Just a gut feeling: Faecal microbiota transplant for treatment of depression - A mini-review.

BACKGROUND: The microbiota-gut-brain axis (MGBA) allows bidirectional crosstalk between the brain and gut microbiota (GM) and is believed to contribute to regulating mood/cognition/behaviour/metabolism/health and homeostasis. Manipulation of GM through faecal microbiota transplant (FMT) is a new, exciting and promising treatment for major depressive disorder (MDD). AIMS: This mini-review examines current research into GM and FMT as a therapy for depression. METHODS: Original research articles published in Medline/Cochrane Library/PubMed/EMBASE/PsycINFO databases/National Institute of Health website Clinicaltrials.gov/controlled-trials.com were searched. Full articles included in reference lists were evaluated. We summarise current data on GM and depression and discuss communication through the MGBA and the interaction of antidepressants and GM through this. We review compositions of dysbiosis in depressed cohorts, focusing on future directions in the treatment of MDD. RESULTS: Studies have demonstrated significant gut dysbiosis in depressed patients compared to healthy cohorts, with overgrowth of pro-inflammatory microbiota, reduction in anti-inflammatory species and reduced overall stability and taxonomic richness. FMT allows the introduction of healthy microbiota into the gastrointestinal tract, facilitating the restoration of eubiosis. CONCLUSION: The GM plays an integral role in human health and disease through its communication with the rest of the body via the MGBA. FMT may provide a means to transfer the healthy phenotype into the recipient and this concept in humans is attracting enormous attention as a prospective treatment for psychopathologies, such as MDD, in the future. It may be possible to manipulate the GM in a number of ways, but further research is needed to determine the exact likelihood and profiles involved in the development and amelioration of MDD in humans, as well as the long-term effects and potential risks of this procedure.

Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy.

Immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration (FDA) for patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin lymphoma. In the latest announcement, the FDA has granted accelerated approval to pembrolizumab for pediatric and adult patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient solid tumors. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than organ-based approach. MSI-H, either due to inherited germline mutations of mismatch repair genes or epigenetic inactivation of these genes, is found in a subset of colorectal and noncolorectal carcinomas. It is known that MSI-H causes a build up of somatic mutations in tumor cells and leads to a spectrum of molecular and biological changes including high tumor mutational burden, increased expression of neoantigens and abundant tumor-infiltrating lymphocytes. These changes have been linked to increased sensitivity to checkpoint inhibitor drugs. In this mini review, we provide an update on MSI-related solid tumors with special focus on the predictive role of MSI for checkpoint immunotherapy.

Intestinal and Extraintestinal Cancers Associated With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) with its 2 most common entities, ulcerative colitis and Crohn's disease, causes an increased risk of developing intestinal cancers. In fact, malignancies are the second most common cause of death after cardiovascular diseases in both sexes of patients with IBD. Risk factors for colorectal cancer in IBD correlate with the duration of the disease, extent of disease, the association with primary sclerosing cholangitis, family history, and early age at onset. Patients with IBD also have an increased risk for developing a variety of extraintestinal malignancies. In particular, lymphomas, mostly non-Hodgkin lymphomas and skin cancers, are more frequently observed in IBD patients. Longstanding inflammation and the degree of immunosuppression as a result of IBD treatment appear to be the main driving factors for IBD-related carcinogenesis. This review provides an update on the clinical and pathological features of IBD-related intestinal and extraintestinal malignancies.

Clinical and radiological diagnosis of gallstone ileus: a mini review.

Gallstone ileus is a rare cause of bowel obstruction, which mainly affects the elderly population. The associated mortality is estimated to be up to 30%. The presentation of gallstone ileus is notoriously non-specific, and this often contributes to the delay in diagnosis. The diagnosis of gallstone ileus relies on a radiological approach, and herein we discuss the benefits and drawbacks of the use of different modalities of radiological imaging: plain abdominal films, computed tomography, magnetic resonance imaging, and ultrasound scanning. Based on our case experience and review of the literature, the authors conclude that although an effective first-line tool, plain abdominal films are not adequate for diagnosing gallstone ileus. In fact, the gold standard in an acutely unwell patient is computed tomography.

Expending Role of Microsatellite Instability in Diagnosis and Treatment of Colorectal Cancers.

