Daryn Smith

Factors Associated With Breast Cancer Clinical Trials Participation and Enrollment at a Large Academic Medical Center

PURPOSE The practice patterns of medical oncologists at a large National Cancer Institute Comprehensive Cancer Center in Detroit, MI were evaluated to better understand factors associated with accrual to breast cancer clinical trials. PATIENTS AND METHODS From 1996 to 1997, physicians completed surveys on 319 of 344 newly evaluated female breast cancer patients. The 19-item survey included clinical data, whether patients were offered clinical trial (CT) participation and enrollment, and when applicable, reasons why they were not. Multivariate analyses using logistic regression were performed to evaluate predictors of an offer and enrollment. RESULTS The patients were 57% white, 32% black, and 11% other/unknown race. One hundred six (33%) were offered participation and 36 (34%) were enrolled. In multivariate analysis, CTs were less likely offered to older women (mean age, 52 years for those offered v 57 years for those not offered; P =.0005) and black women (21% of blacks offered v 42% of whites; P =.0009). Women with stage 1 disease, poor performance status, and those who were previously diagnosed were also less likely to be offered trials. None of these factors were significant predictors of enrollment. Women were not offered trials because of ineligibility (57%), lack of available trials (41%), and noncompliance (2%). Reasons for failed enrollment included patient refusal (88%) and failed eligibility (12%). CONCLUSION It is important for cooperative groups to design studies that will accommodate a broader spectrum of patients. Further work is needed to assess ways to improve communication about breast cancer CT participation to all eligible women.

A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers.

BACKGROUND Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. PATIENTS AND METHODS Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0-1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m(2), and oxaliplatin at 75 mg/m(2) administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). RESULTS A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4-10.5] and median survival 11.1 months (95% CI 8.2-15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3-4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%). CONCLUSION The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.

Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation

Chopra T, Chandrasekar P, Salimnia H, Heilbrun LK, Smith D, Alangaden GJ. Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation.
Clin Transplant 2011: 25: E82–E87.

Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

Levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from blood as a marker of breast cancer

Oxidative DNA damage can result from numerous endogenous metabolic processes as well as from exposure to environmental and dietary oxidants. One important type of oxidative DNA damage is the formation of hydroxylated DNA bases. This type of DNA damage may have a role in carcinogenesis.

Oxidative DNA Damage Levels in Blood from Women at High Risk for Breast Cancer are Associated with Dietary intakes of Meats, Vegetables, and Fruits

OBJECTIVE We examined the relationship between intakes of specific foods--namely, meats, vegetables, and fruits--with levels of oxidative DNA damage in women consuming their own usual diet or a diet low in fat. DESIGN Blood was obtained from women who had been assigned randomly to a low-fat or nonintervention diet for 3 to 24 months. Levels of 5-hydroxymethyluracil, a type of oxidative DNA damage, were determined. Diet data were obtained from 3-day food records. SUBJECTS/SETTING The 21 women were participating in an outpatient clinic. All the women were healthy but had a first-degree relative with breast cancer. INTERVENTION The intervention was a self-selected diet with a goal of 15% of energy from fat. MAIN OUTCOME MEASURES Existing data on oxidative DNA damage levels were evaluated for possible relationships to foods eaten. Intakes of raw and cooked vegetables were examined separately. Meat intake was examined by type of meat (pork, beef, fish, chicken) and by cooking temperature. STATISTICAL ANALYSES Initial univariate analyses relied on Spearman rank correlations of each food item with DNA damage. Further analyses of the data were performed with univariate and multivariate weighted least squares regression models. RESULTS The model that best explained DNA damage levels was a bivariate regression model that included the intake of cooked vegetables and the sum of beef and pork intake. This model accounted for 85% of the variation in DNA damage levels among women. Preliminary results are suggestive of a positive association of DNA damage with beef and pork intake and a negative association with cooked vegetable intake. APPLICATION These observations, if confirmed in larger studies, suggest specific dietary changes to reduce oxidative DNA damage levels and possibly cancer risk.

Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2-ERG fusions.

CXCR4 is a chemokine receptor that mediates invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive prostate cancer phenotypes. Previously, we and others have shown that the transcription factor ERG regulates CXCR4 expression in prostate cancer cells and that androgens modulate CXCR4 expression via increasing ERG expression. Herein, the molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as the status of ERG and CXCR4 in human prostate cancer specimens were investigated. Using multiple molecular strategies, it was demonstrated that (i) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds to specific ERG/Ets bindings sites in the CXCR4 promoter; (ii) distal binding sites mediate promoter activation; (iii) exogenously expressed ERG promotes CXCR4 expression; (iv) ERG is phosphorylated at Serine-81 and -215, by both IKK and Akt kinases, and Akt mediates CXCR4 expression; (v) ERG-induced CXCR4 drives CXCL12-dependent adhesion to fibronectin; and (vi) ERG and CXCR4 were coexpressed in human prostate cancer tissue, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrate that ERG activates CXCR4 expression by binding to specific ERG/Ets responsive elements and via intracellular kinases that phosphorylate ERG at discrete serine residues. Implications: These findings provide a mechanistic link between TMPRSS2-ERG translocations and intracellular kinase-mediated phosphorylation of ERG on enhanced metastasis of tumor cells via CXCR4 expression and function in prostate cancer cells. Mol Cancer Res; 11(11); 1349–61. ©2013 AACR.

Benefit of postoperative chemoradiotherapy for patients with unknown primary squamous cell carcinoma of the head and neck.

Postopertative adjuvant chemoradiotherapy recently became an established modality for patients with selected high‐risk locally advanced head and neck cancers. The optimal treatment of unknown primary squamous cell cancer of the head and neck (SCCHN) continues to be controversial, since major randomized studies excluded those patients.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors

Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor–mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan. Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10–50 mg) occurred on days 3 to 14 (cycle 1) and days −1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone. Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227–37. ©2016 AACR.

The outcome of cancer patients with acute respiratory distress syndrome

OBJECTIVE The objective of the study is to determine the 28-day mortality of critically ill cancer patients with acute respiratory distress syndrome (ARDS). DESIGN This is a retrospective cohort study of patients enrolled in the ARDS Network randomized controlled trials. RESULTS A total of 2515 patients did not have cancer, and 116 patients had cancer. Patients with cancer were older (median, 61 vs 49 years; P < .0001), more critically ill (the median Acute Physiology and Chronic Health Evaluation III score without cancer comorbidity was 105 for the cancer group compared with 87 for those without cancer; P < 0.0001), and more likely to have pneumonia or sepsis as cause of acute lung injury (79.31% vs 62.70%; P = .0011). The overall mortality at day 28 was 25.7%. Patients with cancer had significantly higher mortality (55.2%) compared with those without cancer (24.3%) (P < .0001). The odds ratio for mortality from ARDS at 28 days for cancer patients was 2.54 (95% confidence interval [CI], 1.570-4.120). Acute Physiology and Chronic Health Evaluation III score and age were found to be significant predictors of outcome in cancer patients with odds ratio of 1.034 (95% CI, 1.007-1.062; P = .0135) and 1.075 (95% CI, 1.024-1.129, P = .0036), respectively. CONCLUSIONS Cancer patients with ARDS have a significantly higher risk of death compared with those without cancer. The increased risk appeared to be mediated by increased severity of illness at presentation, as well as by age.