Citations

OBJECTIVE—Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials. RESEARCH DESIGN AND METHODS—Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort. RESULTS—Test reproducibility in clinical trial cohorts (rI ∼ 0.7–0.85) approached that in the epidemiologic cohort (rI ∼ 0.85–0.95). Associations between pairs of end points explained <10% of the variability of data (sometimes 15–35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score (Σ 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation. CONCLUSIONS—The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used.

Intranasal sphenoethmoidectomy is one of the most frequently performed operations in otorhinolaryngology. Surgical indications and techniques have evolved with advances in medical technology. Clinical reports describing complications relating to sphenoethmoidectomy, either by traditional or endoscopic technique, have elucidated the potentially dangerous nature of this procedure. 1–6 Intraoperative complications are avoided through a detailed knowledge of anatomy and a technique guided by structural landmarks. We present a case of sphenoethmoidectomy complicated by cerebrospinal fluid (CSF) rhinorrhea and a nasal encephalocele.

Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P ≤ .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P ≤ .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.

OBJECTIVESTo report the oncology and functional outcomes of transoral laser microsurgery (TLM) for untreated glottic carcinoma.STUDY DESIGNA 2 center prospective case series analysis.SETTINGAcademic, tertiary referral centers.RESULTSSeventy‐six patients underwent TLM. Pathologic T stages were: T1, 45 (59%); T2, 21 (28%); T3, 5 (7%); and T4, 5 (7%). Five (7%) patients had neck dissections. Five (7%) patients received adjuvant radiotherapy. Mean follow‐up was 42 months. Respective T1 and T2 5‐year Kaplan‐Meier estimates were: local control, 90% and 93%; loco‐regional control, 90% and 93%; disease specific survival, 90% and 93%; and overall survival, 94% and 93%. The average hospital stay was 2 days. Two (3%) patients experienced major complications. The overall laryngeal preservation rate was 95% (72 of 76).CONCLUSIONSTLM is a safe and effective treatment in select carcinoma of the glottic larynx. Low morbidity and mortality and short periods of hospitalization make TLM an attractive therapeutic option.SIGNIFICANCETLM is an emerging strategy in the treatment of laryngeal cancer.

Abstract Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

Abstract The role of genes that influence the risk of developing pancreatic cancer (PC) has not been well studied. The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and has been implicated in many diseases, including cancer. To evaluate whether single nucleotide polymorphisms in mitochondrial DNA (mtSNP) are associated with increased risk of PC, we screened Caucasian cases diagnosed or seen at the Mayo Clinic with primary pancreatic adenocarcinoma (n = 955), and healthy clinic-based Caucasian controls (n = 1,102). A total of 24 mtSNPs, including 10 of the most common tagSNPs, 7 non-tagSNPs in the coding region, and 7 common SNPs in the regulatory region were genotyped. For analysis, these samples were grouped into two phases, the “testing” set (474 cases and 615 controls), and the “validation” set (481 cases and 487 controls). In the testing set, one mtSNP (SNP11719) suggested an association in single SNP analysis, with an odds ratio of 1.34 (95% confidence intervals, 1.05-1.72; P = 0.020), but did not remain statistically significant after correction for multiple testing. In the validation set, none of the 24 variants indicated any association with PC. For haplogroup analysis, 10 core SNPs that form common haplogroups in Caucasians (1719, 4580, 7028, 8251, 9055, 10398, 12308, 13368, 13708, and 16391) were evaluated. No significant associations with PC were identified either by analyzing the two sets separately or combined (combined global P = 0.17). Overall, these results do not support a significant involvement of mitochondrial DNA variation in the risk of developing PC. Investigation of other mitochondrial genetic variations (i.e., nuclear-encoded mitochondrial proteins) would be necessary to elucidate any role of mitochondrial DNA variation in PC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1455–9)

OBJECTIVE—Type 1 and type 2 diabetes are characterized by an ∼98 and ∼65% loss of pancreatic β-cells, respectively. Efforts to reverse either form of diabetes increasingly focus on the possibility of promoting β-cell replacement and/or regeneration. Islet transplantation has been explored, but it does not provide long-term insulin independence. One possible source of β-cell regeneration is hematopoietic stem cells. In mice, there are conflicting data as to whether hematopoietic stem cells contribute to pancreatic β-cells. We sought to establish whether hematopoietic stem cells (derived from adult donors) transdifferentiate into pancreatic β-cells in adult humans. RESEARCH DESIGN AND METHODS—We addressed this in 31 human pancreata obtained at autopsy from hematopoietic stem cell transplant recipients who had received their transplant from a donor of the opposite sex. RESULTS—Whereas some donor-derived cells were observed in the nonendocrine pancreata, no pancreatic β-cells were identified that were derived from donor hematopoietic stem cells, including two cases with type 2 diabetes. CONCLUSIONS—We conclude that hematopoietic stem cells derived from adult donors contribute minimally to pancreatic β-cells in nondiabetic adult humans. These data do not rule out the possibility that hematopoietic stem cells contribute to pancreatic β-cells in childhood or in individuals with type 1 diabetes.

Compared with adults, infants and children who undergo cardiopulmonary bypass for cardiac surgery present with a myriad of anticoagulation considerations. Inadequate anticoagulation during cardiopulmonary bypass may cause “subclinical” or “overt” thrombosis, while effective anticoagulation decreases excessive bleeding and transfusions. Current strategies for heparinization and its neutralization in pediatric patients undergoing congenital heart repair requiring cardiopulmonary bypass are examined. The coagulation system of the neonate and infant is immature and is further weakened by congenital heart disease. Changes in coagulation and fibrinolytic activity occur during cardiopulmonary bypass as a result of hemodilution and exposure of the blood to the extracorporeal circuit. Adequate anticoagulation is essential to minimize the thrombin generation that will result. The extent of excessive thrombin formation in pediatric patients undergoing cardiopulmonary bypass is better appreciated today than in the past, but no controlled study defines the optimal dose or technique for heparin dosing in these patients. Heparin concentration may even fall to 1.5 U/mL during cardiopulmonary bypass. However, the activated clotting time and heparin concentration correlate poorly. The ideal method to achieve adequate thrombin inhibition is unknown. Additionally, the dangers of excessive protamine are becoming more apparent. Heparin continues to be the most effective agent to achieve anticoagulation and protamine the most effective agent to neutralize it. A technique for heparin and protamine dosing with determination of heparin concentrations, may remove many variables associated with pediatric cardiac surgery that requires cardiopulmonary bypass and may provide clinicians with new therapies to achieve better anticoagulation for patients and consequently better outcomes.