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1.  Nomogram to Predict Cycle-One Serious Drug-Related Toxicity in Phase I Oncology Trials 
Journal of Clinical Oncology  2014;32(6):519-526.
Purpose
All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials.
Patients and Methods
The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program–sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade ≥ 4 hematologic or grade ≥ 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set.
Results
Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64).
Conclusion
This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials.
doi:10.1200/JCO.2013.49.8808
PMCID: PMC3918535  PMID: 24419130
2.  Radioactive Seed Localization Compared to Wire Localization in Breast-Conserving Surgery: Initial 6-Month Experience 
Annals of surgical oncology  2013;20(13):4121-4127.
Introduction
Wire localization (WL) of non-palpable breast cancers on the day of surgery is uncomfortable for patients and impacts OR efficiency. Radioactive seed localization (RSL) before the day of surgery avoids these disadvantages. In this study we compare outcomes of our initial 6-month experience with RSL to those with WL in the preceding 6 months.
Methods
Lumpectomies for invasive or intraductal cancers localized with a single 125iodine seed (January-June 2012) were compared to those using 1 wire (July-December 2011). Surgeons and radiologists did not change. Positive and close margins were defined as tumor on ink and tumor ≤1mm from ink, respectively. Demographic and clinical characteristics and outcomes were compared between RSL and WL patients.
Results
There were 431 RSL and 256 WL lumpectomies performed. Clinicopathologic characteristics did not differ between groups. Most seeds (90%) were placed before the day of surgery. Positive margins were present in 7.7% of RSL versus 5.5% of WL patients, and 16.9% of RSL versus 19.9% of WL had close margins (p=0.38). The median operative time was longer for lumpectomy and sentinel lymph node biopsy (SLNB) in the RSL group (55 versus 48 minutes, p<0.0001). There was no significant difference in the volume of tissue excised between groups.
Conclusions
In the first 6 months of RSL, operative scheduling was simplified, while rates of positive and close margins were similar to those seen after many years of experience with WL. Operative time was slightly longer for RSL lumpectomy and SLNB; we anticipate this will decrease with experience.
doi:10.1245/s10434-013-3166-4
PMCID: PMC4003499  PMID: 23943024
breast-conserving surgery; radioactive seed localization; wire localization
3.  Biliary self-expandable metal stents do not adversely affect pancreaticoduodenectomy 
Objectives
Controversy exists regarding whether to place a plastic or metal endobiliary stent in patients with resectable pancreatic cancer who require biliary drainage. Although self-expandable metal stents (SEMS) provide better drainage compared to plastic stents, concerns remain that SEMS may compromise resection and increase postoperative complications. Our objective was to compare surgical outcomes of patients undergoing pancreaticoduodenectomy (PD) with SEMS in place versus plastic endoscopic stents (PES) and no stents (NS).
Methods
We performed a retrospective analysis from a prospective database of all patients undergoing either attempted or successful PD with SEMS, PES, or NS in place at the time of operation. Patients were compared with regards to perioperative complications, margin status, and the rate of intraoperative determination of unresectability.
Results
593 patients underwent attempted PD. 84 patients were locally unresectable intraoperatively and 509 underwent successful PD, of which 71 had SEMS, 149 had PES, and 289 had NS. Among patients who had a preoperative stent, SEMS did not increase overall or serious postoperative complications, 30 day mortality, length of stay, biliary anastomotic leak, or positive margin, but was associated with more wound infections and longer operative times. In those with adenocarcinoma, intraoperative determination of local unresectability was similar in the SEMS group compared to other groups, with 16 (19.3%) in SEMS, compared to 29 (17.7%) in PES (p = 0.862), and 31 (17.5%) in NS (p = 0.732).
Conclusion
Placement of SEMS is not contraindicated in patients with resectable pancreatic cancer who require preoperative biliary drainage.
doi:10.1038/ajg.2013.93
PMCID: PMC4159071  PMID: 23545711
4.  The effect of metformin on breast cancer outcomes in patients with type 2 diabetes 
Cancer Medicine  2014;3(4):1025-1034.