BACKGROUND: Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. METHODS: Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov . Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers. RESULTS: Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy. CONCLUSIONS: Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.

Magnetic Resonance Imaging (MRI) of Intratumoral Voxel Heterogeneity as a Potential Response Biomarker: Assessment in a HER2+ Esophageal Adenocarcinoma Xenograft Following Trastuzumab and/or Cisplatin Therapy.

We evaluated magnetic resonance imaging (MRI) voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19) as a potential response biomarker. OE19 xenografts treated with saline (controls), monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast), T2 relaxation time, T2* relaxation rate (R2*), and apparent diffusion coefficient obtained before (TIME0), after 24hours (TIME1), and after 2weeks of treatment (TIME2) were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim-to-center) were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX), angiogenesis (CD34), and proliferation (Ki-67). Combination therapy reduced xenograft growth rate (relative change, ∆ +0.58±0.43 versus controls, ∆ +4.1±1.0; P=0.008). More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P=0.009), T2 relaxation time (mean: 1.00 versus 0.92, P=0.006; median: 0.98 versus 0.91, P=0.006; 75th percentile: 1.02 versus 0.94, P=0.007), and R2* (10th percentile: 0.99 versus 1.26, P=0.003). We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.

Dedicated Barrett's surveillance sessions managed by trained endoscopists improve dysplasia detection rate.

Background and study aim Barrett's esophagus (BE)-associated dysplasia is an important marker for risk of progression to esophageal adenocarcinoma (EAC) and an indication for endoscopic therapy. However, BE surveillance technique is variable. The aim of this study was to assess the effect of dedicated BE surveillance lists on dysplasia detection rate (DDR). Patients and methods This was a prospective study of patients undergoing BE surveillance at two hospitals - community (UHL) and upper gastrointestinal center (GSTT). Four endoscopists (Group A) were trained in Prague classification, Seattle protocol biopsy technique, and lesion detection prior to performing BE surveillance endoscopies at both sites, with dedicated time slots or lists. The DDR was then compared with historical data from 47 different endoscopists at GSTT and 24 at UHL (Group B) who had undertaken Barrett's surveillance over the preceding 5-year period. Results A total of 729 patients with BE underwent surveillance endoscopy between 2007 and 2012. There was no significant difference in patient age, sex, or length of BE between the two groups. There was a significant difference in detection rate of confirmed indefinite or low grade dysplasia and high grade dysplasia (HGD)/EAC between the two groups: 18 % (26 /142) Group A vs. 8 % (45/587) in Group B (P  < 0.001). Documentation of Prague criteria and adherence to the Seattle protocol was significantly higher in Group A. Conclusion This study demonstrated that a group of trained endoscopists undertaking Barrett's surveillance on dedicated lists had significantly higher DDR than a nonspecialist cohort. These findings support the introduction of dedicated Barrett's surveillance lists.

Extent of Lymphadenectomy and Prognosis After Esophageal Cancer Surgery.

IMPORTANCE: The prognostic role of the extent of lymphadenectomy during surgery for esophageal cancer is uncertain and requires clarification. OBJECTIVE: To clarify whether the number of removed lymph nodes influences mortality following surgery for esophageal cancer. DESIGN, SETTING, AND PARTICIPANTS: Conducted from January 1, 2000, to January 31, 2014, this was a cohort study of patients who underwent esophagectomy for cancer in 2000-2012 at a high-volume hospital for esophageal cancer surgery, with follow-up until 2014. EXPOSURES: The main exposure was the number of resected lymph nodes. Secondary exposures were the number of metastatic lymph nodes and positive to negative lymph node ratio. MAIN OUTCOMES AND MEASURES: The independent role of the extent of lymphadenectomy in relation to all-cause and disease-specific 5-year mortality was analyzed using Cox proportional hazard regression models, providing hazard ratios (HRs) with 95% CIs. The HRs were adjusted for age, pathological T category, tumor differentiation, margin status, calendar period of surgery, and response to preoperative chemotherapy. RESULTS: Among 606 included patients, 506 (83.5%) had adenocarcinoma of the esophagus, 323 (53%) died within 5 years of surgery, and 235 (39%) died of tumor recurrence. The extent of lymphadenectomy was not statistically significantly associated with all-cause or disease-specific mortality, independent of the categorization of lymphadenectomy or stratification for T category, calendar period, or chemotherapy. Patients in the fourth quartile of the number of removed nodes (21-52 nodes) did not demonstrate a statistically significant reduction in all-cause 5-year mortality compared with those in the lowest quartile (0-10 nodes) (HR, 0.86; 95% CI, 0.63-1.17), particularly not in the most recent calendar period (HR, 0.98; 95% CI, 0.57-1.66 for years 2007-2012). A greater number of metastatic nodes and a higher positive to negative node ratio was associated with increased mortality rates, and these associations showed dose-response associations. CONCLUSIONS AND RELEVANCE: This study indicated that the extent of lymphadenectomy during surgery for esophageal cancer might not influence 5-year all-cause or disease-specific survival. These results challenge current clinical guidelines.

