Nevin Manimala

Clin Cancer Res. 2024 Aug 6. doi: 10.1158/1078-0432.CCR-24-1215. Online ahead of print.

ABSTRACT

PURPOSE: In radiotherapy (RT) for brain tumors, patient heterogeneity masks treatment effects, complicating the prediction and mitigation of radiation-induced brain necrosis. Therefore, understanding this heterogeneity is essential for improving outcome assessments and reducing toxicity.

EXPERIMENTAL DESIGN: We developed a clinically practical pipeline to clarify the relationship between dosimetric features and outcomes by identifying key variables. We processed data from a cohort of 130 patients treated with proton therapy for brain and head and neck tumors, utilizing an expert-augmented Bayesian network to understand variable interdependencies and assess structural dependencies. Critical evaluation involved a 3-level grading system for each network connection and a Markov blanket analysis to identify variables directly impacting necrosis risk. Statistical assessments included log-likelihood ratio (LLR), integrated discrimination index (IDI), net reclassification index (NRI), and receiver operating characteristic (ROC).

RESULTS: The analysis highlighted tumor location and proximity to critical structures like white matter and ventricles as major determinants of necrosis risk. The majority of network connections were clinically supported, with quantitative measures confirming the significance of these variables in patient stratification (LLR=12.17, p=0.016; IDI=0.15; NRI=0.74). The ROC curve area was 0.66, emphasizing the discriminative value of non-dosimetric variables.

CONCLUSIONS: Key patient variables critical to understanding brain necrosis post-RT were identified, aiding the study of dosimetric impacts and providing treatment confounders and moderators. This pipeline aims to enhance outcome assessments by revealing at-risk patients, offering a versatile tool for broader applications in RT to improve treatment personalization in different disease sites.

PMID:39106090 | DOI:10.1158/1078-0432.CCR-24-1215

JAMA Netw Open. 2024 Aug 1;7(8):e2426830. doi: 10.1001/jamanetworkopen.2024.26830.

NO ABSTRACT

PMID:39106071 | DOI:10.1001/jamanetworkopen.2024.26830

JAMA Netw Open. 2024 Aug 1;7(8):e2425993. doi: 10.1001/jamanetworkopen.2024.25993.

NO ABSTRACT

PMID:39106070 | DOI:10.1001/jamanetworkopen.2024.25993

JAMA Netw Open. 2024 Aug 1;7(8):e2425288. doi: 10.1001/jamanetworkopen.2024.25288.

ABSTRACT

IMPORTANCE: Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant.

OBJECTIVE: To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC.

DESIGN, SETTING, AND PARTICIPANTS: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022.

INTERVENTION: The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo.

MAIN OUTCOMES AND MEASURES: The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS.

RESULTS: Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo.

CONCLUSIONS AND RELEVANCE: In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01120249.

PMID:39106067 | DOI:10.1001/jamanetworkopen.2024.25288

JAMA Netw Open. 2024 Aug 1;7(8):e2426076. doi: 10.1001/jamanetworkopen.2024.26076.

ABSTRACT

IMPORTANCE: The role of olanzapine has not been adequately evaluated in moderately emetogenic chemotherapy (MEC) regimens with or without neurokinin-1 receptor antagonists.

OBJECTIVE: To evaluate whether addition of olanzapine to an MEC regimen reduces nausea, vomiting, and use of nausea rescue medications among patients with solid malignant tumors.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, open-label phase 3 randomized clinical trial included patients aged 18 years or older with solid malignant tumors who were receiving oxaliplatin-, carboplatin-, or irinotecan-based chemotherapy. The trial was conducted at 3 institutes in India from March 26, 2019, to August 26, 2023; the final cutoff date for analysis was September 10, 2023.

EXPOSURE: Patients were randomized 1:1 to dexamethasone, aprepitant, and palonosetron with olanzapine (experimental group) or without olanzapine (observation group). The experimental group received 10 mg of olanzapine orally once at night on days 1 through 3 of the chemotherapy regimen.

MAIN OUTCOMES AND MEASURES: The primary end point was complete response (CR), defined as the proportion of patients with no vomiting, no significant nausea (scored as <5 on a visual analog scale of 1 to 100), and no use of rescue medications for nausea. Secondary end points included the proportion of patients experiencing nausea and chemotherapy-induced nausea and vomiting (CINV), receiving rescue medications, and experiencing adverse events.