Observational data suggest that metformin use decreases breast cancer (BC) incidence in women with diabetes; the impact of metformin on BC outcomes in this population is less clear. The purpose of this analysis was to explore whether metformin use influences BC outcomes in women with type 2 diabetes. Prospective institutional databases were reviewed to identify patients with diabetes who received chemotherapy for stages I–III BC from 2000 to 2005. Patients diagnosed with diabetes before or within 6 months of BC diagnosis were included. Males and those with type I, gestational, or steroid-induced diabetes were excluded. Patients were stratified based on metformin use, at baseline, defined as use at time of BC diagnosis or at diabetes diagnosis if within 6 months of BC diagnosis. Kaplan–Meier methods were used to estimate rates of recurrence-free survival (RFS), overall survival (OS), and contralateral breast cancer (CBC). We identified 313 patients with diabetes who received chemotherapy for BC, 141 (45%) fulfilled inclusion criteria and 76 (54%) used metformin at baseline. There were no differences in clinical presentation or tumor characteristics between metformin users and nonusers. At a median follow-up of 87 months (range, 6.9–140.4 months), there was no difference in RFS (P = 0.61), OS (P = 0.462), or CBC (P = 0.156) based on metformin use. Five-year RFS was 90.4% (95% CI, 84–97) in metformin users and 85.4% (95% CI, 78–94) in nonusers. In this cohort of patients with type 2 diabetes receiving systemic chemotherapy for invasive BC, the use of metformin was not associated with improved outcomes.
doi:10.1002/cam4.259
PMCID: PMC4303170  PMID: 24944108
Breast neoplasms; diabetes mellitus, type 2; metformin; mortality
5.  Blurry Boundaries: Do Epithelial Borderline Lesions of the Breast and Ductal Carcinoma In Situ Have Similar Rates of Subsequent Invasive Cancer? 
Annals of surgical oncology  2012;20(4):10.1245/s10434-012-2719-2.
Background
The histology of epithelial “borderline lesions” of the breast, which have features in between atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), is well described, but the clinical behavior is not. This study reports subsequent ipsilateral breast events (IBE) in patients with borderline lesions compared with those with DCIS.
Methods
Patients undergoing breast-conserving surgery for borderline lesions or DCIS from 1997 to 2010 were identified from a prospective database. IBE was defined as the diagnosis of subsequent ipsilateral DCIS or invasive ductal carcinoma.
Results
A total of 143 borderline-lesion patients and 2,328 DCIS patients were identified. Median follow-up was 2.9 and 4.4 years, respectively. 7 borderline-lesion and 172 DCIS patients experienced an IBE. 5 year IBE rates were 7.7 % for borderline lesions and 7.2 % for DCIS (p = .80). 5 year invasive IBE rates were 6.5 and 2.8 %, respectively (p = .25). Similarly, when analyses were restricted to patients who did not receive radiotherapy, or endocrine therapy, or both, borderline-lesion and DCIS patients did not demonstrate statistically significant differences in rates of IBE or invasive IBE.
Conclusions
When compared with DCIS, borderline lesions do not demonstrate lower rates of IBE or invasive IBE. Despite “borderline” histology, a 5 year IBE rate of 7.7 % and an invasive IBE rate of 6.5 % suggest that the risk of future carcinoma is significant and similar to that of DCIS.
doi:10.1245/s10434-012-2719-2
PMCID: PMC3833840  PMID: 23161115
6.  A 10-Year Trend Analysis of Sentinel Lymph Node Frozen Section and Completion Axillary Dissection for Breast Cancer: Are These Procedures Becoming Obsolete? 
Annals of surgical oncology  2011;19(1):225-232.
Background
Recent results from the ACOSOG Z0011 trial question the use of intraoperative frozen section (FS) during sentinel lymph node (SLN) biopsy and the role of axillary dissection (ALND) for SLN-positive breast cancer patients. Here we present a 10-year trend analysis of SLN-FS and ALND in our practice.
