Citations

Abstract Background and Aims: Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy. Based on its anatomical location, CCA can be divided into intrahepatic (iCCA) or extrahepatic (eCCA), with differences in etiology, pathogenesis and clinical management. Few studies have focused on the molecular profiling of eCCA as a single entity, even though it accounts for the most prevalent subtype. Thus, integrative genomic analysis of eCCA would provide critical understanding for the biological traits of this tumor. Methods: 189 FFPE primary eCCA treated by resection were collected at seven international centers from 1995 to 2015. Median survival of the cohort was of 48.5mo. Whole gene-expression profiles were submitted to unsupervised clustering by NMF consensus. Clusters were characterized by Gene Set Enrichment Analysis and Ingenuity Pathway Analysis. Activation of signaling pathways (mTOR/pRPS6 and HER2) was assessed by immunohistochemistry (IHC). Molecular features were correlated with clinico-pathological data. Screening of most prevalent somatic mutations and copy number aberrations is ongoing. Results: We have identified four distinct molecular subtypes of eCCA (cophenetic coefficient=0.995). Tumors classified within the metabolic class (18.7%) were enriched by gene signatures defining bile and fatty acid metabolism (p<0.001) and presented overexpression of classic hepatocyte markers, with HNF4A as the major activated upstream transcription factor (p<0.001). The proliferation class (22.5%) was associated with papillary histology (p=0.004) and presented enrichment of MYC (p<0.001), mTOR (p=0.018) and HER2 (p=0.024) signaling. Subclass mapping identified similarity with the iCCA proliferation subclass (p<0.001). The mesenchymal class (47.3%) was associated with signatures defining epithelial-mesenchymal transition (p<0.001) as well as stromal activation (p<0.001), which was in accordance with TGFB1 as the major activated upstream regulator (p<0.001) and the presence of higher desmoplasia at pathological analysis (p=0.046). Moreover, mesenchymal tumors were significantly associated with poor prognosis in terms of OS (33.2 vs 55.5mo, HR=2.02, p=0.022). Finally, tumors classified as immune class (11.5%) presented increased tumor-infiltrating lymphocytes (p=0.001) and were characterized by enrichment of IFNγ signaling (p<0.001). Conclusions: Transcriptome-based subtyping of eCCA identifies four distinct molecular classes (metabolic, proliferation, mesenchymal and immune) that correlate with clinical-pathological characteristics. These findings enhance the opportunities for therapeutic development in this tumor with dismal prognosis and without approved molecular treatments. Citation Format: Robert Montal, Wei Qiang Leow, Carla Montironi, Laia Bassaganyas, Agrin Moeini, Daniela Sia, Roser Pinyol, Laia Cabellos, Judit Peix, Miho Maeda, Carlos Villacorta, Parissa Tabrizian, Christine Sempoux, Beatriz Minguez, Tim Pawlik, Ismail Labgaa, Lewis Roberts, Manel Sole, Maria Isabel Fiel, Swan Thung, Sasan Roayaie, Augusto Villanueva, Myron Schwartz, Josep Maria Llovet. Integrative molecular classification of extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4618.

Abstract Ovarian cancer (OC) is the most lethal gynecologic malignancy and the fifth leading cause of cancer death in the United States. Metformin, an antidiabetic drug, has been shown to decrease the risk of mortality in cancer patients, particularly those with OC. Though the drug acts through inhibition of the PI3K/mTOR/AKT pathway, which is commonly altered in OC, knockout of key proteins in the pathway does not attenuate metformin’s antidiabetic effects. Further, intravenous metformin administration is less effective than oral, implying that some crucial interaction takes place in the gut. The gut is home to some 1013 bacterial cells, collectively known as the microbiota. These bacteria play important roles in fermentation of fiber, producing short-chain fatty acids (SCFA) that have positive health benefits, including prevention of metabolic syndrome, bowel disorders, and certain cancers. Mechanistically, SCFAs inhibit the PI3K/mTOR/AKT pathway, similar to metformin. Conditions such as obesity, metabolic syndrome, and diabetes significantly alter gut microbiota composition, possibly leading to a reduction in beneficial SCFAs. However, in type II diabetes, treatment with metformin leads to an increase in SCFA-producing bacteria, suggesting that metformin may positively influence the microbiota to improve patient metabolic profiles. In OC, metformin may play a similar role in promoting the presence of SCFA-producing bacteria. We hypothesized that metformin increases the abundance of SCFA-producing bacteria in the gut, with which it acts synergistically to decrease growth of OC cells in combination with OC chemotherapy. To investigate our hypothesis, we have employed the OC patient-derived xenograft (PDX) mouse model established at Mayo Clinic. Immunocompromised SCID mice received OC cells from Mayo Clinic patients and the tumors were allowed to grow to an appropriate size before treatment was started. Cage mates were split into one of four treatment arms: a control (no treatment) group, metformin only, carboplatin/paclitaxel (CP) chemotherapy only, or CP with metformin. Mice received 2mg/ml metformin in their water continuously and/or 51mg/kg carboplatin and 15mg/kg paclitaxel intravenously weekly. Stool was collected weekly prior to tumor injection, during tumor growth, and through the four weeks of treatment. DNA was extracted from stool and bacterial 16S rRNA amplicon sequencing was used to determine microbiota profiles. Mice with chemosensitive tumors treated with only CP chemotherapy had significant reductions in tumor growth along with significantly less microbial gut diversity than pretumor and pretreatment mice. Chemosensitive mice treated with metformin alone did not lose significant microbial diversity but did not have significant reductions in tumor growth as compared to the control mice. CP in combination with metformin both reduced tumor growth and protected against loss of microbiota diversity. Further, mice treated with only metformin had significant increases in abundance in the Firmicutes genera Ruminococcus and Oscillospira, SCFA producers that are associated with leanness and health. Mice treated with both metformin and CP had significant increases in another SCFA-producing Firmicute, Moryella. Finally, mice with chemoresistant tumors showed improved tumor growth inhibition with combination CP/metformin therapy, suggesting that metformin-associated changes in the gut microbiota may increase sensitivity to CP. These data support the hypothesis that metformin protects against detrimental loss of gut microbiota diversity induced by chemotherapy treatment, enriching beneficial SCFA producers. This work implies a role for the gut microbiota in OC treatment and provides support for metformin’s potential use as a beneficial addition to chemotherapy treatment. Citation Format: Dana M. Walsh, Ismail Mert, Chen Jun, Xiaonan Hou, Saravut John Weroha, Marina Walther-Antonio. Metformin alters the gut microbiota of ovarian cancer patients treated with carboplatin/paclitaxel chemotherapy and enhances sensitivity in resistant tumors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A70.

