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Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Biliary tract cancers (BTC) comprise a group of uncommon malignancies in which the standard therapies are minimally effective and evolve slowly. Like the majority of gastrointestinal cancers, with some notable exceptions, the impact of immune-based approaches has yet to be seen. However, the etiological background of BTC-overlapping in almost every known causative or associated factor with inflammation-provides a strong clue that these approaches may have an impact in this group of diseases. This review covers what we currently know about the role of the immune system in the etiology of BTC, highlighting differences by subtype, and pointing to the therapeutic opportunities currently entering the clinic or about to do so. (Hepatology 2016;64:1785-1791).

BACKGROUND Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non-small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug-drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.

SUMMARY Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations.

Squamous metaplasia is commonly detected in pancreatic parenchyma; however, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis.Surveillance, Epidemiology, and End Results (SEER) registries were examined identifying pancreatic SCC and adenocarcinoma cases from 2000 to 2012. Age-adjusted incidence rates were calculated. Patients with SCC versus adenocarcinoma were compared by clinical features and relative survival outcomes.We identified 214 patients with SCC and 72,860 with adenocarcinoma. For SCC, incidence rates tripled between 2000 and 2012. Significantly higher SCC incidence rates were observed in older age groups, blacks, and males. Greater proportion of patients with SCC than those with adenocarcinoma had poorly differentiated histology (73.0% vs 43.7%, P0.001). In both subtypes, majority of patients had stage IV disease, 59.0% for adenocarcinoma versus 62.6% for SCC. The 1- and 2-year relative survival rate was significantly lower in patients with SCC versus adenocarcinoma. The 1-year relative survival was 14.0% (95% confidence interval, 9.5%-19.4%) for SCC, compared with 24.5% (95% confidence interval, 24.2%-24.8%) for adenocarcinoma.Although primary pancreatic SCC is a rare neoplasm, incidence rates for this subtype are increasing. Relative to adenocarcinoma, pancreatic SCC is characterized by poorly differentiated histology and worse survival.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors.The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib.Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105.A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study.TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

SummaryCurrent systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD-L1 pathway inhibitor, immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment. Here we present a review of immunological mechanisms in the liver relevant for tumor progression and treatment. We summarize our current knowledge on immune activating and immune suppressing mechanisms during tumor initiation, development, and treatment. We try to explain the paradox of how inflammatory responses in a setting of chronic infection promote tumor development, while the primary aim of immunotherapy is to activate immunity. Finally we summarize recent advances in addition to providing an outlook for the immunotherapy of HCC.

