Rangaswamy Govindarajan

Thiazolidinediones and the Risk of Lung, Prostate, and Colon Cancer in Patients With Diabetes

PURPOSE Peroxisome proliferator-activated receptor gamma (PPARgamma) mediates cell cycle arrest and adipocyte differentiation; has tumor suppressor activity in liposarcoma, lung, and prostate cancers; and suppresses colonic polyp formation in adenomatous polyposis coli (APC)min/+ mice. To assess the influence of thiazolidinediones (TZDs), which are PPAR ligands used to treat diabetes mellitus, a retrospective analysis of a database from 10 Veteran Affairs medical centers was conducted. PATIENTS AND METHODS Data on male patients 40 years and older diagnosed to have diabetes mellitus between 1997 and 2003 were obtained from the Veterans Integrated Services Network 16 (VISN 16) data warehouse. Subsequent diagnoses of colorectal, lung, and prostate cancer and use of TZD, other antidiabetic agents, and insulin were identified. Cox regression with time-dependent covariates was used to estimate the association between TZD use and cancer risk. Relative risks were adjusted for confounders (age, race/ethnicity, body mass index, use of insulin, and other oral antidiabetic agents). RESULTS Of 87,678 individuals, 1,137 had colorectal cancer, 3,246 had prostate cancer, and 1,371 had lung cancer. We observed a 33% reduction in lung cancer risk among TZD users compared with nonusers after adjusting for confounder interactions (relative risk, 0.67; 95% CI, 0.51 to 0.87). The risk reduction for colorectal and prostate cancers did not reach statistical significance. CONCLUSION TZD use was associated with reduced risk of lung cancer. Further studies are warranted to confirm our findings.

Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma.

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) have been reported after autologous transplantation (AT) for lymphoma. It is not clear whether myeloablative therapy used in conjunction with autologous transplantation contributes to the development of MDS/AML or whether the conventional chemotherapy preceding the transplant, and administered over a prolonged period, causes these secondary malignancies. To address this issue, we examined 188 patients with multiple myeloma (MM) who had received AT. 71 patients with no more than one cycle of standard chemotherapy were enrolled in our Total Therapy program, designed to avoid exposure to alkylating agents prior to peripheral blood stem cell mobilization (group 1). The median duration of pre‐transplant therapy in group 1 was 7.6 months and significantly shorter than the 24 months of 117 patients (group 2) with more prolonged conventional therapy (P = 0.0001). All seven patients developing MDS post‐transplantation belonged to group 2 (P = 0.02); the median durations from initial therapy and first transplant were 66 months (range 38–86) and 24 months (range 9–39), respectively. Our findings provide evidence that prolonged standard‐dose alkylating agent therapy prior to transplantation, rather than autotransplant‐supported myeloablative treatment, is associated with development of MDS/AML. Stem cell damaging alkylator treatment should be avoided, not to compromise PBSC collection, but also to reduce the risk of treatment‐related MDS/AML.

Racial differences in the outcome of patients with colorectal carcinoma.

African‐American (AA) patients with colorectal carcinoma have a worse prognosis compared with Caucasians. To analyze the causes of this disparity in survival, a retrospective study of patients with colorectal carcinoma was undertaken. The impact of treatments received and the role of socioeconomic factors such as income, education, and poverty levels were studied.

Effect of thalidomide on gastrointestinal toxic effects of irinotecan

Irinotecan is the only accepted second-line treatment for colorectal cancer in the USA. Doses are, however, frequently limited by associated late-onset diarrhoea. Thalidomide has antiangiogenic and immunomodulatory properties and is being investigated as an antineoplastic. We did a pilot study of combination therapy with thalidomide and irinotecan for metastatic colorectal cancer. In an interim analysis of nine patients, thalidomide had almost eliminated the dose-limiting gastrointestinal toxic effects of irinotecan, especially diarrhoea and nausea (each p<0.0001), and eight of nine patients were able to complete the chemotherapy course.

Bevacizumab and erlotinib in previously untreated inoperable and metastatic hepatocellular carcinoma.

Purpose:To evaluate the combination of erlotinib and bevacizumab in subjects with hepatocellular carcinoma (HCC) who are not candidates for local therapy. Patients and Methods:Twenty-one subjects with metastatic or inoperable HCC who had not received local or systemic therapy were treated with 15 mg/kg bevacizumab every 3 weeks and a daily dose of 150 mg oral erlotinib. The primary endpoint was progression-free survival (PFS) at 27 weeks. The secondary endpoints were median time to progression and median overall survival. Results:Twenty-one subjects were enrolled. Eighteen were evaluable for the primary endpoint; all subjects were evaluable for toxicity. The median age was 60 years (range, 33 to 81 y). Five subjects (28%) were progression free at 27 weeks (90% confidence interval (CI), 12%-50%). Median time to progression was 2.57 months (95% CI, 2.13-4.20 mo). Median overall survival was 8.33 months (95% CI, 5.73-13.97 mo). Two subjects withdrew consent, and 1 subject did not have adequate baseline scans. Conclusions:The 28% progression-free survival rate at 27 weeks was not significantly higher than the recent historical control rate of 20% observed on the placebo arm of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial (P=0.28). The combination of bevacizumab and erlotinib does not appear to have sufficient efficacy in patients with unresectable and metastatic HCC not amenable to local therapy, and may not warrant further investigation. However, this could be evaluated as an alternative to those intolerant to sorafenib therapy.

Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia.

To the editor: Ibrutinib is a potent inhibitor of Bruton tyrosine kinase with promising efficacy in chronic lymphocytic leukemia (CLL). It is well tolerated, and grade 3/4 adverse events are infrequent (12%).[1][1] Lymphocytosis has been reported in ∼70% of patients receiving ibrutinib.[1][1

Programmed Cell Death-Ligand 1 (PD-L1) Expression in Anal Cancer.

Objective: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) in anal cancer. Patients and Methods: In a retrospective cohort analysis, subjects with squamous cell carcinoma of the anal canal were tested for PD-L1 expression, then followed for recurrence and survival. Crude recurrence rates (CRRs), crude mortality rates (CMRs), and crude event rates (CERs) were assessed for PD-L1-dependent differences using Poisson regression. All 3 types of crude rate were expressed as the number that occurred per hundred person-years (hPY) of follow-up. Results: Samples from 41 subjects were evaluated for PD-L1 expression; 23 (56%) were positive. Subjects with PD-L1-expressing versus PD-L1-negative tumors respectively had CRRs of 30.8 versus 12.1 recurrences/hPY (P=0.082), CMRs of 16.7 versus 12.0 deaths/hPY (P=0.47), and CERs of 39.2 versus 16.9 events/hPY (P=0.069). Conclusions: PD-L1 positivity was associated with worse CRR and CER, and marginally worse CMR. The effect on progression-free and overall survival needs to be validated in a study with a larger sample size.

Recurrence score distributions in stage II colon cancers of African American (AA) and Caucasian (CA) patients.

613 Background: The 12-gene colon cancer assay (Oncotype DX) can identify groups of stage II colon cancer patients with lower or higher recurrence risk, but distribution of scores based on race/ethnicity has not been assessed. This study compared the distribution of Recurrence Score results and gene expression profiles between African American (AA) and Caucasian (CA) stage II colon cancer patients. Methods: Stage II colon cancer patients were identified from tumor registry data from four institutions: University of Arkansas for Medical Sciences, Little Rock; Veterans Administration Medical Center, Little Rock; Baptist Medical Center, Memphis, and University of Alabama at Birmingham. The 12-gene assay and mismatch repair (MMR) status were performed on formalin-fixed paraffin-embedded tissues by Genomic Health (Redwood City, CA). T-test and Wilcoxon test were used to compare data from the two groups (SAS Enterprise Guide 5.1). Results: Of the 244 subjects, there were 118 women (63 AA, 55 CA) and 126 men (59...

Ectopic Adrenocorticotropic Hormone Syndrome Due to a Pancreatic Neuroendocrine Tumor.

Ectopic adrenocorticotropic hormone (ACTH) secretion can occur due to a spectrum of lesions, from occult undetectable lesions to aggressive, metastatic tumors. Ectopic ACTH syndrome due to a pancreatic neuroendocrine tumor (PNET) is very rare. Patients with this tumor usually develop early metastases, even prior to symptoms and have a poor prognosis. We present a woman with ACTH-secreting PNET with liver metastasis who presented with new-onset diabetes, hypertension, and some features of Cushing’s syndrome associated with weight loss, which were reversed with resection of the tumor. We summarize the treatment advances in the management of PNETs.

The effect of exposure to thiazolidinediones on the development of head-and-neck cancer in patients with diabetes mellitus

Background: Thiazolidinediones (TZDs) are proliferator-activated receptor-γ (PPAR-γ) ligands with a variety of metabolic activities approved for the treatment of type 2 diabetes mellitus. In addition to being potent hypoglycemic agents, they are recognized through in-vitro studies as having antiproliferative activity. This study was conducted to explore the impact of TZD exposures on the development of head-and-neck cancer. Methods: A retrospective cohort analysis was conducted on subjects attending 10 Veterans Affairs medical centers comprising Veterans Integrated Services Network 16 (VISN-16). Data were collected from the VISN-16 database created from the electronic patient charts. Male diabetics who were eligible to be prescribed TZDs were followed for the development of head-and-neck cancer. Head-and-neck cancers were identified by International Statistical Classification of Diseases 9 (ICD 9) codes; exposures to TZDs and other antidiabetic agents were determined from pharmacy dispensing records. Results: A total of 130,406 subjects who met the study criteria were followed for a total of 571,237 person-years, during which time 911 head-and-neck cancers developed. There was a significant reduction in the incidence of head-and-neck cancers among subjects exposed to TZDs after adjusting for other antidiabetic agents, race, age, body mass index (BMI), and glycosylated hemoglobin [hemoglobin A1C (HbA1C)] (hazard ratio 0.43, confidence interval 0.21–0.89; p = 0.023). Conclusion: A statistically significant reduction was noted in the incidence of head-and-neck cancers among male diabetic veterans exposed to TZDs. These data warrant further investigation.