Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

Antibiotics from Gram-negative bacteria: a comprehensive overview and selected biosynthetic highlights.

Covering: up to 2017The overwhelming majority of antibiotics in clinical use originate from Gram-positive Actinobacteria. In recent years, however, Gram-negative bacteria have become increasingly recognised as a rich yet underexplored source of novel antimicrobials, with the potential to combat the looming health threat posed by antibiotic resistance. In this article, we have compiled a comprehensive list of natural products with antimicrobial activity from Gram-negative bacteria, including information on their biosynthetic origin(s) and molecular target(s), where known. We also provide a detailed discussion of several unusual pathways for antibiotic biosynthesis in Gram-negative bacteria, serving to highlight the exceptional biocatalytic repertoire of this group of microorganisms.

A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Playskin Lift: Development and Initial Testing of an Exoskeletal Garment to Assist Upper Extremity Mobility and Function.

BACKGROUND: A person's ability to move his or her arms against gravity is important for independent performance of critical activities of daily living and for exploration that facilitates early cognitive, language, social, and perceptual-motor development. Children with a variety of diagnoses have difficulty moving their arms against gravity. OBJECTIVE: The purpose of this technical report is to detail the design process and initial testing of a novel exoskeletal garment, the Playskin Lift, that assists and encourages children to lift their arms against gravity. DESIGN: This report details the design theory and process, the device, and the results of field testing with a toddler with impaired upper extremity function due to arthrogryposis multiplex congenita. RESULTS: The Playskin Lift is an inexpensive (<$30 material costs), easy to use (5/5 rating), comfortable (5/5 rating), and attractive (4/5 rating) device. While wearing the device, the child was able to contact objects more often throughout an increased play space, to look at toys more while contacting them, and to perform more complex interactions with toys. LIMITATIONS: This report details initial testing with one child. Future testing with more participants is recommended. CONCLUSIONS: These results suggest that by considering the broad needs of users, including cost, accessibility, comfort, aesthetics, and function, we can design inexpensive devices that families and clinicians can potentially fabricate in their own communities to improve function, participation, exploration, and learning for children with disabilities.

Real-time polymerase chain reaction (PCR) assays for the specific detection and quantification of seven Eimeria species that cause coccidiosis in chickens.

Coccidiosis of chickens is an economically important disease caused by infection with species of Eimeria. The oocysts of some of the seven recognized species are difficult to distinguish morphologically and for this reason diagnostic laboratories are increasingly utilizing DNA-based technologies for the specific identification of Eimeria. The real-time PCR provides both sensitivity and speed for the analysis of DNA samples, and the approach has the capability of quantifying DNA. Together with a protocol for the extraction of DNA directly from faecal samples, real-time PCR assays have been established for the detection and quantification of seven species of Eimeria that infect chickens in Australia. The assays target one genetic marker, the second internal transcribed spacer of nuclear ribosomal DNA (ITS-2), use TaqMan MGB technology with species-specific probes, and can be multiplexed in pairs such that the seven species of Eimeria can be screened in four reaction tubes. A test screen of commercial flocks identified more Eimeria-infected chickens than were detected by coproscopic examination for oocysts. These molecular assays can also be used for the quality control of mixed-species vaccines. The ability to multiplex the assays makes them particularly practical for screening samples from chickens with mixed-species infections where the relative abundance of each Eimeria species present is required.

The risk of antimalarials in patients with renal failure.

We present here a patient with end stage renal failure who received two weeks antimalarial prophylaxis at full dose leading to life threatening toxicity with severe acute megaloblastic anaemia, symptomatic pancytopenia and exfoliative dermatitis. Prompt recognition and treatment can rapidly reverse these fatal effects but more importantly, education of patients before travel is imperative in preventing such events.

The successful treatment of chylous effusions in malignant disease with octreotide.

Chylous effusions in adults are commonly associated with malignant disease. Although the condition is rare, their occurrence presents a significant management problem. A review of the literature demonstrates the high mortality of this condition in the past from cachexia and infection or after surgical attempts at correction. The first report of somatostatin use in chylous effusions was a decade ago. Since 2000, case reports of successful treatment in infants and neonates with intravenous somatostatin or octreotide have been published. For adults, few reports exist. We describe a case series of seven patients, all with malignancy. In each case, there was a systematic approach to treatment using subcutaneous octreotide and a fat-free diet, resulting in complete resolution of the condition. Although no guidelines are available for the management of chylous effusions, our non-invasive approach avoided lymphangiogram, surgery and allowed early discharge.

Insulin lispro lowers postprandial glucose in prepubertal children with diabetes.

OBJECTIVE: This study compared the glucose-lowering effect of insulin lispro, given before or after meals, with regular human insulin given before meals in prepubertal children with diabetes. RESEARCH DESIGN AND METHODS: A 3-way crossover, open-label study involving 61 prepubertal children (ages 2.9-11.4 years) with type 1 diabetes. The children were randomly assigned to receive regular human insulin 30 to 45 minutes before meals, insulin lispro within 15 minutes before or immediately after meals, combined with basal insulin. Each treatment lasted 3 months. Hemoglobin A(1c) levels and home glucose monitoring profiles were measured at the end of each treatment period. RESULTS: Treatment with insulin lispro before breakfast resulted in lower 2-hour postprandial glucose values than regular human insulin (11.7 +/- 4.4 mmol/L vs 15.0 +/- 5.4 mmol/L). Similarly, insulin lispro given before dinner resulted in lower blood glucose values 2 hours postprandially (8.8 +/- 5.0 mmol/L vs 10.8 +/- 5.4 mmol/L) than regular human insulin. When insulin lispro was administered after meals, the 2-hour glucose levels were between those seen with either insulin lispro or regular human insulin given before meals. The number and types of adverse events, the rates of hypoglycemia, and the HbA(1c) levels did not differ among the 3 therapies. CONCLUSIONS: In prepubertal children, insulin lispro given before meals is safe and significantly lowers postprandial glucose levels after breakfast and dinner compared with regular human insulin, and insulin lispro given after the meal provides similar benefits as regular human insulin before the meal.

