Nevin Manimala

ESMO Open. 2021 Apr 30;6(3):100124. doi: 10.1016/j.esmoop.2021.100124. Online ahead of print.

ABSTRACT

BACKGROUND: The role of tumor mutational burden (TMB) is still debated for selecting advanced non-oncogene addicted non-small-cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs). Of note, TMB failed to predict a benefit in overall survival (OS) among such patients.

MATERIALS AND METHODS: The purpose of this meta-analysis was to compare efficacy outcomes among first-line immune-oncology (IO) agents versus standard platinum-based chemotherapy (CT) within two subgroups (TMB-low and TMB-high on either tissue or blood). We collected hazard ratios (HRs) to evaluate the association for progression-free survival (PFS) and OS, with the relative 95% confidence intervals (CIs). Risk ratios (RRs) were used as an association measure for objective response rate (ORR).

RESULTS: Eight different cohorts of five randomized controlled phase III studies (3848 patients) were analyzed. In TMB-high patients, IO agents were associated with improved ORR (RRs 1.37, 95% CI 1.13-1.66), PFS (HR 0.69, 95% CI 0.61-0.79) and OS (HR 0.67, 95% CI 0.59-0.77) when compared with CT, thus suggesting a possible predictive role of high TMB for IO regimens. In TMB-low patients, the IO strategy did not lead to any significant benefit in survival and activity, whereas the pooled results of both ORR and PFS were intriguingly associated with a statistical significance in favor of CT.

CONCLUSIONS: This meta-analysis resulted in a proven benefit in OS in favor of IO agents in the TMB-high population. Although more prospective data are warranted, we postulated the hypothesis that monitoring TMB, in addition to the existing programmed death-ligand 1 (PD-L1) expression level, could represent the preferable option for future clinical research in the first-line management of advanced non-oncogene addicted NSCLC patients.

PMID:33940346 | DOI:10.1016/j.esmoop.2021.100124

Arch Endocrinol Metab. 2021 Apr 29:2359-3997000000367. doi: 10.20945/2359-3997000000367. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine sonographic features of malignancy in partially cystic thyroid nodules and assess the diagnostic efficacy of these features for differentiating between benign and malignant lesions in the nodules with indeterminate cytology.

METHODS: From January 2016 to December 2017, a total of 91 patients with 94 partially cystic thyroid nodules who had undergone ultrasound-guided fine-needle aspiration biopsy and thyroid surgery in our hospital were included in this study. The sonographic features of the thyroid nodules were analyzed to identify the predictive features of malignancy and assess the diagnostic efficacy of these features.

RESULTS: The features of hypoechogenicity, microcalcification, composition, and an eccentric solid component with an acute angle had statistically significant associations with malignant nodule (p<005) by univariable analysis. Binary logistic regression analysis showed that microcalcification and hypoechogenicity were significantly associated with malignancy. Using the combination of microcalcification, hypoechogenicity, and a solid component comprising of greater than or equal to 50% of the total volume, the diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 97.6%, 32.7%, 53.9%, and 94.4%, respectively. In these nodules with indeterminate cytology, this combination also exhibited a high sensitivity of 92.3% and an NPV of 83.3%.

CONCLUSION: This study demonstrated that microcalcification and hypoechogenicity were independently associated with malignancy in partially cystic thyroid nodules. The combination of microcalcification, hypoechogenicity, and a solid portion that is greater than or equal to 50% of the total volume will help guide clinical decisions in mixed cystic solid nodules.

PMID:33939910 | DOI:10.20945/2359-3997000000367

Arch Endocrinol Metab. 2021 Apr 29:2359-3997000000365. doi: 10.20945/2359-3997000000365. Online ahead of print.

ABSTRACT

OBJECTIVE: People with Down’s syndrome (DS) have a higher risk of developing type 1 diabetes mellitus (T1D) and may have specific clinical features compared to T1D patients without DS. This study evaluated the clinical and laboratory aspects of T1D in children and adolescents with DS in an admixed population.

METHODS: A case-control study comparing patients with T1D and DS (T1D+DS) to patients with T1D without DS (T1D controls) from two tertiary academic Hospitals in São Paulo, Brazil.

