Citations

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Background— The goal of this study was to determine whether the expression of vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Previous studies have provided an association between coronary collateral growth and VEGF, but none have allowed determination of a causal role. Methods and Results— We measured coronary collateral growth in rats subjected to repetitive episodes of myocardial ischemia (RI; one 40-second occlusion every 20 minutes for 2 hours 40 minutes, followed by 5 hours 20 minutes of rest, with this 8-hour cycle repeated 3 times per day for 10 days). Collateral growth was measured from blood flow (radioactive microspheres), visualization of arterial-arterial anastomoses (x-ray micro-CT), and maintenance of function during complete coronary occlusion in 3 groups of animals: sham (received instrumentation but no RI), experimental (subjected to RI), and anti–vascular endothelial growth factor (RI+anti-VEGF 0.6 mg/100 g per day) to block the endogenous actions of VEGF. In the 3 groups, native collateral flow (measurement for RI or sham protocol) averaged 0.2 to 0.3 mL · min −1 · g −1 of tissue. In the sham group, collateral flow did not increase during the protocol. Collateral flow in the control RI group increased by ≈6-fold to 1.63 mL · min −1 · g −1 tissue, but in the anti-VEGF group, collateral flow did not increase after the RI protocol (0.22 mL · min −1 · g −1 ). In acute experiments, collateral flow was unchanged during vasodilation with dipyridamole, indicating the increases in collateral flow are due to collateral growth and not vasodilation. X-ray micro-CT analysis revealed a 3-fold increase (versus sham group) in the number of arterial-arterial anastomoses per heart after RI, which was prevented by treatment with anti-VEGF. The growth of the collateral circulation was functional in the RI group because complete coronary occlusion did not induce any untoward effects on hemodynamics or arrhythmias. In the sham or anti-VEGF groups, coronary occlusion at the end of the protocol induced many arrhythmias and deterioration of function. Conclusions— From these results, we conclude that the expression of VEGF is critical to the growth of coronary collaterals.

Purpose The objective of this study was to determine prognostic factors for overall survival in patients with post-transplantation lymphoproliferative disorders (PTLDs). Patients and Methods This study focused on the 107 adult solid organ transplantation patients who were diagnosed with PTLDs at Mayo Clinic (Rochester, MN) between December 1970 and May 2003. Results The median age at the time of diagnosis was 48 years (range, 15 to 75 years). Extranodal disease including grafted organ involvement was present in 85 patients (80%). The graft organ was involved in 30 patients (28%). At the time of these analyses, 62 patients (58%) had died. The median survival for the entire cohort was 31.5 months (95% CI, 10.7 to 72.5 months). The median follow-up of living patients was 51.8 months (range, 5.6 to 202.6 months). In univariate analyses for overall survival from the time of PTLD diagnosis, the following poor prognostic factors were identified: poor performance status with Eastern Cooperative Oncology Group levels 3 and 4 (P < .0001), grafted organ involvement (P = .0005), the presence of one or more extranodal sites (P = .005), both nodal and extranodal disease (P = .002), high International Prognostic Index (P = .006), advanced stage (P = .001), and elevated lactate dehydrogenase (P = .03). A final multivariable model for survival was constructed using three factors: poor performance status (3 to 4), monomorphic disease, and graft organ involvement. Conclusion A prognostic model has been developed for PTLD patients using one center's 30 years of experience. We propose additional confirmation and validation of these prognostic factors in larger prospective studies.

Abstract Purpose: Patients with a preoperative cytologic diagnosis of a suspicious thyroid nodule present a therapeutic dilemma because surgery differs for benign and malignant lesions. To address this issue, several molecular markers, including human telomerase reverse transcriptase (TERT), have been tested as markers of thyroid cancer. Because most studies select cases falling into well-defined categories to test new markers, they may overestimate their discriminatory power when applied to samples that are difficult to classify. Fine-needle aspirates (FNAs) of the thyroid with indeterminate cytology are an example of such cases. Experimental Design: We examined whether assessing TERT mRNA by reverse transcription-PCR could have improved the surgical management in a cohort of 100 patients undergoing thyroidectomy for indeterminate FNA results. Results: Ninety percent of 48 cancers were TERT positive, as were 35% of 52 benign lesions. When 10 cases with concomitant lymphocytic thyroiditis were excluded, the overall sensitivity of TERT was 91% (95% confidence interval, 80–98%) and specificity was 79% (64–90%). No clinical or tumor variable contributed to the predictive ability of TERT except for tumor size, which added only marginally. Basing the surgical approach on the TERT assay alone would have reduced lobectomies performed for malignant disease from 11 to 4 cases and reduced total thyroidectomies for benign lesions from to 15 to 9, an overall 50% reduction in suboptimal treatment. Conclusions: The overall performance of preoperative differential diagnosis for thyroid tumors with indeterminate FNA results can be substantially improved by the inclusion of molecular markers such as TERT.