Recognising and Managing Refractory Coeliac Disease: A Tertiary Centre Experience.

Refractory coeliac disease (RCD) is a rare complication of coeliac disease (CD) and involves malabsorption and villous atrophy despite adherence to a strict gluten-free diet (GFD) for at least 12 months in the absence of another cause. RCD is classified based on the T-cells in the intra-epithelial lymphocyte (IEL) morphology into type 1 with normal IEL and type 2 with aberrant IEL (clonal) by PCR (polymerase chain reaction) for T cell receptors (TCR) at the ß/γ loci. RCD type 1 is managed with strict nutritional and pharmacological management. RCD type 2 can be complicated by ulcerative jejunitis or enteropathy associated lymphoma (EATL), the latter having a five-year mortality of 50%. Management options for RCD type 2 and response to treatment differs across centres and there have been debates over the best treatment option. Treatment options that have been used include azathioprine and steroids, methotrexate, cyclosporine, campath (an anti CD-52 monoclonal antibody), and cladribine or fluadribine with or without autologous stem cell transplantation. We present a tertiary centre's experience in the treatment of RCD type 2 where treatment with prednisolone and azathioprine was used, and our results show good response with histological recovery in 56.6% of treated individuals.

Rare case of severe cholangiopathy following critical illness.

Secondary sclerosing cholangitis is a rare condition caused by disorders directly damaging the biliary tree. We present a case of a 34-year-old man with no pre-existing hepatobiliary disease who developed significant cholestasis and subsequent cholangitis while in the intensive care unit for multiorgan failure secondary to H1N1 influenza A (swine flu). After discharge from the intensive care unit, jaundice, fevers, abdominal pain, pruritus and ongoing cholestasis persisted, consistent with recurrent cholangitis. Secondary sclerosing cholangitis was confirmed by liver biopsy and endoscopic retrograde cholangiopancreatography. This is a case of the recently described syndrome of secondary sclerosing cholangitis following critical illness, with associated severe hypoxic and ischaemic injury. He subsequently developed recognised complications of sclerosing cholangitis, including fat-soluble vitamin deficiencies, recurrent cholangitis and liver fibrosis. To the best of our knowledge, this is the first reported case of secondary sclerosing cholangitis following critical illness in the UK.

Gastrointestinal effects of eating quinoa (Chenopodium quinoa Willd.) in celiac patients.

OBJECTIVES: Celiac disease is an enteropathy triggered by dietary gluten found in wheat, rye, and barley. Treatment involves a strict gluten-free diet (GFD). Quinoa is a highly nutritive plant from the Andes that has been recommended as part of a GFD. However, in-vitro data suggested that quinoa prolamins can stimulate innate and adaptive immune responses in celiac patients. Therefore, we aimed to evaluate the in-vivo effects of eating quinoa in adult celiac patients. METHODS: Nineteen treated celiac patients consumed 50 g of quinoa every day for 6 weeks as part of their usual GFD. We evaluated diet, serology, and gastrointestinal parameters. Furthermore, we carried out detail histological assessment of 10 patients before and after eating quinoa. RESULTS: Gastrointestinal parameters were normal. The ratio of villus height to crypt depth improved from slightly below normal values (2.8:1) to normal levels (3:1), surface-enterocyte cell height improved from 28.76 to 29.77 µm and the number of intra-epithelial lymphocytes per 100 enterocytes decreased from 30.3 to 29.7. Median values for all the blood tests remained within normal ranges, although total cholesterol (n=19) decreased from 4.6 to 4.3 mmol/l, low-density lipoprotein decreased from 2.46 to 2.45 mmol/l, high-density lipoprotein decreased from 1.8 to 1.68 mmol/l and triglycerides decreased from 0.80 to 0.79 mmol/l. CONCLUSIONS: Addition of quinoa to the GFD of celiac patients was well tolerated and did not exacerbate the condition. There was a positive trend toward improved histological and serological parameters, particularly a mild hypocholesterolemic effect. Overall, this is the first clinical data suggesting that daily 50 g of quinoa for 6 weeks can be safely tolerated by celiac patients. However, further studies are needed to determine the long-term effects of quinoa consumption.