RESULTS: The sample consisted of 9 patients with T1D+DS and 18 T1D age and sex-matched controls. Anti-glutamic acid decarboxylase 65 antibodies were positive in 7/7 of the 9 T1D+DS patients, confirming the presence of diabetes autoimmunity in this group. Mean age at diagnosis of T1D was 4.9 ± 3.9 years in the T1D+DS group and 6.4 years ± 3 in the T1D control group; early diagnosis (<2 years old) occurred in three T1D+DS patients but only in one T1D control patients, both suggesting lower age of diagnosis in T1D+DS group, although without statistical significance (p = 0.282 and p = 0.093, respectively). The T1D+DS group presented lower total insulin dose (0.7 IU/kg/day ± 0.2) and HbA1c (7.2% ± 0.6) than the control group (1.0 IU/kg/day ± 0.3 and 9.1% ± 0.7, respectively) (p = 0.022 and p = 0.047, respectively).

CONCLUSION: We confirmed the autoimmune etiology of diabetes in people with DS in this admixed population. T1D+DS patients developed diabetes earlier and achieved better metabolic control with a lower insulin dose than T1D controls. These findings are in agreement with previous studies in Caucasian populations.

PMID:33939908 | DOI:10.20945/2359-3997000000365

Radiol Oncol. 2021 May 4. doi: 10.2478/raon-2021-0019. Online ahead of print.

ABSTRACT

BACKGROUND: Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy.

PATIENTS AND METHODS: A retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups.

RESULTS: Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.

CONCLUSIONS: Patients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.

PMID:33939899 | DOI:10.2478/raon-2021-0019

J Pediatr Endocrinol Metab. 2021 May 3. doi: 10.1515/jpem-2020-0642. Online ahead of print.

ABSTRACT

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the pediatric population at global level. Present study aims to assess the effect of l-carnitine supplementation on the NAFLD in children and adolescents.

METHODS: This randomized, triple-blind, placebo-controlled clinical trial was conducted in 2018-2019. Study was carried out in NAFLD participants (5-15 years). They were randomly assigned to receive either 50 mg/kg/day l-carnitine twice a day or identical placebo per day for three months. Liver enzymes and liver ultrasonography were assessed before and after the intervention. Both groups received similar consultation for lifestyle changes.

RESULTS: Overall, 55 participants completed the study, 30 patients in the l-carnitine group and 25 patients in placebo group. Mean changes of anthropometric measurements did not have significant differences between groups (p>0.05). No significant differences in the mean changes of aspartate aminotransferase (AST) (p=0.82) and alanine aminotransferase (ALT) (p=0.76) levels were documented between two groups. Based on within-group analysis, there were significant changes in AST and ALT levels before and after the intervention in both groups. The sonographic grades of fatty liver were not significantly different between two groups before (p=0.94) and after intervention (p=0.93).

CONCLUSIONS: In the present clinical trial, L-carnitine did not have significant effect on improving biochemical and sonographic markers of NAFLD in children and adolescents. Future studies are necessary to evaluate the applicability and efficacy of long-term l-carnitine supplementation to treatment of NAFLD in pediatric population.

TRIAL REGISTRATION: IRCT20170628034786N2.

PMID:33939897 | DOI:10.1515/jpem-2020-0642

Environ Microbiol. 2021 May 3. doi: 10.1111/1462-2920.15554. Online ahead of print.

ABSTRACT

Fungi have evolved diverse lifestyles and adopted pivotal new roles in both natural ecosystems and human environments. However, the molecular mechanisms underlying their adaptation to new lifestyles are obscure. Here, we hypothesize that genes shared across all species with the same lifestyle, but absent in genera with alternative lifestyles, are crucial to that lifestyle. By analyzing dozens of species within four genera in a fungal order, with each genus following a different lifestyle, we find that genus-specific genes are typically few in number. Notably, not all genus-specific genes appear to derive from de novo birth, with most instead reflecting recurrent loss across the fungi. Importantly, however, a subset of these genus-specific genes are shared by fungi with the same lifestyle in quite different evolutionary orders, thus supporting the view that some genus-specific genes are necessary for specific lifestyles. These lifestyle-specific genes are enriched for key functional classes and often exhibit specialized expression patterns. Genus-specific selection also contributes to lifestyle transitions, and is especially associated with intensity of pathogenesis. Our study therefore suggests that fungal adaptation to new lifestyles often requires just a small number of core genes, with gene turnover and positive selection playing complementary roles. This article is protected by copyright. All rights reserved.