Localisation of a novel region of recurrent amplification in follicular lymphoma to an approximately 6.8 Mb region of 13q32-33.

Follicular lymphoma (FL) is characterised by the presence of the t(14;18)(q32;q21) and represents approximately 25% of new cases of non-Hodgkin's lymphoma. While the t(14;18) is a well-documented rearrangement, the role of secondary cytogenetic abnormalities in the development and progression of these tumours remains unclear. Comparative genomic hybridisation was used to characterise changes in DNA copy number in tumour DNA from patients with this malignancy. The mean numbers of deletion and amplification events found in each of the 45 samples studied were 1.8 and 2.3, respectively. Regions of recurrent (>10% tumour samples) gain involved chromosomes 2p13-16 (16%), 7 (20%), 12 (16%), 13q21-33 (18%), 18 (27%), and X (36%) and frequent losses localised to 6q (29%) and 17p (20%). Amplification of chromosome 13 represents a novel finding in FL. The minimal amplified region was refined to a 6.8-Mb interval of 13q32-33 between the BAC clones 88K16 and 44H20 by fluorescence in situ hybridisation studies using metaphase chromosomes derived from tumour material. There are a number of reports in the literature suggesting that amplification of chromosome 13 also occurs in other human cancers. The location of the putative oncogene on 13q described here in follicular and transformed lymphoma may also be important in the evolution of many other malignancies.

Successful therapy of transplant-associated veno-occlusive disease with a combination of tissue plasminogen activator and defibrotide.

A 36-year-old man underwent matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia. He developed severe hepatic veno-occlusive disease as an early post-transplant complication. Tissue plasminogen activator was initially felt to be contraindicated since the patient had concomitant pericarditis. Defibrotide was therefore commenced as treatment for veno-occlusive disease. The pericarditis improved but the veno-occlusive disease continued to worsen (peak bilirubin 353 micromol/l). Tissue plasminogen activator followed by a heparin infusion was therefore administered. However, he proceeded to develop haemorrhagic cardiac tamponade that required drainage. Thrombolysis was therefore discontinued and treatment with defibrotide resumed after an interval of 48 h. The veno-occlusive disease gradually resolved and defibrotide was discontinued once the bilirubin had plateaued. He was discharged home on day +52 post-transplant.

Cyclosporin A treatment of young children with newly-diagnosed type 1 (insulin-dependent) diabetes mellitus. London Diabetes Study Group.

Several studies have demonstrated the efficacy of cyclosporin A in modifying the initial course of Type 1 (insulin-dependent) diabetes mellitus in older children and adults but none have reported the effects in very young children. We treated 14 newly-diagnosed Type 1 diabetic patients aged 22 months to 95 months with cyclosporin A. Mean insulin dose at entry was 0.7 +/- 0.07 IU.kg-1.day-1. Initial cyclosporin A dose was 10 mg.kg-1.day-1. Insulin dose reached a nadir of 0.13 IU.kg-1.day-1 by 180 days. Mean glucagon-stimulated connecting peptide levels were maximal at 6 months (0.75 nmol/l) and were maintained while on cyclosporin A. Insulin was discontinued in four patients for 4, 12, 15 and 30 months respectively. In five other patients the insulin dose was less than 0.15 IU.kg-1.day-1 for at least 3 months. Glycated haemoglobin levels for all patients were within the normal range. Side effects included anorexia, stomach pains, poor weight gain, hypertrichosis, gum hyperplasia, mild anaemia and elevated creatinine. All patients have now discontinued cyclosporin A and all but one have been followed for 5 years after discontinuation. Reasons for discontinuing cyclosporin A included exposure to chicken pox (varicella), non-resolving otitis media, incomplete or no response and relapse. All side effects have resolved since the treatment was discontinued. Following discontinuation of cyclosporin A insulin requirements and glycated hemoglobin levels increased while glucagon-stimulated connecting peptide levels declined dramatically.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatotoxicity in a rat model caused by orally administered methotrexate.

We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 micrograms/kg/day doses for variable lengths of time. The 300 micrograms/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 micrograms/kg/day, four of the five rats receiving 150 micrograms/kg/day and five of the five rats on 100 micrograms/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 micrograms/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity.

Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis.

Serial liver biopsy specimens from 18 patients with rheumatoid arthritis receiving a weekly dose of methotrexate 7.5-20 mg for a minimum of 12 months were assessed semiquantitatively and by a microcomputer image analysis system. The semiquantitative histological method showed a significant increase in pericellular collagen and in overall disease while morphometry showed a significant increase in pericellular, perivenular, and portal tract collagen. There was a significant correlation between the two methods, but morphometry had the advantage of objectivity and efficiency. There was no correlation between the increase in collagen and the accumulated dose of methotrexate, which suggests that other factors in addition to methotrexate may contribute to liver injury.

Endocrine-metabolic function in remission-phase IDDM during administration of cyclosporine.

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)