Abstract In this review, we aimed to provide insight into the microbiome and its association with endometrial and ovarian cancer and their risk factors. We reviewed the literature focusing on the relationship between the microbiome and cancer, as well as the relationship between gynecologic diseases and cancers. The human body contains different kinds of microorganisms in various body parts, which is termed the microbiome . The number of microorganisms that live in and on the human body is greater than that of the human germ and somatic cells by 10‐fold. The relationship between a human and their microbiome is complex; it is also one of the most important components of homeostasis. Impairment of microbiome–host homeostasis has been associated with obesity, several cancers, preterm labor, inflammatory and allergic conditions and neurodevelopmental disorders. Direct and strong causal relationships have been established for several cancers and microorganisms, such as gastric lymphoma and Helicobacter pylori infection. Interestingly, eradication of the infectious agents has also been shown to be therapeutic. The association between cancer and the microbiome, however, is more complicated than a 1 bacteria–1 cancer model, and a shift in a healthy microbiome can result in various cancers via inflammation, change in microenvironment or DNA‐damaging toxins. The human microbiome is an integral part of homeostasis. Understanding the mechanisms that cause dysbiosis will enable us to elucidate the pathways that result in malignancy and investigate new treatment modalities.

Background. Clostridium difficile infection (CDI) is the leading cause of hospital-associated gastrointestinal illness. Previous studies reported that patients with active malignancy are at high risk for CDIs, and yet they are still classified as nonsevere CDI and initially treated with metronidazole. Our aim is to investigate the need for the escalation of antibiotic therapy in patients with CDI and active cancer treated with oral metronidazole versus oral vancomycin. Methods. This is a retrospective study of adult patients admitted with CDI and any underlying active malignancy at Beaumont Hospital, Royal Oak, Michigan, from January 2008 to December 2014. Inclusion criteria included age > 18 years old, polymerase chain reaction- (PCR-) proven CDI, and active malignancy. Results. 197 patients were included in the final analysis. 44.8% of the metronidazole group required escalation of therapy compared to 15.2% in the vancomycin group (p value = 0.001). 29.8% of the combination group (metronidazole and vancomycin) underwent deescalation of antibiotics, which was significantly higher compared to 2.2% of patients in the vancomycin group (p value < 0.001). Discussion. Our results support the initial use of vancomycin or a combination (metronidazole and vancomycin) versus metronidazole in patients with CDI and active malignancy.

SummaryObjectiveThe multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia.MethodsPatients aged 2 months to 2 years were enrolled prospectively with new‐onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation.ResultsEighty‐two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first‐line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4–4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR3.2, 95%CI1.9–5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR1.09 per month, 95%CI1.03–1.15) and absence of preexisting epilepsy (OR1.7, 95%CI1.06–2.81) had a small impact on the likelihood of responding to the first‐line treatment. However, receiving standard first‐line treatment increased the likelihood of responding dramatically: vigabatrin (OR5.2 ,95%CI2–13.7), prednisolone (OR8, 95%CI3.1–20.6), and adrenocorticotropic hormone (ACTH;OR10.2, 95%CI4.1–25.8) .SignificanceFirst‐line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.