Citations

PurposeLenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL).Patients and MethodsPatients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety.ResultsForty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively).ConclusionOral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.

AbstractThe clinical management of amyloidosis is based on the treatment of the underlying etiology, and accurate identification of the protein causing the amyloidosis is of paramount importance. Current methods used for typing of amyloidosis such as immunohistochemistry have low specificity and sensitivity. In this study, we report the development of a highly specific and sensitive novel test for the typing of amyloidosis in routine clinical biopsy specimens. Our approach combines specific sampling by laser microdissection (LMD) and analytical power of tandem mass spectrometry (MS)–based proteomic analysis. We studied 50 cases of amyloidosis that were well-characterized by gold standard clinicopathologic criteria (training set) and an independent validation set comprising 41 cases of cardiac amyloidosis. By use of LMD/MS, we identified the amyloid type with 100% specificity and sensitivity in the training set and with 98% in validation set. Use of the LMD/MS method will enhance our ability to type amyloidosis accurately in clinical biopsy specimens.

ABSTRACTCryptococcus neoformansandCryptococcus gattiiare closely related pathogenic fungi.Cryptococcus neoformansis ecologically widespread and affects primarily immunocompromised patients, whileC. gattiiis traditionally found in tropical climates and has been reported to cause disease in immunocompetent patients.l-Canavanine glycine bromothymol blue (CGB) agar can be used to differentiateC. neoformansandC. gattii, but there are few reports of its performance in routine clinical practice. Growth ofC. gattiion CGB agar produces a blue color, indicating the assimilation of glycine, whileC. neoformansfails to cause a color change. Using reference and clinical strains, we evaluated the ability of CGB agar and D2 large ribosomal subunit DNA sequencing (D2 LSU) to differentiateC. neoformansandC. gattii.One hundred two yeast isolates were screened for urease activity, melanin production, and glycine assimilation on CGB agar as well as by D2 sequencing. Seventeen of 17 (100%)C. gattiiisolates were CGB positive, and 54 of 54C. neoformansisolates were CGB negative. Several yeast isolates other than theC. gattiiisolates were CGB agar positive, indicating that CGB agar cannot be used alone for identification ofC. gattii.D2 correctly identified and differentiated allC. gattiiandC. neoformansisolates. This study demonstrates that the use of CGB agar, in conjunction with urea hydrolysis and Niger seed agar, or D2 LSU sequencing can be reliably used in the clinical laboratory to distinguishC. gattiifromC. neoformans. We describe how CGB agar and D2 sequencing have been incorporated into the yeast identification algorithm in our laboratory.

Abstract Eosinophils (Eos) are found at increased numbers within necrotic areas of tumors. We show that necrotic material from cell lysates containing damage-associated molecular pattern molecules induce eosinophil degranulation (release of major basic protein and eosinophil peroxidase) and enhance their oxidative burst while the stimulatory capacity of cell lysates is significantly diminished following oxidation. High mobility group box 1 (HMGB1), a prototypic damage-associated molecular pattern molecule, released following necrosis but not apoptosis, induced a similar effect on Eos. Additionally, we demonstrate that HMGB1 enhances eosinophil survival and acts as a chemoattractant. Consistently, we show that Eos express an HMGB1 receptor, the receptor for advanced glycation end product, and that anti-receptor for advanced glycation end product could diminish the HMGB1-mediated effects. Of all tested biologic activities, Eos respond most sensitively to the presence of necrotic material including HMGB1 with generation of peroxide. We postulate that Eos “sense” necrotic cell death, migrating to and responding to areas of tissue injury/necrosis. Oxidation of cell lysates reduces their biologic activity when compared with native lysates. We postulate that eosinophil-associated modulation of immunity within tumor and other damaged tissues may be primarily by promoting oxidative degradation of necrotic material. Novel therapeutic strategies may be considered by advancing oxidative denaturation of released necrotic material using Eos or other aerobic strategies.

AbstractBackgroundThe burden of disease, disability, and mortality that could be averted by surgery is growing. However, few low and middle income countries (LMICs) have the infrastructure or capacity to provide surgical services to meet this growing need. Equally, few of these countries have been assessed for key infrastructural capacity including surgical and anesthesia providers, equipment, and supplies. These assessments are critical to revealing magnitude of the evolving surgical and anesthesia workforce crisis, related morbidity and mortality, and necessary steps to mitigate the impact of the crisis.MethodsA pilot Internet‐based survey was conducted to estimate per‐capita anesthesia providers in LMICs. Information was obtained from e‐mail respondents at national health care addresses, and from individuals working in‐country on anesthesia‐related projects.ResultsWorkers from 6 of 98 countries responded to direct e‐mail inquiries, and an additional five responses came from individuals who were working or had worked in‐country at the time of the survey. The data collected revealed that the per‐capita anesthesia provider ratio in the countries surveyed was often 100 times lower than in developed countries.ConclusionsThis pilot study revealed that the number of anesthesia providers available per capita of population is markedly reduced in low and lower middle income countries compared to developed countries. As anesthesia providers are an integral part of the delivery of safe and effective surgical care, it is essential that more data is collected to fully understand the deficiencies in workforce and capacity in low and middle income countries.