RESULTS: A total of 560 patients (259 [64%] male; median age, 51 years [range, 19-80 years]) were randomized. The analysis included 544 patients with evaluable data (274 assigned to olanzapine and 270 to observation). Baseline characteristics were evenly matched between the 2 groups. The proportion of patients with CR was significantly greater in the group with (248 [91%]) than without (222 [82%]) olanzapine in the overall 120-hour treatment period (P = .005). Likewise, there were significant differences between the olanzapine and observation groups for nausea control (264 [96%] vs 234 [87%]; P < .001) and CINV (262 [96%] vs 245 [91%]; P = .02) during the overall assessment period, and the proportion of patients receiving rescue medications significantly increased in the observation group (30 [11%]) compared with the olanzapine group (11 [4%]) (P = .001). Grade 1 somnolence was reported by 27 patients (10%) following administration of chemotherapy and olanzapine and by no patients in the observation group.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of olanzapine significantly improved CR rates as well as nausea and vomiting prevention rates in chemotherapy-naive patients who were receiving MEC regimens containing oxaliplatin, carboplatin, or irinotecan. These findings suggest that use of olanzapine should be considered as one of the standards of care in these chemotherapy regimens.

TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) Identifier: CTRI/2018/12/016643.

PMID:39106066 | DOI:10.1001/jamanetworkopen.2024.26076

JAMA Netw Open. 2024 Aug 1;7(8):e2426209. doi: 10.1001/jamanetworkopen.2024.26209.

ABSTRACT

IMPORTANCE: Deliberate self-poisoning using pesticides as a means of suicide is an important public health problem in low- and middle-income countries. Three highly toxic pesticides-dimethoate, fenthion, and paraquat-were removed from the market in Sri Lanka between 2008 and 2011. In 2015, less toxic pesticides (chlorpyrifos, glyphosate, carbofuran, and carbaryl) were restricted. Subsequent outcomes have not been well described.

OBJECTIVE: To explore the association of pesticide bans with pesticide self-poisonings and in-hospital deaths.

DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study with an interrupted time series design, data were prospectively collected on all patients with deliberate self-poisonings presenting to 10 Sri Lankan hospitals between March 31, 2002, and December 31, 2019, and analyzed by aggregated types of poisoning. The correlates of pesticide bans were estimated within the pesticide group and on self-poisonings within other substance groups. The data analysis was performed between April 1, 2002, and December 31, 2019.

EXPOSURES: Implementation of 2 sets of pesticide bans.

MAIN OUTCOMES AND MEASURES: The main outcomes were changes in hospital presentations and in-hospital deaths related to pesticide self-poisoning as measured using segmented Poisson regression.

RESULTS: A total of 79 780 patients (median [IQR] age, 24 [18-34] years; 50.1% male) with self-poisoning from all causes were admitted to the study hospitals, with 29 389 poisonings (36.8%) due to pesticides. A total of 2859 patients died, 2084 (72.9%) of whom had ingested a pesticide. The first restrictions that targeted acutely toxic, highly hazardous pesticides were associated with an abrupt and sustained decline of the proportion of poisonings with pesticides (rate ratio [RR], 0.85; 95% CI, 0.78-0.92) over the study period and increases in poisonings with medications (RR, 1.11; 95% CI, 1.02-1.21) and household and industrial chemicals (RR, 1.20; 95% CI, 1.05-1.36). The overall case fatality of pesticides significantly decreased (RR, 0.33; 95% CI, 0.26-0.42) following the implementation of the 2008 to 2011 restrictions of highly hazardous pesticides. Following the 2015 restrictions of low-toxicity pesticides, hospitalizations were unchanged, and the number of deaths increased (RR, 1.98; 95% CI, 1.39-2.83).

CONCLUSIONS AND RELEVANCE: These findings support the restriction of acutely toxic pesticides in resource-poor countries to help reduce hospitalization for and deaths from deliberate self-poisonings and caution against arbitrary bans of less toxic pesticides while more toxic pesticides remain available.

PMID:39106063 | DOI:10.1001/jamanetworkopen.2024.26209

Radiol Med. 2024 Aug 6. doi: 10.1007/s11547-024-01863-2. Online ahead of print.

ABSTRACT

PURPOSE: There is an unmet clinical need for non-invasive imaging biomarkers that could replace liver biopsy in the management of patients with autoimmune hepatitis (AIH). In this study, we sought to evaluate the diagnostic accuracy of a simple uncorrected, non-contrast T1 mapping for detecting fibrosis and inflammation in AIH patients using histopathology as a reference standard.

MATERIAL AND METHODS: Over 3 years, 33 patients with AIH were prospectively studied using a multiparametric liver MRI protocol which included T1 mapping. Biopsies were performed up to 3 months before imaging, and a standardized histopathological score for fibrosis (F0-F4) and inflammatory activity (PPA0-4) was used as a reference. Statistical analysis included independent t test, Mann-Whitney U-test, and ROC (receiver operating characteristic) analysis.

