Citations

Objectives/Hypothesis Pharyngocutaneous fistulae (PCF) are known to occur in nearly one‐third of patients after salvage total laryngectomy (STL). PCF has severe impact on duration of admission and costs and quality of life and can even cause severe complications such as bleeding, infection and death. Many patients need further surgical procedures. The implications for functional outcome and survival are less clear. Several studies have shown that using vascularized tissue from outside the radiation field reduces the risk of PCFs following STL. This review and meta‐analysis aims to identify the evidence base to support this hypothesis. Data Sources English language literature from 2004 to 2013 Review Methods We searched the English language literature for articles published on the subject from 2004 to 2013. Results Adequate data was available to identify pooled incidence rates from seven articles. The pooled relative risk derived from 591 patients was 0.63 (95% CI: 0.47 to 0.85), indicating that patients who have flap reconstruction/reinforcement reduced their risk of PCF by one‐third. Conclusion This pooled analysis suggests that there is a clear advantage in using vascularized tissue from outside the radiation field in the laryngectomy defect. While some studies show a clear reduction in PCF rates, others suggest that the fistulae that occur are smaller and rarely need repair. Laryngoscope , 124:1848–1853, 2014

PurposeTo examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course.Patients and MethodsIn all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients.ResultsAuto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT.ConclusionFor patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

Abstract Aims Prognostic benefit from CRT compared with controls is well established. Symptomatic response rates, however, are controversial and have never been systematically evaluated with standard subtraction of control rates to establish the incremental symptomatic response effect of CRT pacing. Methods and results First, we identified 150 consecutive CRT papers and assessed researchers’ perceptions of the symptomatic response to CRT. The mean quoted response rate was 66%. Only 26 studies acknowledged the existence of response without the device. Secondly, we examined actual symptomatic response rates in the randomized trials (CARE-HF, COMPANION, CONTAK-CD, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, MUSTIC, and REVERSE) totalling 3904 patients. The NYHA status improved in 51% of those randomized to CRT vs. 35% of controls (incremental effect 16%). This incremental improvement was significantly greater in open studies (with no device for controls) than in blinded studies (control arm receiving a device but no CRT, such as a defibrillator or a CRT programmed off), 20% vs. 13%, P < 0.001. Conclusions Quoting CRT responder rates in isolation without recognizing spontaneous ‘response’ is common but unwise. The incremental symptomatic response rate from CRT pacing is ∼16%, much lower than widely reported. This value is similar to that for drugs in heart failure and should not be considered disappointing: they both exert powerful prognostic benefits. For scientific purposes, e.g. to explore potential improvements, symptomatic benefit from CRT should be quantified, like all other effects, by comparison with a control.

Insulin-stimulated glucose oxidation is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this decrease is due to a primary defect in the oxidative pathway or is secondary to impaired glucose transport and/or phosphorylation. To address this issue, glucose oxidation was measured under steady-state conditions at low (∼270 pmol) and high (∼17 μmol) insulin concentrations in seven patients with NIDDM and seven healthy nondiabetic subjects matched for sex, age, and obesity. Glucose oxidation was measured simultaneously by indirect calorimetry and the isotopedilution technique. Although glucose oxidation and nonoxidative storage were lower (P < 0.05) in diabetic than nondiabetic subjects during the low- and highdose insulin infusions, oxidation of intracellularly derived glucose, estimated by subtracting the rate of oxidation measured isotopically (i.e., glucose oxidation derived from the extracellular space) from that measured by indirect calorimetry (i.e., total glucose oxidation), did not differ in diabetic and nondiabetic subjects during the low-dose insulin infusion (3.3 ± 0.1 vs. 3.0 ± 0.1 μmol · kg−1 · min−1). Both techniques provided identical estimates of glucose oxidation during the high-dose insulin infusion. Impaired oxidation of extracellularly but not intracellularly derived glucose strongly suggests that the cause of decreased glucose oxidation in patients with NIDDM is secondary to impaired glucose transport and/or phosphorylation rather than a primary abnormality in the oxidative pathway.

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 ± 0.7 to 7.6 ± 0.5 and 7.1 ± 0.2%, respectively, P <.01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P <.001). Both agents comparably increased (P <.01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P <.05). Tolazamide (P <.05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P <.05) lowered postabsorptive hepatic glucose release (from 2.8 ± 0.3 to 2.3 ± 0.2 mg · kg−1 · min−1), but not to normal rates (1.8 ± 0.1 mg · kg−1 · min−1). Endogenous glucose release after carbohydrate ingestion was lowered (P <.001) by insulin (from 633 ± 52 to 460 ± 41 mg kg−1 7 h−1) but not by tolazamide (625 ± 62 mg · kg−1 · 7 h−1) to rates observed in nondiabetic subjects (470 ± 32 mg · kg−1 · 7 h−1). Unmetabolized meal glucose reaching the systemic circulation did not differ before or after therapy with either insulin or tolazamide. Total postprandial glucose uptake was not changed by tolazamide (1308 ± 85 mg kg−1 · 7 h−1) but was lowered (P <.01) by exogenous insulin (from 1269 ± 57 to 1088 ± 67 mg · kg−1 · 7 h−1) to normal rates (1023 ± 64 mg kg−1 7 h−1). Forearm glucose uptakedid not differ among any group. We conclude that, although tolazamide and exogenous insulin, as administered in this study, both improve carbohydrate tolerance, therapy with exogenous insulin results in a pattern of postprandial carbohydrate metabolism that more closely approximates that observed in nondiabetic subjects.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

ObjectiveTo identify new genetic associations with juvenile and adult dermatomyositis (DM).MethodsWe performed a genome‐wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single‐nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS‐level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non‐MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C–like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C‐C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM.ConclusionOur findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non‐MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.

ABSTRACTIntroduction: We assessed proficiency (accuracy and intra‐ and intertest reproducibility) of smart quantitative sensation tests (smart QSTs) in subjects without and with diabetic sensorimotor polyneuropathy (DSPN). Methods: Technologists from 3 medical centers using different but identical QSTs independently assessed 6 modalities of sensation of the foot (or leg) twice in patients without (n = 6) and with (n = 6) DSPN using smart computer assisted QSTs. Results: Low rates of test abnormalities were observed in health and high rates in DSPN. Very high intraclass correlations were obtained between continuous measures of QSTs and neuropathy signs, symptoms, or nerve conductions (NCs). No significant intra‐ or intertest differences were observed. Conclusions: These results provide proof of concept that smart QSTs provide accurate assessment of sensation loss without intra‐ or intertest differences useful for multicenter trials. Smart technology makes possible efficient testing of body surface area sensation loss in symmetric length‐dependent sensorimotor polyneuropathies. Muscle Nerve 49: 645–653, 2014