cardiovascular, metabolic, immune-mediated, neuro-psychiatric, and oncological disorders. The next challenges will be to elaborate standard protocols with definite outcomes predictors in disease-specific settings

Effect of a multistrain probiotic on leaky gut in patients with diarrhea-predominant irritable bowel syndrome (IBS-D): a pilot study

Background: A probiotic mixture prevented epithelial barrier impairment in various experimental models. The objective was to evaluate its effects in patients suffering from IBS-D with confirmed leaky gut. Methods: IBS D patients with increased intestinal permeability measured by radionuclide tracers were enrolled in this pilot, open-label, prospective, interventional, single-center, Phase IV study. Patients received two capsules of a multistrain probiotic a day for 30 days and were evaluated by repeated intestinal permeability test, the Bristol Stool Scale, and patient-perceived quality of life and satisfaction. Results: Of the 30 enrolled patients (mean age: 42.1 [SD: 13.1] years; female: 60%), 27 completed the study (Full Analysis Set [FAS]), 18 had no major protocol violation (Per Protocol Set [PPS]). On D30, an improvement of intestinal permeability was observed in 81.5% of patients in FAS, normalization being observed in 37% of the participants (44% in PPS). Mean intestinal permeability was significantly decreased: baseline minus D30, 3.4 (95%CI: 1.7, 5.2); IBS-QOL Total score was significantly increased: D30 minus baseline, 8.0 (95%CI: 3.0, 12.9); stool consistency was significantly improved. On D15 and D30, 96.3% of patients claimed that their IBS symptoms had been satisfactory alleviated, and a significant improvement was reported for the following VAS-IBS items: Abdominal pain, Diarrhea, Impact of gastrointestinal problems in daily life. Compliance and tolerance were satisfactory. Conclusion: The multistrain probiotic tested may reduce intestinal permeability in a considerable proportion of patients and may improve abdominal pain, stool consistency, and quality of life. These results pave the way for larger, placebo-controlled clinical studies

Ecology and Machine Learning-Based Classification Models of Gut Microbiota and Inflammatory Markers May Evaluate the Effects of Probiotic Supplementation in Patients Recently Recovered from COVID-19

Gut microbiota (GM) modulation can be investigated as possible solution to enhance recovery after COVID-19. An open-label, single-center, single-arm, pilot, interventional study was performed by enrolling twenty patients recently recovered from COVID-19 to investigate the role of a mixed probiotic, containing Lactobacilli, Bifidobacteria and Streptococcus thermophilus, on gastrointestinal symptoms, local and systemic inflammation, intestinal barrier integrity and GM profile. Gastrointestinal Symptom Rating Scale, cytokines, inflammatory, gut permeability, and integrity markers were evaluated before (T0) and after 8 weeks (T1) of probiotic supplementation. GM profiling was based on 16S-rRNA targeted-metagenomics and QIIME 2.0, LEfSe and PICRUSt computational algorithms. Multiple machine learning (ML) models were trained to classify GM at T0 and T1. A statistically significant reduction of IL-6 (p p p p value 1. GM global distribution and microbial biomarkers strictly reflected probiotic composition, with a general increase in Bifidobacteria at T1. Twelve unique KEGG orthologs were associated only to T0, including tetracycline resistance cassettes. ML classified the GM at T1 with 100% score at phylum level. Bifidobacteriaceae and Bifidobacterium spp. inversely correlated to reduction of citrulline and inflammatory cytokines. Probiotic supplementation during post-COVID-19 may trigger anti-inflammatory effects though Bifidobacteria and related-metabolism enhancement

Gut microbiota in anxiety and depression: Pathogenesis and therapeutics

Depression and anxiety disorders represent a burdensome clinical issue. Considering the unsatisfactory clinical response of some patients to antidepressant therapy, new personalized approaches are being studied. In recent years, pre-clinical and clinical studies have investigated the role of intestinal microbiota demonstrating the importance of the gut-brain axis in these diseases. Indeed, gut microbes are able to interact with the brain interfering with behavior through some mechanisms such as amino acid metabolism, short–chain fatty acids, vagus nerve, endocrine signaling and immune responses. Experiments of gut microbiota transfer from subjects with major depression to animal models corroborated the causative role of intestinal microbes in mood disorders and anxiety. Furthermore, the incidence of dysbiosis in patients with anxiety and depression suggests a potential role for gut microbiota modulators in the treatment of these disorders. In particular, several probiotics and synbiotics have been shown to be effective in improving clinical symptoms, promising results have emerged also from fecal microbiota transplantation, but the evidence is still limited. These promising results switch on the use of gut microbiota modulators as an adjunctive tool to antidepressant therapy. Developing pharmaceutical or nutraceutical strategies to modify the composition of gut microbiota may offer novel and personalized therapeutic tools against anxiety and depression

Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma

Tyrosine kinase inhibitors (TKIs) have improved the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), however TKI-related diarrhoea is a common and serious adverse effect. Here the authors show in a randomized clinical trial that faecal microbiota transplantation from healthy donors can improve TKI-induced diarrhoea in patients with mRCC