Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

HCV/HTLV coinfection: Does HTLV-1 interfere in the natural history of HCV-related diseases?

Hepatitis C virus (HCV) and human T-lymphotropic virus type 1 (HTLV-1) coinfection occurs in many regions. However, few studies have focused on the natural history of HCV-induced liver disease in coinfected patients. To describe the clinical, epidemiological, and histopathological aspects of HTLV-1/HCV coinfection in Brazil. A cross-sectional study with 23 patients coinfected with HCV/HTLV. The control groups consisted of 21 patients monoinfected with HCV and 20 patients monoinfected with HTLV-1. The cytokine profiles (Th1 and Th2 cell responses), clinical, laboratory features, and histopathological aspects were examined. The control group for cytokine analysis validation consisted of patients monoinfected with HTLV, and a fourth group consisted of healthy blood donors. No anthropometric differences present between the three infected groups. We observed higher serum concentrations of IFN-γ in patients coinfected with HCV/HTLV-1 than those in HCV monoinfected patients. The HCV/HTLV-1 coinfected group also exhibited a higher degree of liver steatosis than the HCV monoinfected patients. Results suggest that HCV/HTLV-1 coinfection may result in a different pattern of HCV infection due to the immunologic disorders likely associated with HTLV-1, but there is no clear evidence of the HTLV role in the natural history of HCV infection. J. Med. Virol. 88:1967-1972, 2016. © 2016 Wiley Periodicals, Inc.

Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

A meta-analysis of patients with chronic hepatitis C treated with interferon-alpha to determine the risk of autoimmune thyroiditis.

OBJECTIVE: In order to analyze the effect on autoimmune thyroiditis (AT) of current anti-hepatitis C virus (HCV) treatment in HCV-infected patients, we performed a systematic review with meta-analysis of the available literature. The present meta-analysis was conducted to evaluate the strength and the consistency of the association between treatments with interferon-alpha (IFN-alpha) for HCV infection and AT. MATERIAL AND METHODS: A search in Medline, PubMed, and EMBASE was conducted with a systematic review of clinical studies in English and other languages. Only studies in HCV subjects compared to a control group with hepatitis B (positive HBsAg) were considered. The relative risk (RR) of AT was regarded as the most reliable outcome end-point. The pooled odds ratio (OR) and 95% confidence intervals (95% CI) were calculated from the raw study data using the Mantel-Haenszel methods. We used a statistical evaluation of heterogeneity by the chi2-test to assess whether the variation in treatment effect within trials of the same group was greater than it might be expected. RESULTS: We identified 35 clinical trials with a total of 6.403 patients. Five trials were selected for analysis involving a total of 625 patients with hepatitis C treatment with IFN-alpha and 456 HBsAg-positive controls. These studies yielded a combined adjusted OR of 4.98 (95% IC 1.56-15.91). The test for heterogeneity was significant (P = 0.0008), and the test for overall effect was Z statistic 2.71 (P = 0.007). CONCLUSION: Our meta-analysis indicates that treatment with IFN-alpha for HCV infection has an increased risk of AT.

Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients.

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.

Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis.

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

Clinical, endoscopic and histopathological profiles of parasitic duodenitis cases diagnosed by upper digestive endoscopy.

CONTEXT: Intestinal parasites induce detectable histopathological changes, which have been studied in groups with known diagnosis of parasitic disease. There is no available study with a larger base without previous diagnosis. OBJECTIVE: To describe clinical and histopathological findings of parasitosis diagnosed by endoscopic biopsy in patients submitted to upper digestive endoscopy. METHODS: Recorded biopsies archive at "Complexo Hospitalar Professor Edgar Santos" , a general teaching Hospital in the state of Bahia, Northeast Brazil, from January 1995 to January 2009, were reviewed. One thousand ten duodenal biopsy reports were found. Reports positive for parasites had their specimens reviewed and photographed. All blocks of biopsy selected as case were retrieved and reviewed by an experienced pathologist. Clinical, laboratorial and endoscopic data were collected. RESULTS: Eleven biopsies showed parasites, including cases of Cryptosporidium sp. and Strongyloides stercoralis. Vomiting (91%), abdominal pain (78%), diarrhea (78%) and weight loss (78%) were usual symptoms. Seventy-five percent had duodenal mucosa changes on endoscopy, while 25% have no changes. Anemia and low serum albumin were important laboratorial data. HIV infection association was observed. Villus atrophy and reactive epithelium were usual in Strongyloides cases. CONCLUSIONS: No endoscopic or histopathologic finding was pathognomonic. One percent of duodenal endoscopic biopsies showed parasites.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers.

