Citations

Background Anesthetics administered to immature brains may cause histopathological changes and long-term behavioral abnormalities. The association between perinatal exposure to anesthetics during Cesarean delivery (CD) and development of learning disabilities (LD) was determined in a population-based birth cohort. Methods The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976-1982 and remaining in the community at age 5 were reviewed to identify those with LDs. Cox proportional hazards regression was used to compare rates of LD between children delivered vaginally and via CD (with general or regional anesthesia). Results Of the 5,320 children in this cohort, 497 were delivered via CD (under general anesthesia n = 193, and regional anesthesia n = 304). The incidence of LD depended on mode of delivery (P = 0.050, adjusted for sex, birth weight, gestational age, exposure to anesthesia before age 4 yr, and maternal education). LD risk was similar in children delivered by vagina or CD with general anesthesia, but was reduced in children receiving CD with regional anesthesia (hazard ratio = 0.64, 95% confidence interval 0.44 to 0.92; P = 0.017 for comparison of CD under regional anesthesia compared to vaginal delivery). Conclusion Children exposed to general or regional anesthesia during CD are not more likely to develop LD compared to children delivered vaginally, suggesting that brief perinatal exposure to anesthetic drugs does not adversely affect long-term neurodevelopmental outcomes. The risk of LD may be lower in children delivered by CD whose mothers received regional anesthesia.

Abstract The recent approval of 3 drugs for the treatment of myelodysplastic syndromes (MDSs) has resulted in a revolution in therapeutic options that was absent a decade ago. At the same time, the changing MDS environment is raising new challenges in clinical trial design and defining new indications for MDS drugs. Many current trials still rely on IPSS-based enrollment criteria, despite the well-recognized limitations of the IPSS. Clinical trialists designing studies struggle with several important trial design challenges, including which patients constitute the “previously treated” and “relapsed/refractory” MDS populations, and how specifically to define disease “progression.” This article considers some of these issues as they relate to study design, including how to identify certain MDS populations and define disease progression.

Abstract Data on long-term follow-up for definitive therapy of prostate cancer are limited, especially for radiation therapy. Either surgery or radiation was used in 322 patients for treatment with curative intent, and follow-up was for a minimum of 15 years. Overall survival was nearly identical to that in an age-matched cohort. 5-, 10-, and 15-year recurrence-free survival rates were 77%, 63% and 53%, respectively. Grade and stage were significant prognostic factors for both recurrence and survival. More than 60% of the initial failures were local, and more than 25% of the failures occurred after 10 years. Radiation therapy was used in 137 patients with clinically staged disease. Radical retropubic prostatectomy and perineal prostatectomy were performed in 133 and 44 patients, respectively. In this group, pathological staging was used. Survival rates for surgically treated patients were better than those in the cohort population. In conclusion, overall long-term follow-up demonstrates that definitive treatment does not have an adverse effect on survival from prostate cancer. Local recurrence is a frequent cause of failure. Caution must be used in interpreting any prostate study with less than 10 years of follow-up, because 25% to 50% of the failures occur after that time.

AbstractStromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell–derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironment's role in T cell–derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/coinhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach.

PurposeSingle-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m2/30 minutes versus GEM FDR 1,500 mg/m2/150 minutes or GEM 1,000 mg/m2/100 minutes/day 1 plus oxaliplatin 100 mg/m2/day 2 every 14 days (GEMOX).MethodsThis trial included patients with metastatic or locally advanced pancreatic cancer, normal organ function, and performance status of 0 to 2. The study was designed to detect a 33% difference in median survival (hazard ratio [HR] ≤ 0.75 for either of the experimental arms) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons.ResultsEight hundred thirty-two patients were enrolled. The median survival and 1-year survival were 4.9 months (95% CI, 4.5 to 5.6) and 16% for GEM, 6.2 months (95% CI, 5.4 to 6.9), and 21% for GEM FDR (HR, 0.83; stratified log-rank P = .04), and 5.7 months (95% CI, 4.9 to 6.5) and 21% for GEMOX (HR, 0.88; stratified log-rank P = .22). Neither of these differences met the prespecified criteria for significance. Survival was 9.2 months for patients with locally advanced disease, and 5.4 months for those with metastatic disease. Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR. GEMOX caused higher rates of nausea, vomiting, and neuropathy.ConclusionNeither GEM FDR nor GEMOX resulted in substantially improved survival or symptom benefit over standard GEM in patients with advanced pancreatic cancer.

Purpose Intensive postoperative surveillance is associated with improved survival and recommended for patients with late stage (stage IIB and III) colon cancer. We hypothesized that stage I and IIA colon cancer patients would experience similar benefits. Patients and Methods Secondary analysis of data from the Clinical Outcomes of Surgical Therapy trial was performed by analyzing results according to TNM stage; early (stage I and IIA, 537 patients) and late (stage IIB and III, 254 patients) stage disease. Five-year recurrence rates were higher in patients with late (35.7%) versus early stage disease (9.5%). Early and late stage salvage rates, recurrence patterns and methods of first detection were compared by χ2 test. Results Salvage rates for early- and late-stage disease patients with recurrence were the same (35.9% v 37%; P = .9, respectively). Median survival after second surgery after recurrence was 51.2 and 35.8 months for early- and late-stage patients, respectively. Single sites of first recurrence did not significantly differ between early and late stage, but multiple sites of recurrence occurred less often in early-stage patients (3.6% v 28.6%, for early v late, respectively; P < .001). Methods of first detection of recurrence were not significantly different: carcinoembryonic antigen (29.1% v 37.4%), computed tomography scan (23.6% v 26.4%), chest x-ray (7.3% v 12.1%), and colonoscopy (12.7% v 8.8%), for early versus late stage disease, respectively. Conclusion Patients with early-stage colon cancer have similar sites of recurrence, and receive similar benefit from postrecurrence therapy as late-stage patients; implementation of surveillance guidelines for early-stage patients is appropriate.

Abstract This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.