Austin G. Duffy

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC)

The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10‐year period.

The yin and yang of evasion and immune activation in HCC

Current 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.

Fibrolamellar hepatocellular carcinoma in the USA, 2000–2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database

Objective Epidemiological and clinical information on fibrolamellar hepatocellular carcinoma (fHCC) is scarce. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis with the aim of collecting information to better understand the biology and clinical aspects of this rare disease. Design Incidence trends, race- and age-specific rates, tumor size, first course surgery and five-year relative survival of 191 US cases (SEER) diagnosed with fHCC during 2000–2010 were compared to cases with hepatocellular carcinoma (HCC), HCC-not otherwise specified (HCC-NOS) and other HCC-types. Results While HCC-NOS incidence rates increased by 5.2% annually from 2000–2008 (p < 0.05) before leveling, the 1.3% change in fHCC incidence was not statistically significant. The rates of fHCC were similar across ethnic groups while HCC-NOS incidence rates were higher among non-whites. Although 16% of fHCC patients had primary tumors ≤5 cm compared to 37% of HCC-NOS cases five-year survival was better among fHCC (34%) than HCC-NOS cases (16%). Fibrolamellar HCC cases of 0–39 years of age were more likely to receive radiofrequency ablation, transplant or resection than HCC-NOS cases of that age. Survival was similar among fibrolamellar and HCC-NOS cases receiving surgery. Conclusion In this largest case series, fibrolamellar and HCC-NOS age- and race-specific incidence rates and time trends differed. Despite larger tumor size than HCC-NOS cases fibrolamellar cases received surgery more often and had better survival rates. Differences in co-morbidity may influence treatment. Studies of fHCC biology, including by age, are recommended.

Pancreatic adenocarcinoma in a young patient population—12‐year experience at Memorial Sloan Kettering Cancer Center

There is a dearth of data in a younger population of patients with pancreatic ductal adenocarcinoma (PAC) regarding epidemiology, genetics, prognosis, and outcome. This report examines a large cohort of patients with PAC ≤45 years of age evaluated at MSKCC over a 12‐year period.

Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies

The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with antiangiogenic agents. We performed a systematic review and meta‐analysis of antiangiogenic studies in HCC from 1995 to 2011. For nonrandomized studies we compared bleeding risk with other HCC single‐arm studies that did not include an antiangiogenic agent. To separate disease‐specific factors we also performed a comparison analysis with renal cell cancer (RCC)) studies that evaluated sorafenib. Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.04, 3.0) but not grade 3‐5 events in both HCC and RCC (OR 1.46; 95% CI 0.9, 2.36; P = 0.45). When comparing the risk of bleeding in single‐arm phase 2 studies evaluating antiangiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. Conclusion: This analysis of both randomized and nonrandomized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower‐grade events and similar in magnitude to the risk encountered in RCC. (HEPATOLOGY 2013)

Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

Medina-Echeverz and colleagues show that agonistic anti-CD40 activates tumor-induced CD80+ and CD40+ hepatic myeloid-derived suppressor cells (MDSC), which cause ROS-mediated hepatotoxicity; these results are recapitulated in human CD14+HLA−DRlow MDSCs, which lose arginase expression and suppressor function in vitro. Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/−, and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody–induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation–dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. Cancer Immunol Res; 3(5); 557–66. ©2015 AACR.

Collision Tumor of the Large Bowel in the Context of Advanced Pregnancy and Ulcerative Colitis

A woman aged 33 years, during week 30 of pregnancy, presented with metastatic, high-grade neuroendocrine cancer. Investigation revealed a collision-type primary tumor of the large bowel, containing adenocarcinoma and neuroendocrine elements. Platinum-based chemotherapy resulted in a divergent pathologic response as assessed after colectomy. The diagnosis and classification of mixed endocrine-exocrine tumors of the colon are discussed, along with treatment considerations.

Liver cancer: Regorafenib as second-line therapy in hepatocellular carcinoma

Drug development in hepatocellular carcinoma had essentially stalled since 2008 when sorafenib was established as the modest standard of care. Now, a positive result in a phase III study evaluating regorafenib challenges us to weigh its clinical significance as well as its real-world benefits and potential harms.

Indications for Neoadjuvant, Adjuvant, and Palliative Chemotherapy in the Treatment of Biliary Tract Cancers

Advanced biliary tract carcinomas represent a group of aggressive diseases that still carries a poor prognosis. Chemotherapy has been shown to provide disease control and may also prolong survival. An established role for systemic therapy in the adjuvant setting is still lacking. This article reviews the available evidence to support indications of systemic chemotherapy in the palliative setting and discuss the attempts to study it in the perioperative settings.

Pathologic complete response to neoadjuvant FOLFOX in combination with bevacizumab in unresectable metastatic colorectal carcinoma.

A 32-year-old Asian male presented with perforated sigmoid colorectal cancer (CRC) and large, unresectable hepatic metastasis. After surgery for his primary tumor, he received 6 months of FOLFOX (5-fluorouracil/leucovorin/ oxaliplatin) plus bevacizumab and achieved a partial response. He underwent hepatic metastasectomy and was found to have had a complete pathologic response (pCR) to treatment. The literature regarding pCR with chemotherapy in CRC and the implications for further management is discussed herein.