Background: Signet ring carcinoma (SRC) is a distinct histological phenotype of adenocarcinoma. There are only a few published studies specifying the epidemiology of SRC with extragastric presentation. The purpose of our study was to define the most common primary sites of extragastric SRC, determine the incidence, and to compare survival by primary site and disease stage. Methods: The Surveillance Epidemiology and End Result (SEER) database was examined from 2000 to 2012 in order to identify SRC histology (8490) and determine its most common primary sites, incidence, and survival by site and stage. The five most common primary extragastric sites were identified by utilizing ICD-0-3/WHO 2008 classification. Age-adjusted incidence rates for extragastric SRC were calculated and compared to gastric SRC. Relative survival (RS) and overall survival (OS) at 1 and 3 years were analyzed by primary site and stage using Kaplan-Meier method. Chi-square test was used for categorical variables. Results: A total of 24,522 histologically confirmed cases of SRC were identified, and SRC comprised 0.5% of all malignant neoplasms. Among cases with known histological grade, 89.7% had poorly differentiated tumors. Overall, digestive system origin was recorded for 90% of SRC cases. Approximately half (44.2%) of primary SRC tumors were detected outside of the stomach. The most common primary sites for extragastric SRC were colon (40.5%), esophagus (11.9%), rectum (9.8%), lung/bronchus (7.3%), and pancreas (4.7%). The incidence rates for common extragastric SRC were much lower than for gastric SRC, and were higher for males than females (p Conclusion: Our study indicated that extragastric SRC most commonly occurs in the colorectum, esophagus and lung/bronchus. We confirmed that the primary site substantially impacts survival. Thus, development of unique molecular or histologic markers may help to identify the organ of origin and thereby determine prognosis in these phenotypically similar neoplasms. Citation Format: Chul Kim, Susanna Ulahannan, Julius Strauss, Jaydira Del Rivero, Austin Duffy, Tim F. Greten, Oxana V. Makarova-Rusher. Epidemiology and survival in patients with extragastric signet ring carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3421.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Primary liver cancer is the sixth most common cancer worldwide, with HCC representing the majority of the cases. In the U.S., HCC rates are higher among Hispanics, Asians and blacks than among whites. Whether the higher risks are due to different distributions of risk factors is not clear. Thus, we conducted an analysis of HCC risk factors by race/ethnicity in the SEER-Medicare database for the years 2000-2009. Methods: HCC cases (n = 8,116), identified by ICD-O morphology codes 8170-8175, were compared to a 5% random sample of cancer-free persons in the SEER areas (n = 313,525). Risk factors examined included type II diabetes (DM II), obesity, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related disorders. Multivariate logistic regression analyses, which adjusted for age, location, gender, income and date of diagnosis as well as the other risk factors were used to compare risk factors by racial/ethnic group. Results: Risk factors by race/ethnicity | Risk factor | White | Black | Asians | Hispanics | |:----------------- | ------- | ---------------- | ------ | ---------------- | ---- | | | N 6,120 | N 668 | N 971 | N 357 | | | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | | Obesity | 6.3 | 1.06 (0.9-1.2) | 5.5 | 1.0 (0.7-1.5) | 0.7 | 0.2 (0.1-0.8) | 7.8 | 1.2 (0.7-1.9) | | DM II | 44.5 | 2.9 (2.8-3.1) | 41.8 | 1.3 (1.1-1.6) | 38.1 | 1.8 (1.5-2.1) | 54.6 | 2.0 (1.5-2.7) | | HBV | 1.8 | 3.8 (2.6-5.7) | 3.6 | 1.6 (0.7-3.7) | 17.7 | 17.1 (11.8-25.0) | 2.0 | 1.4 (0.2-11.1) | | HCV | 16.8 | 19.7 (17.1-22.6) | 34.0 | 36.8 (28.0-48.6) | 31.1 | 21.4 (15.4-29.9) | 22.7 | 16.0 (9.2-28.1) | | Alcohol cirrhosis | 11.4 | 4.7 (3.7-5.8) | 7.6 | 4.5 (2.4-8.5) | 4.0 | 3.8 (1.3-11.7) | 17.1 | 3.3 (1.7-6.8) | | Alcohol NOS | 13.1 | 2.7 (2.2-2.9) | 13.2 | 1.6 (1.1-2.4) | 3.7 | 2.0 (1.0-4.1) | 14.8 | 1.6 (0.8-3.0) | | Cirrhosis NOS | 33.3 | 45.5 (41.2-50.4) | 24.1 | 17.9 (12.3-25.9) | 36.8 | 36.9 (26.2-52.0) | 44.8 | 27.6 (18.9-40.3) | NOS not otherwise specified. Conclusion: Major HCC risk factor profile is differ across race/ethnical groups. While diabetes is most common risk factor overall, it is most prevalent in Hispanics. HCC related to HCV is more common in blacks and Asians, and to HBV in Asians. Citation Format: Oxana V. Makarova-Rusher, Sean F. Altekruse, Timothy S. McNeel, Barry I. Graubard, Austin G. Duffy, Susanna V. Ulahannan, Tim F. Greten, Katherine A. McGlynn. Risk factors for hepatocellular carcinoma (HCC) by race/ ethnicity in the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2015-875