PMID:33939870 | DOI:10.1111/1462-2920.15554

J Gastroenterol Hepatol. 2021 May 3. doi: 10.1111/jgh.15535. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Despite widespread recommendations and use of intravenous corticosteroids (IVCS) for the treatment of acute flares of ulcerative colitis and Crohn’s disease, limited evidence exists comparing outcomes of the two most common regimens, intravenous methylprednisolone (IVMP) and intravenous hydrocortisone (IVHC). IVHC has stronger mineralocorticoid effects compared to IVMP and may cause higher rates of hypokalaemia. We aimed to determine differences in clinical outcomes including requirement for inpatient rescue therapy, bowel resection and rates of hypokalaemia.

METHODS: We conducted a multicentre cohort study of all adult patients admitted with an acute flare of inflammatory bowel disease (IBD) to the three tertiary hospitals in Auckland, New Zealand where the protocol at each institution is either IVMP 60 mg daily or IVHC 100 mg four times daily. All patients requiring IVCS between 20 June 2016 and 30 June 2018 were included. The IVCS protocol was then changed at one hospital, where further data was collected for a further 12 months from 30 January 2019 until 30 December 2019.

RESULTS: There were 359 patients, including 129 (35.9%) patients receiving IVMP and 230 (64.1%) patients receiving IVHC. IVMP treatment was associated with a greater requirement for rescue therapy than IVHC (36.4% vs 19.6%, p=0.001; odds ratio [OR]= 2.79; 95% confidence interval [CI], 1.64-4.75, p<0.001), but also reduced rates of hypokalaemia (55.8% vs 67.0%, p=0.04; OR=0.49; 95% CI, 0.30-0.81, p=0.005). There was no difference between treatment groups for the median length of admission (5 days, interquartile range, IQR 3-8), median duration of IVCS treatment (3 days, IQR 2-5) or bowel resection within 30 days of admission (12.4% vs 11.7%; OR=1.04).

CONCLUSION: For the treatment of an acute flare of IBD, treatment with IVMP results in significantly more requirement for inpatient rescue biologic or cyclosporin. In addition, it causes statistically significant less hypokalemia than IVHC, although in practice differences are negligible.

PMID:33939853 | DOI:10.1111/jgh.15535

Environ Toxicol Chem. 2021 May 3. doi: 10.1002/etc.5078. Online ahead of print.

ABSTRACT

The Amphibian Metamorphosis Assay (AMA, OPPTS 890.1100, 2009 and OECD TG 231, 2009) has been used for over a decade to assess potential thyroid (T)-mediated endocrine activity of chemicals. In 2013, in the context of the Endocrine Disruptor Screening Program of the United States Environmental Protection Agency, a Scientific Advisory Panel reviewed the results from 18 studies and recommended changes to the AMA Test Guideline (TG), including a modification to a fixed-stage design rather than a fixed-time (i.e., 21-day) design. In this paper, we describe an extended test design for the AMA (or EAMA) that includes thyroid histopathology and time to metamorphosis (Nieuwkoop-Faber, NF stage 62) in order to address both the issues with the fixed-time design and the specific question of T-mediated adversity in a shorter assay than the Larval Amphibian Growth and Development Assay (LAGDA, OECD TG 241), using fewer animals and resources. A demonstration study was conducted with the EAMA (up to NF stage 58) using sodium-perchlorate. Data analyses and interpretation of the fixed-stage design of the EAMA are more straightforward than the fixed-time design because it avoids confounded morphometric measurements and thyroid histopathology, caused by varying developmental stages at test termination. It also results in greater statistical power to detect metamorphic delays than the fixed-time design. By preferentially extending the AMA to NF stage 62, suitable data can be produced to evaluate T-mediated adversity and preclude the need to perform a LAGDA for thyroid mode of action analysis. The LAGDA remains of further interest should investigations of longer-term effects related to sexual development modulated though the hypothalamus-pituitary gonadal (HPG) axis be necessary. However, reproduction assessment or life-cycle testing is currently not addressed in the LAGDA study design. This is better addressed by higher-tier studies in fish, which should then include specific T-related endpoints. This article is protected by copyright. All rights reserved.

PMID:33939850 | DOI:10.1002/etc.5078

Schizophr Bull. 2021 May 3:sbab041. doi: 10.1093/schbul/sbab041. Online ahead of print.