A role for gut-associated lymphoid tissue in shaping the human B cell repertoire.

We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans.

Histopathologic examination and reporting of esophageal carcinomas following preoperative neoadjuvant therapy: practical guidelines and current issues.

Neoadjuvant chemoradiotherapy is being increasingly offered to patients with invasive esophageal carcinoma in an effort to downstage the tumor and consequently increase the rate of curative resection. A substantial amount of data has suggested that pathologic tumor regression following neoadjuvant therapy is an important predictor of local recurrence and long-term survival in esophageal cancer. Therefore, it is important that these posttreatment resection specimens are handled in a standardized manner and a reproducible method of tumor regression grading is used. Pathologic examination of such specimens is not straightforward, and, in fact, it presents a particular challenge to pathologists, especially when a good response to neoadjuvant therapy has been achieved and little or no residual tumor remains. We provide some guidelines for handling and reporting such specimens and outline the commonly used tumor regression grading systems for posttreatment esophagectomy specimens.

Clinical and pathological features of eosinophilic oesophagitis: a review.

Eosinophilic oesophagitis (EOE) is a newly described clinicopathological entity that is being diagnosed with increasing frequency both in children and in adults. It is presumed to be an atopic disease involving both immediate and delayed-type hypersensitivity to inhaled and ingested allergens. Because of the reflux-type symptomatology, it is commonly misdiagnosed and treated as severe gastro-oesophageal reflux disease (GORD) before an appropriate diagnosis is made. Pathologically, EOE is an inflammatory disorder with a predominantly eosinophilic infiltrate that is unresponsive to acid suppression therapy. The diagnosis of this disease requires histological confirmation with oesophageal biopsy specimens showing an intense eosinophilic infiltration. Although precise criteria or a specific cutoff point for the diagnosis of eosinophilic oesophagitis have not been established, many authors suggest that one high-power field with >20 eosinophils or multiple high-power fields with >15 eosinophils, together with clinical and endoscopic findings, should be sufficient for diagnosis. Recognition of EOE and differentiation from GORD are important, since allergen elimination or anti-inflammatory therapy appears to be more effective than acid suppression in these patients. This review focuses on clinicopathological features and diagnosis of EOE in adults and children.

Gastrointestinal malignancies in HIV-infected or immunosuppressed patients: pathologic features and review of the literature.

The gastrointestinal (GI) tract is a common internal organ to be involved by human immunodeficiency virus (HIV)-related malignancies. It is the second most common site for Kaposi sarcoma after skin, and the commonest visceral site, for Kaposi sarcoma in AIDS patients. GI lymphomas have been documented in approximately 25% of AIDS patients with systemic lymphomas. Moreover, GI involvement of AIDS-lymphoma has been associated with poor prognosis and short survival. Several other malignancies that occur in the GI tract are also closely related to HIV-infected or immunosuppressed individuals; these include posttransplant lymphoproliferative disorder, Epstein-Barr virus-associated smooth muscle tumors, anal precancerous lesions, and squamous cell carcinoma. As a result of active antiretroviral therapy, patients infected with HIV are living longer and are consequently at increased risk for development of cancer. Therefore, it is possible that the number of AIDS-associated malignancies will rise and the pattern of tumors may change in the future. In this paper, the clinicopathologic features of GI malignancies associated with AIDS patients are reviewed and the differential diagnosis with other mimic lesions is discussed.