Marta L. Davila

Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma

PURPOSE The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. PATIENTS AND METHODS Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. RESULTS The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). CONCLUSION The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.

Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment.

Association Between Hepatitis B Virus and Pancreatic Cancer

PURPOSE Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development. PATIENTS AND METHODS At The University of Texas M. D. Anderson Cancer Center, Houston, TX, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). RESULTS Anti-HCV was positive in seven cases (1.5%) and nine controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV-positive, 0.9 (95% CI, 0.3 to 2.8), anti-HBc-positive, 2.5 (95% CI, 1.5 to 4.2), anti-HBc-positive/anti-HBs-positive, 2.3 (95% CI, 1.2 to 4.2), and anti-HBc-positive/anti-HBs-negative, 4 (95% CI, 1.4 to 11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7 to 28.7). CONCLUSION Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights into the etiology of pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among patients with HBV-related pancreatic cancer during chemotherapy.

Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States†

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case‐control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long‐term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3‐6.3). Restricted analyses among hepatitis virus–negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two‐fold to three‐fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7‐32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3‐153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6‐5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC. (HEPATOLOGY 2009;49:1563–1570.)

Association between hypothyroidism and hepatocellular carcinoma

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case‐control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long‐term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3‐6.3). Restricted analyses among hepatitis virus–negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two‐fold to three‐fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7‐32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3‐153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6‐5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC. (HEPATOLOGY 2009;49:1563–1570.)

Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients

BACKGROUND & AIMS Data on acute exacerbation and reactivation of chronic hepatitis C virus (HCV) infection following chemotherapy are very limited. We sought to characterize the episodes of acute exacerbation and viral reactivation of HCV infection in cancer patients. METHODS The medical records of HCV-infected patients seen at our institution (2008-2009) were analyzed retrospectively. Acute exacerbation was defined as greater than 3-fold increase in serum level of alanine aminotransferase, and viral reactivation as ≥ 1 log(10) IU/ml increase of HCV viral load following chemotherapy. RESULTS Acute exacerbation occurred in 33 (11%) of 308 patients with proven HCV infection. Patients with acute exacerbation more often had underlying hematological malignancies (73% vs. 29%; p<0.001) and lymphopenia (6% vs. 0%; p=0.01) than patients without it. In multivariate analysis, underlying hematological malignancies (p=0.02; odds ratio, 3.2; 95% confidence interval, 1.2-8.7) and use of rituximab (p=0.004; odds ratio, 4.2; 95% confidence interval, 1.6-10.9) were associated with acute exacerbation. Patients with acute exacerbation received higher median cumulative dose of rituximab than those without exacerbation. Discontinuation of chemotherapy due to liver dysfunction was more common in patients with acute exacerbation than in patients without it (45% vs. 11%; p<0.001). Eight (36%) of 22 patients with known pre- and post-chemotherapy viral load had viral reactivation. CONCLUSIONS Acute exacerbation and reactivation of chronic HCV infection occur often after chemotherapy. Liver dysfunction can lead to discontinuation of potentially life-saving chemotherapy in nearly one-half of the patients with exacerbation of HCV infection.

Clinical and endoscopic factors predict higher pathologic grades of Barrett dysplasia

Barrett esophagus is highly prevalent in the Western world; however, only a minority of affected individuals progress to esophageal adenocarcinoma. Whereas many studies have examined risk factors for development of Barrett metaplasia, few data are available on risk factors for progression to neoplasia. Identifying simple, reliable, clinical, and endoscopic predictors of high‐grade dysplasia and adenocarcinoma would be helpful for risk stratification in screening and surveillance programs.

Gastrointestinal complications of oncologic therapy

Gastrointestinal complications are common in patients undergoing various forms of cancer treatment, including chemotherapy, radiation therapy, and molecular-targeted therapies. Many of these complications are life-threatening and require prompt diagnosis and treatment. Complications of oncologic therapy can occur in the esophagus (esophagitis, strictures, bacterial, viral and fungal infections), upper gastrointestinal tract (mucositis, bleeding, nausea and vomiting), colon (diarrhea, graft–versus–host disease, colitis and constipation), liver (drug hepatotoxicity and graft–versus–host disease), and pancreas (pancreatitis). Treatment of the different gastrointestinal complications should be tailored to the individual patient and based on the underlying pathophysiology of the complication.

Dysfunctional transforming growth factor-β signaling with constitutively active Notch signaling in Barrett's esophageal adenocarcinoma.

Esophageal adenocarcinoma is often considered to arise from a clonal stem‐like population of cells, which is potentially responsible for its poor prognosis. Transforming growth factor β (TGF‐β) and Notch signaling pathways play important roles in regulating self‐renewal of stem cells and cell‐fate determination. Both pathways are frequently implicated in gastrointestinal carcinogenesis. However, their contributions to esophageal adenocarcinoma remain unclear.

Loss of TGF-β Adaptor β2SP Activates Notch Signaling and SOX9 Expression in Esophageal Adenocarcinoma

TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. Loss of TGF-β signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear. Here we report that loss of TGF-β adapter β2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells. Expression of the stem cell marker SOX9 was markedly higher in esophageal adenocarcinoma tumor tissues than normal tissues, and its higher nuclear staining in tumors correlated with poorer survival and lymph node invasion in esophageal adenocarcinoma patients. Downregulation of β2SP by lentivirus short hairpin RNA increased SOX9 transcription and expression, enhancing nuclear localization for both active Notch1 (intracellular Notch1, ICN1) and SOX9. In contrast, reintroduction into esophageal adenocarcinoma cells of β2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity. Tumor sphere formation and invasive capacity in vitro and tumor growth in vivo were increased in β2SP-silenced esophageal adenocarcinoma cells. Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of β2SP. Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of β2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-β targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin. Taken together, our findings suggest that loss of β2SP switches TGF-β signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9.