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8% and cryoglobulinemia was demonstrated in 36.9% patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

Clinical, endoscopic and histopathological profiles of parasitic duodenitis cases diagnosed by upper digestive endoscopy / Perfil clínico, endoscópico e histopatológico de casos de duodenite parasitária diagnosticados por endoscopia digestiva alta

CONTEXT: Intestinal parasites induce detectable histopathological changes, which have been studied in groups with known diagnosis of parasitic disease. There is no available study with a larger base without previous diagnosis. OBJECTIVE: To describe clinical and histopathological findings of parasitosis diagnosed by endoscopic biopsy in patients submitted to upper digestive endoscopy. METHODS: Recorded biopsies archive at "Complexo Hospitalar Professor Edgar Santos" , a general teaching Hospital in the state of Bahia, Northeast Brazil, from January 1995 to January 2009, were reviewed. One thousand ten duodenal biopsy reports were found. Reports positive for parasites had their specimens reviewed and photographed. All blocks of biopsy selected as case were retrieved and reviewed by an experienced pathologist. Clinical, laboratorial and endoscopic data were collected. RESULTS: Eleven biopsies showed parasites, including cases of Cryptosporidium sp. and Strongyloides stercoralis. Vomiting (91 percent), abdominal pain (78 percent), diarrhea (78 percent) and weight loss (78 percent) were usual symptoms. Seventy-five percent had duodenal mucosa changes on endoscopy, while 25 percent have no changes. Anemia and low serum albumin were important laboratorial data. HIV infection association was observed. Villus atrophy and reactive epithelium were usual in Strongyloides cases. CONCLUSIONS: No endoscopic or histopathologic finding was pathognomonic. One percent of duodenal endoscopic biopsies showed parasites.

CONTEXTO: Parasitas intestinais podem induzir alterações histopatológicas, que têm sido estudadas em subgrupos com diagnóstico firmado de parasitose. Não há estudo disponível com base mais ampla, sem diagnóstico prévio. OBJETIVO: Descrever os achados clínicos e histopatológicos de parasitoses diagnosticadas por biopsia em pacientes submetidos a endoscopia digestiva alta. MÉTODO: Laudos de biopsias realizadas de janeiro de 1995 a janeiro de 2009, no Complexo Hospitalar Professor Edgar Santos, hospital geral universitário localizado no nordeste brasileiro, foram revisados. Mil e dez laudos de biopsia duodenal foram revistos. Biopsias positivas para parasitas tiveram suas lâminas revisadas e fotografadas. Todos os blocos de biopsia selecionados como casos foram recuperados e revisados por experiente patologista. Dados clínicos, laboratoriais e endoscópicos foram coletados. RESULTADOS: Onze biopsias mostraram parasitas, incluindo casos de Cryptosporidium sp. e Strongyloides stercoralis. Vômitos (91 por cento), dor abdominal (78 por cento), diarreia (78 por cento) e perda ponderal (78 por cento) foram sintomas comuns. Setenta e cinco por cento apresentaram alterações na mucosa duodenal à endoscopia, enquanto 25 por cento não apresentaram modificações. Anemia e hipoalbuminemia foram importantes dados laboratoriais. Foi observada associação com infecção pelo HIV. Atrofia de vilosidades e epitélio reativo foram comuns nos casos de S. stercoralis. CONCLUSÕES: Nenhum achado endoscópico ou histopatológico foi patognomônico. Um por cento das biopsias duodenais por via endoscópica mostraram parasitas.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8 percent and cryoglobulinemia was demonstrated in 36.9 percent patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.