Citations

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

Abstract Background Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. Methods DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan–Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. Results In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan–Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. Conclusion DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

AimsRecently, a novel isoform of anaplastic lymphoma kinase, with alternative transcription initiation (ALKATI), has been described in melanoma and is susceptible to targeted ALK‐inhibitor therapy. Clinical outcomes of patients with ALKATI mutated melanoma as well as correlation with immunohistochemical (IHC) methods have not yet been described.Methods and resultsClinicopathological characteristics were abstracted for 324 patients with metastatic melanoma (MM). IHC, fluorescence in‐situ hybridisation and RNA‐based digital molecular analysis assays were performed on archival tissue from 173 stage III and 192 stage IV tumours. ALKATI was identified in 12.7 and 4.8% stage III and IV tumours, respectively. Discrete presentations of the ALKATI are seen: isolated ALKATI (n = 20) and mixed ALKATI (combined ALKATI and ALKWT; n = 7). Isolated ALKWT expression (n = 4) was seen with no ALK fusions. Stage III patients showed improved survival with ALKATI expression compared to those with ALKWT or no expression [5‐year survival 80, 95% confidence interval (CI) = 57–100% versus 43%, 95% CI = 34–55%, P = 0.013]. Clinicopathological characteristics were not statistically significant. Strong diffuse cytoplasmic staining of ALK IHC (n = 12) has a sensitivity of 52.2%, specificity 100%, PPV of 100% and NPV of 92.5% of detecting isolated ALKATI.ConclusionPresence of ALKATI is a good prognostic indicator in MM. ALK IHC and digital molecular analysis can be incorporated into MM evaluation to identify patients with ALKATI for targeted therapy.

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Weight gain or loss is determined by the difference between calorie intake and energy expenditure. The Mifflin metabolic equation most accurately predicts resting energy expenditure (REE) in morbidly obese patients. Hypometabolizers have a measured REE that is much less than predicted and pose the greatest challenge for weight loss induced by restriction of calorie intake. We studied 628 morbidly obese patients (467 female and 161 men, aged 52.5 ± 15.7 years, body mass index [BMI] of 42.6 ± 7.6 m/kg 2 [mean ± SD]). REE was measured using the MedGem® device (REEm) and the percentage variance (δREE%) from the Mifflin-predicted expenditure (REEp) was calculated. Patients with δREE% more than 1 standard deviation from the mean were defined as hypometabolizers (REEm greater than 27% below REEp) and hypermetabolizers (REEm less than 13% above REEp), respectively. Hypometabolizers had greater REEp (1900 ± 301 vs 1719 ± 346 calories, P = 0.005) and lower REEm (1244 ± 278 vs 2161 ± 438 calories, P < 0.0001) than hypermetabolizers. Hypometabolizers, when compared with hypermetabolizers, were taller (167.2 ± 8.4 vs 164.0 ± 10.9 cm, P = 0.04), heavier (123.6 ± 22.2 vs 110.2 ± 23.1 kg, P = 0.006), and had increased BMI (44.1 ± 6.5 vs 40.8 ± 6.5 kg/m 2 , P = 0.04). Other measured anthropometrics were not different between hypo- and hypermetabolizers. Hypometabolizers were less likely to be diabetic (23 vs 43%, P = 0.03) and more likely to be black (25 vs 5%, P = 0.002) than hypermetabolizers. This study defines hypometabolizers as having variance in REEm more than 27 per cent below that predicted by the Mifflin equation. We could not identify any distinguishing phenotypic characteristics of hypometabolizers, suggesting an influence unrelated to body composition.

The objective of this study was to examine whether preoperative recommendation for specific reductions in body mass index (BMI) influenced weight loss in obese surgical patients. We retrospectively reviewed the electronic medical records of 48 patients who enrolled between January 2007 to June 2010 in an 800-calorie per day liquid meal replacement (LMR) weight loss program. Of these, 9 patients (surgical group) enrolled as a result of general surgeon-directed weight loss to enable nonbariatric surgery and 39 enrolled seeking weight loss (medical group). Patients enrolled in the LMR program before bariatric surgery were excluded from analysis. All patients were seen in the setting of a comprehensive weight loss program supervised by a medical bariatrician and followed for a period of 4 months. There were no significant differences in mean initial BMI between surgical and medical patients (41.7 ± 4.55 and 41.6 ± 8.54 kg/m 2 , respectively) or participation time in the weight loss program (120 days vs 133 days). Of the nine surgical patients, only five (56%) reached their weight goal and underwent the planned surgical procedure. Weight loss was significantly less in the surgical compared with medical patients (BMI reduction 4.03 ± 3.99 vs 7.75 ± 4.90 kg/m 2 , respectively; P < 0.05). Weight loss was significantly lower in patients directed to undergo BMI reduction to enable a general surgical procedure. Future studies are needed to assess factors influencing weight loss (metabolism, exercise capacity, motivation) in patients requiring weight loss to enable a surgical procedure.

Abstract BACKGROUND The tarnished plant bug, Lygus lineolaris (Palisot de Beauvois), has emerged as a major pest of cotton, Gossypium hirsutum L, in the mid‐southern USA. In the early 1990s L. lineolaris populations developed resistance to several classes of conventional insecticides, increasing the need for insecticides with alternative modes of action such as insect growth regulators (IGRs) for integrated pest management (IPM). The benzoylphenyl urea (BPU) class of IGRs acts by disrupting the growth and development of immature stages of insects, but little is known about its impact on adult stages. RESULTS The effect of novaluron (Diamond™ 0.83EC), a BPU with known chitin synthesis inhibitor activity, was investigated on adult females of L. lineolaris . Treatment of 1‐day‐old adults with 600 ppm of novaluron in the diet prevented oviposition, while treatment of older females had no impact on oviposition. Oral novaluron exposure of adults of all ages reduced the viability of eggs laid. Novaluron treatment caused ultrastructural changes in the ovaries of 1‐day‐old adults (48 h post exposure), distorting the follicular epithelial cell architecture of developing oocytes. Additionally, novaluron treatment decreased the chitin content in ovarian tissue. CONCLUSION Our results suggest that chitin or chitin‐like components in the developing ovaries of adult L. lineolaris are a target of IGRs such as novaluron, but its activity is specific to a critical time during development. This enhances our understanding of the effects of BPUs on adult insects and could lead to incorporation of IGRs in IPM for controlling adult insect pest populations in the field. © 2020 Society of Chemical Industry