RESULTS: T1 mapping values were significantly higher in patients with advanced fibrosis (F0-2 vs. F3-4; p < 0.015), significant fibrosis (F0-1 vs. F2-4; p < 0.005), and significant inflammatory activity (PPA 0-1 vs. PPA 2-4 p = 0.048). Moreover, the technique demonstrated a good diagnostic performance in detecting significant (AUC 0.856) and advanced fibrosis (AUC 0.835), as well as significant inflammatory activity (AUC 0.763).

CONCLUSION: A rapid, simple, uncorrected, non-contrast T1 mapping sequence showed satisfactory diagnostic performance in comparison with histopathology for detecting significant tissue inflammation and fibrosis in AIH patients, being a potential non-invasive imaging biomarker for monitoring disease activity in such individuals.

PMID:39106024 | DOI:10.1007/s11547-024-01863-2

Daru. 2024 Aug 6. doi: 10.1007/s40199-024-00529-8. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.

OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.

METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model.

RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔG_bind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.

PMID:39106020 | DOI:10.1007/s40199-024-00529-8

J Robot Surg. 2024 Aug 6;18(1):305. doi: 10.1007/s11701-024-02062-x.

ABSTRACT

Standardised proficiency-based progression is the cornerstone of safe robotic skills acquisition, however, is currently lacking within surgical training curricula. Expert consensuses have defined a modular pathway to accredit surgeons. This study aimed to address the lack of a formal, pre-clinical core robotic skills, proficiency-based accreditation curriculum in the UK. Novice robotic participants underwent a four-day pre-clinical core robotic skills curriculum incorporating multimodal assessment. Modifiable-Global Evaluative Assessment of Robotic Skills (M-GEARS), VR-automated performance metrics (APMs) and Objective Clinical Human Reliability Analysis (OCHRA) error methodology assessed performance at the beginning and end of training. Messick’s validity concept and a curriculum evaluation model were utilised. Feedback was collated. Proficiency-based progression, benchmarking, tool validity and reliability was assessed through comparative and correlational statistical methods. Forty-seven participants were recruited. Objective assessment of VR and dry models across M-GEARS, APMs and OCHRA demonstrated significant improvements in technical skill (p < 0.001). Concurrent validity between assessment tools demonstrated strong correlation in dry and VR tasks (r = 0.64-0.92, p < 0.001). OCHRA Inter-rater reliability was excellent (r = 0.93, p < 0.001 and 81% matched error events). A benchmark was established with M-GEARS and for the curriculum at 80%. Thirty (63.82%) participants passed. Feedback was 5/5 stars on average, with 100% recommendation. Curriculum evaluation fulfilled all five domains of Messick’s validity. Core robotic surgical skills training can be objectively evaluated and benchmarked to provide accreditation in basic robotic skills. A strategy is necessary to enrol standardised curricula into national surgical training at an early stage to ensure patient safety.

PMID:39106003 | DOI:10.1007/s11701-024-02062-x

Brain Imaging Behav. 2024 Aug 6. doi: 10.1007/s11682-024-00903-9. Online ahead of print.

ABSTRACT

Cigarette smoking is associated with elevated risk of disease and mortality and contributes to heavy healthcare-related economic burdens. The nucleus accumbens is implicated in numerous reward-related behaviors, including reinforcement learning and incentive salience. The established functional connectivity of the accumbens includes regions associated with motivation, valuation, and affective processing. Although the high comorbidity of cigarette smoking with drinking behaviors may collectively affect brain activity, there could be independent effects of smoking in alcohol use disorder that impact brain function and behavior. We hypothesized that smoking status, independent of alcohol use, would be associated with aberrations of nucleus accumbens functional connectivity to brain regions that facilitate reward processing, salience attribution, and inhibitory control. Resting state functional magnetic resonance imaging data from thirty-one nonsmokers and nineteen smoking individuals were analyzed using seed-based correlations of the bilateral accumbens with all other brain voxels. Statistical models accounted for drinks consumed per week. The smoking group demonstrated significantly higher functional connectivity between the left accumbens and the bilateral insula and anterior cingulate cortex, as well as hyperconnectivity between the right accumbens and the insula. Confirmatory analyses using the insula and cingulate clusters generated from the original analysis as seed regions reproduced the hyperconnectivity in smokers between the bilateral insular regions and the accumbens. In conclusion, smoking status had distinct effects on neural activity; hyperconnectivity between the accumbens and insula in smokers may reflect enhanced encoding of the reinforcing effects of smoking and greater orientation toward smoking-associated stimuli.

PMID:39106000 | DOI:10.1007/s11682-024-00903-9