Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities. ...Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal. We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM. Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002-2011). African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase. Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents. While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival. While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials. Improved minority accrual in therapeutic clinical trials needs to be a priority.
In the light of experiences gathered in the surgical treatment of over 1500 cases of rhegmatogenous retinal detachment in a period of 12 years the authors believe that, despite advances in surgical ...technique and the prospects of further technical improvements outlined here our therapeutic capability will not be increased sufficiently to enable us to cure "malignant" detachments. Hence the authors think that there is a certain limit to the number of successful operations which will not be exceeded. This limit is 80-85% in unselected material and about 95% in cases with good prognosis.
The analysis of plasma cell-free DNA (cfDNA) is expected to provide useful biomarkers for early diagnosis of non-small-cell lung cancer (NSCLC). However, it remains unclear whether the intense ...release of cfDNA into the bloodstream of NSCLC patients results from malignancy or chronic inflammatory response. Consequently, the current diagnostic utility of plasma cfDNA quantification has not been thoroughly validated in subjects with chronic respiratory inflammation. Here we assess the effect of chronic respiratory inflammation on plasma cfDNA levels and evaluate the potential clinical value of this phenomenon as an early lung cancer diagnostic tool.
We measured plasma cfDNA concentrations in 50 resectable NSCLC patients, 101 patients with chronic respiratory inflammation (chronic obstructive pulmonary disease, sarcoidosis, or asthma) and 40 healthy volunteers using real-time PCR.
We found significantly higher plasma cfDNA levels in NSCLC patients than in subjects with chronic respiratory inflammation and healthy individuals (P<0.0001). There were no significant differences in plasma cfDNA levels between patients with chronic respiratory inflammation and healthy volunteers. The cutoff point of >2.8 ng ml(-1) provided 90% sensitivity and 80.5% specificity in discriminating NSCLC from healthy individuals (area under the curve (AUC)=0.90). The receiver-operating characteristics curve distinguishing NSCLC patients from subjects with chronic respiratory inflammation indicated 56% sensitivity and 91% specificity at the >5.25-ng ml(-1) cutoff (AUC=0.76).
We demonstrated that elevated plasma cfDNA levels in NSCLC resulted primarily from tumour development rather than inflammatory response, raising the potential clinical implications for lung cancer screening and early diagnosis. Further research is necessary to better characterise and identify factors and processes regulating cfDNA levels in the blood under normal and pathological conditions.
Branched-chain amino acid requirements have traditionally been determined using dose-response titrations without accounting for the influence of branched-chain amino acid antagonism. As recent data ...has indicated that inherent levels of the non-tested amino acid may influence response curves in diets mimicking industry, these methods may result in over or under estimation of requirement values. Therefore, an experiment was conducted to determine if dietary levels of isoleucine and leucine influence 29 to 42 day valine needs through the implementation of a 5 × 2 × 2 factorial design. Twenty diets were fed to 7 replicate pens of 12 broilers. Body weight gain, feed intake, and FCR were determined for the 29 to 42 day period, and carcass traits were assessed on day 44. Valine × isoleucine and valine × leucine interactions were observed for BW gain and total breast yield (P < 0.10). Body weight gain requirements ranged from 73 to 81 Val/Lys, whereas responses for total breast yield were generally negative. A 3 way interaction was observed for FCR in which requirements varied from 75 to 82 Val/Lys. These interactions indicate that formulation strategies based on previous data concerning valine or isoleucine may not produce the desired response in Cobb MV × 500 broilers and that the branched-chain amino acids should be considered as a whole and not individually.
Summary
Carfilzomib is a next‐generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed ...and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open‐label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1–3 prior therapies, including at least one bortezomib‐based regimen, received carfilzomib 20 mg/m2 in a twice‐weekly, consecutive‐day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single‐agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.
Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of ...resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.
► P5091 is a potent and selective inhibitor of deubiquitylating enzyme USP7 ► P5091 triggers in vitro and in vivo antimyeloma activity ► P5091 activates HDM2/p53/p21 signaling axis ► Synergistic anti-MM activity of P5091 with SAHA, lenalidomide, or dexamethasone
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