Methods
We reviewed our prospective SLN database over 10 years (1997–2006, 7509 SLN procedures) for time trends and variation between surgeons in the use of SLN-FS and ALND in patients with cN0 invasive breast cancer.
Results
Use of SLN-FS decreased from 100% to 62% (P < 0.0001) and varied widely by surgeon (66% to 95%). There were no statistically significant trends in the performance of ALND for patients with SLN metastases detected by FS (n = 1370, 99–99%) or routine hematoxylin and eosin (H&E) (n = 333; 69–77%), but only for those detected by serial section H&E with or without immunohistochemistry (n = 438; 73–48%; P = 0.0054) or immunohistochemistry only (n = 294; 48–28%; P < 0.0001). These trends coincided with an increase in the proportion of completion versus immediate ALND (30–40%; P = 0.0710).
Conclusions
Over 10 years, we have observed a diminishing rate of SLN-FS and, for patients with low-volume SLN metastases, fewer ALND, trends that suggest a more nuanced approach to axillary management. If the Z0011 selection criteria had been applied to our cohort, 66% of SLN-FS (4159 of 6327) and 48% of ALND (939 of 1953) would have been avoided, sparing 13% of all patients the morbidity of ALND.
doi:10.1245/s10434-011-1823-z
PMCID: PMC3788632  PMID: 21647763
7.  Prognostic value of quantitative fluorodeoxyglucose measurements in newly diagnosed metastatic breast cancer 
Cancer Medicine  2013;2(5):725-733.
The aim of this study was to determine the prognostic value of quantitative fluorodeoxyglucose (FDG) measurements (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) in patients with newly diagnosed metastatic breast cancer (MBC). An IRB-approved retrospective review was performed of patients who underwent FDG positron emission tomography (PET)/computed tomography (CT) from 1/02 to 12/08 within 60 days of diagnosis MBC. Patients with FDG-avid lesions without receiving chemotherapy in the prior 30 days were included. Target lesions in bone, lymph node (LN), liver, and lung were analyzed for SUVmax, MTV, and TLG. Medical records were reviewed for patient characteristics and overall survival (OS). Cox regression was used to test associations between quantitative FDG measurements and OS. A total of 253 patients were identified with disease in bone (n = 150), LN (n = 162), liver (n = 48), and lung (n = 66) at the time of metastatic diagnosis. Higher SUVmax tertile was associated with worse OS in bone metastases (highest vs. lowest tertile hazard ratio [HR] = 3.1, P < 0.01), but not in LN, liver or lung (all P > 0.1). Higher MTV tertile was associated with worse OS in LN (HR = 2.4, P < 0.01) and liver (HR = 3.0, P = 0.02) metastases, but not in bone (P = 0.22) or lung (P = 0.14). Higher TLG tertile was associated with worse OS in bone (HR = 2.2, P = 0.02), LN (HR = 2.3, P < 0.01), and liver (HR = 4.9, P < 0.01) metastases, but not in lung (P = 0.19). We conclude measures of FDG avidity are prognostic biomarkers in newly diagnosed MBC. SUVmax and TLG were both predictors of survival in breast cancer patients with bone metastases. TLG may be a more informative biomarker of OS than SUVmax for patients with LN and liver metastases.
Measures of fluorodeoxyglucose (FDG) avidity are prognostic biomarkers in newly diagnosed metastatic breast cancer. Volumetric measurements, such as total lesion glycolysis (TLG), may be more informative biomarkers for survival than the more commonly used standardized uptake value (SUV).
doi:10.1002/cam4.119
PMCID: PMC3892804  PMID: 24403238
Breast cancer; FDG PET/CT; mean tumor volume; SUV max; total lesion glycolysis
8.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Background
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
Methods
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Results
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Conclusions
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
doi:10.1186/1742-6405-9-4
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count

Results 1-8 (8)