ABSTRACT

There is limited research in adolescents at risk for psychosis. The new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition attenuated psychosis syndrome (DSM-5 APS) criteria have not been validated in this group. We conducted a RECORD-compliant, real-world, prospective, 5-year cohort study addressing clinical profile, transition to psychosis, and prognostic accuracy of DSM-5 APS in help-seeking inpatient/outpatient adolescents accessing Children and Adolescent Neuropsychiatric services at IRCCS Mondino Foundation (Pavia, Lombardy, Italy) between 2012 and 2019. About 243 adolescents (31 early-onset psychosis [EOP]; 110 meeting DSM-5 APS criteria, DSM-5 APS; 102 not meeting psychotic or DSM-5 APS criteria, non-APS) were included. At baseline, DSM-5 APS adolescents (aged 15.4 ± 1.6) had on average 2.3 comorbid disorders (higher than EOP/non-APS, P < .001). DSM-5 APS adolescents had an intermediate psychopathological profile between non-APS/EOP (P < .001) and worsen Clinical Global Impression-Severity than non-APS (P < .001). DSM-5 APS functioning was intermediate between non-APS and EOP. 39.1% of DSM-5 APS were treated with psychotropic drugs (average = 64 days); 53.6% received psychotherapy. Follow-up of DSM-5 APS and non-APS groups lasted 33 and 26 months, respectively (median). The cumulative risk of transition at 1-5 years was 13%, 17%, 24.2%, 26.8%, and 26.8% in the DSM-5 APS group, 0%, 0%, 3.2%, 3.2%, and 3.2% in the non-APS group. The 5-year prognostic accuracy of the DSM-5 APS in adolescent was adequate (area under the curve = 0.77; Harrell’s C = 0.736, 95%CI 0.697-0.775), with high sensitivity (91.3%) and suboptimal specificity (63.2%). The DSM-5 APS diagnosis can be used to detect help-seeking adolescents at risk of psychosis and predict their long-term outcomes. Future research should consolidate these findings.

PMID:33939829 | DOI:10.1093/schbul/sbab041

Mil Med. 2021 May 3:usab168. doi: 10.1093/milmed/usab168. Online ahead of print.

ABSTRACT

INTRODUCTION: Special Weapons and Tactics (SWAT) personnel who practice breaching with blast exposure are at risk for blast-related head trauma. We aimed to investigate the impact of low-level blast exposure on underlying white matter (WM) microstructure based on diffusion tensor imaging (DTI) and neurite orientation and density imaging (NODDI) in SWAT personnel before and after breacher training. Diffusion tensor imaging is an advanced MRI technique sensitive to underlying WM alterations. NODDI is a novel MRI technique emerged recently that acquires diffusion weighted data from multiple shells modeling for different compartments in the microstructural environment in the brain. We also aimed to evaluate the effect of a jugular vein compression collar device in mitigating the alteration of the diffusion properties in the WM as well as its role as a moderator on the association between the diffusion property changes and the blast exposure.

MATERIALS AND METHODS: Twenty-one SWAT personnel (10 non-collar and 11 collar) completed the breacher training and underwent MRI at both baseline and after blast exposure. Diffusion weighted data were acquired with two shells (b = 1,000, 2,000 s/mm2) on 3T Phillips scanners. Diffusion tensor imaging metrices, including fractional anisotropy, mean, axial, and radial diffusivity, and NODDI metrics, including neurite density index (NDI), isotropic volume fraction (fiso), and orientation dispersion index, were calculated. Tract-based spatial statistics was used in the voxel-wise statistical analysis. Post hoc analyses were performed for the quantification of the pre- to post-blast exposure diffusion percentage change in the WM regions with significant group difference and for the assessment of the interaction of the relationship between blast exposure and diffusion alteration.

RESULTS: The non-collar group exhibited significant pre- to post-blast increase in NDI (corrected P < .05) in the WM involving the right internal capsule, the right posterior corona radiation, the right posterior thalamic radiation, and the right sagittal stratum. A subset of these regions showed significantly greater alteration in NDI and fiso in the non-collar group when compared with those in the collar group (corrected P < .05). In addition, collar wearing exhibited a significant moderating effect for the alteration of fiso for its association with average peak pulse pressure.

CONCLUSIONS: Our data provided initial evidence of the impact of blast exposure on WM diffusion alteration based on both DTI and NODDI. The mitigating effect of WM diffusivity changes and the moderating effect of collar wearing suggest that the device may serve as a promising solution to protect WM against blast exposure.

PMID:33939823 | DOI:10.1093/milmed/usab168