Abstract Purpose: YKL-40 is a secreted protein that has been reported to be overexpressed in epithelial cancers and gliomas, although its function is unknown. Previous data in a smaller sample set suggested that YKL-40 was a marker associated with a poorer clinical outcome and a genetically defined subgroup of glioblastoma. Here we test these findings in a larger series of patients with glioblastoma, and in particular, determine if tumor YKL-40 expression is associated with radiation response. Experimental Design: Patients (n = 147) with subtotal resections were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. An additional set (n = 140) of glioblastoma patients who underwent a gross-total resection was tested to validate the survival association and extend them to patients with minimal residual disease. Results: In the subtotal resection group, higher YKL-40 expression was significantly associated with poorer radiation response, shorter time to progression and shorter overall survival. The association of higher YKL-40 expression with poorer survival was validated in the gross-total resection group. In multivariate analysis with both groups combined (n = 287), YKL-40 was an independent predictor of survival after adjusting for patient age, performance status, and extent of resection. YKL-40 expression was also compared with genetically defined subsets of glioblastoma by assessing epidermal growth factor receptor amplification and loss at chromosome 10q, two of the common recurring aberrations in these tumors, using fluorescent in situ hybridization. YKL-40 was significantly associated with 10q loss. Conclusions: The findings implicate YKL-40 as an important marker of therapeutic response and genetic subtype in glioblastomas and suggest that it may play an oncogenic role in these tumors.

AbstractWhereas excisional surgery and radiotherapy have resulted in a favorable outcome when non‐Hodgkin's lymphoma of the thyroid (NHLT) is confined to the thyroid gland, controversy persists over the potential advantage of aggressive debulking in favor of diagnostic biopsy alone when disease cannot be completely resected. Our aims in this study were to delineate the present role of surgery in NHLT in pre‐operative staging, the impact of the extent of resection on achieving complete remission and cause‐specific survival, and patterns of failure. All 62 patients who underwent primary surgery for NHLT at the Mayo Clinic between 1965 and 1989 were analyzed. By postoperative staging, 50 patients were stage IE or IIE. Overall survival was 53% and 46% at 5 and 10 years; 80% for stage IE confined to the thyroid, 58% for stage IE‐extrathyroid, 50% for stage IIE, and 36% for stages IIIE and IVE. Complete remission was achieved in 88% of patients who underwent diagnostic biopsy plus adjuvant therapy alone compared to 85% for patients in whom debulking plus adjuvant therapy was used. There was no difference in cause‐specific survival in these two groups or in cause‐specific survival in two subgroups who achieved complete remission. Relapse after complete remission occurred in 12 (26%) of 46 patients, only 2 of whom survived long‐term after salvage therapy. The role of surgery in NHLT is diminishing and advances that will increase complete remission and relapse‐free survival will not likely involve more aggressive surgical resections.

Purpose The purpose of this study was to determine whether “clinical inertia”—inadequate intensification of therapy by the provider—could contribute to high A1C levels in patients with type 2 diabetes managed in a primary care site. Methods In a prospective observational study, management was compared in the Medical Clinic, a primary care site supervised by general internal medicine faculty, and the Diabetes Clinic, a specialty site supervised by endocrinologists. These municipal hospital clinics serve a common population that is largely African American, poor, and uninsured. Results Four hundred thirty-eight African American patients in the Medical Clinic and 2157 in the Diabetes Clinic were similar in average age, diabetes duration, body mass index, and gender, but A1C averaged 8.6% in the Medical Clinic versus 7.7% in the Diabetes Clinic (P < .0001). Use of pharmacotherapy was less intensive in the Medical Clinic (less use of insulin), and when patients had elevated glucose levels during clinic visits, therapy was less than half as likely to be advanced in the Medical Clinic compared to the Diabetes Clinic (P < .0001). Intensification rates were lower in the Medical Clinic regardless of type of therapy (P < .0001), and intensification of therapy was independently associated with improvement in A1C (P < .001). Conclusions Medical Clinic patients had worse glycemic control, were less likely to be treated with insulin, and were less likely to have their therapy intensified if glucose levels were elevated. To improve diabetes management and glycemic control nationwide, physicians in training and generalists must learn to overcome clinical inertia, to intensify therapy when appropriate, and to use insulin when clinically indicated.