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To validate lead (Pb) nuclear cross sections, a series of integral experiments to measure lead void reactivity worth was conducted systematically in three fast neutron spectra with different fuel compositions on the Comet critical assembly of the National Criticality Experiments Research Center. Previous experiments in high-enriched uranium (HEU)/Pb and low-enriched uranium (LEU)/Pb systems had been performed in 2016 and 2017, respectively. A follow-on experiment in a plutonium (Pu)/Pb system has been completed. The Pu/Pb system was constructed using lead plates and weapons-grade Pu plates that had been used in the Zero Power Physics Reactor (ZPPR) of Argonne National Laboratory until the 1990s. Furthermore, the HEU/Pb system was reexamined on the Comet critical assembly with a newly installed device that can measure the compression of the stack, improving reproducibility. Using the lead void reactivity worth measured in these three cores with different fuel compositions, the latest nuclear data libraries, JENDL-4.0 and ENDF/B-VIII.0, were tested with the Monte Carlo calculation code MCNP® version 6.1. As a result, the calculations by ENDF/B-VIII.0 were confirmed to agree with lead void reactivity worth measured in all the cores. It was furthermore found that the calculations by JENDL-4.0 overestimate by more than 20% for the Pu/Pb core while being in good agreement for the HEU/Pb and LEU/Pb cores. [ABSTRACT FROM AUTHOR]

Background: Several studies have been published comparing deep learning (DL)/machine learning (ML) to radiologists in differentiating PCNSLs from GBMs with equivocal results. We aimed to perform this meta-analysis to evaluate the diagnostic accuracy of ML/DL versus radiologists in classifying PCNSL versus GBM using MRI., Methodology: The study was performed in accordance with PRISMA guidelines. Data was extracted and interpreted by two researchers with 12 and 23 years' experience, respectively, and QUADAS-2 tool was used for quality and risk-bias assessment. We constructed contingency tables to derive sensitivity, specificity accuracy, summary receiver operating characteristic (SROC) curve, and the area under the curve (AUC)., Results: Our search identified 11 studies, of which 8 satisfied our inclusion criteria and restricted the analysis in each study to reporting the model showing highest accuracy, with a total sample size of 1159 patients. The random effects model showed a pooled sensitivity of 0.89 [95% CI:0.84-0.92] for ML and 0.82 [95% CI:0.76-0.87] for radiologists. Pooled specificity was 0.88 [95% CI: 0.84-0.91] for ML and 0.90 [95% CI: 0.81-0.95] for radiologists. Pooled accuracy was 0.88 [95% CI: 0.86-0.90] for ML and 0.86 [95% CI: 0.78-0.91] for radiologists. Pooled AUC of ML was 0.94 [95% CI:0.92-0.96]and for radiologists, it was 0.90 [95% CI: 0.84-0.93]., Conclusions: MRI-based ML/DL techniques can complement radiologists to improve the accuracy of classifying GBMs from PCNSL, possibly reduce the need for a biopsy, and avoid any unwanted neurosurgical resection of a PCNSL., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, -43 ± 9 mV) to overcome the O 6 -methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (C max fivefold and AUC 0-24 4.9 fold) with early t max (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol ® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM., (© 2022. Controlled Release Society.)

Primary CNS lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma with the worst outcomes amongst all extranodal lymphomas. There is a scarcity of data on real-world outcomes of primary CNS lymphoma (PCNSL) owing to the rarity of the disease. This study analyzed the demographic patterns, risk stratification, treatment regimens used, & outcomes of patients treated at Tata Memorial Center Mumbai, India. This is a retrospective analysis of newly diagnosed primary CNS lymphoma patients treated at our centre over seven years from January 2013 to December 2019. A total of 142 patients with PCNSL were diagnosed during this period. Thirty (21.1%) patients were deemed ineligible for any systemic or local therapies,ten patients were referred to other hospitals, two patients had relapsed disease, and one was excluded because age less than 18 years. Finally 99 patients were included in the final analysis. Among these 99 patients,72 patients (72.7%) were < 60 years,70 (70.7%) patients had Eastern cooperative oncology group (ECOG) performance status (PS) less than equal to 2. DLBCL was the most common histology (86.4%) while rests were high grade B cell NHL NOS (11.4%),Burkitt's Lymphoma(1%),Peripheral T-cell Lymphoma NOS (1.2%). Only one of 99 patients was positive for HIV serology. Multiple intracranial lesions were found in 59.5%. Surgical resection was performed in 28.4% of patients. Out of 63 patients in whom the International extranodal lymphoma study group (IELSG) score is available, 34(54%) were IELSG high-risk groups. As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups, with 32(32.3%) patients in risk group 1 (age < 50 years), 36(36.4%) patients in risk group 2 (age > 50 years, KPS >  = 70), and 31(31.3%) patients in risk group 3 age > 50 years, KPS < 70). First-line treatment with high dose methotrexate (HD-MTX) based regimens was administered to 92 (92.9%) patients, and 72.8% of these patients received rituximab. Of these 92 patients, 59 (64.1%) patients could complete induction, and 52 patients received consolidation. Thirty-one patients received high dose cytarabine based chemo consolidation, one patient underwent high dose chemotherapy followed by autologous stem cell transplantation (ACST), and 19 patients received whole-brain radiotherapy (WBRT) and 1 patient received temozolomide as consolidation regimen. Thus only 52 patients completed the entire course of induction with consolidation therapy. The response to treatment was assessed using International PCNSL Collaborative Group Criteria. Post completion of consolidation, 49(94.2%) patients had a complete response. With a median follow-up duration of 39.2 months, the median progression-free survival (PFS) and the median overall survival (OS) of the patients taken into the analysis (N = 99) were 21 and 37 months respectively. On multivariate analysis, age < 60 yrs, >  = 5 HD-MTX cycles received & the use of rituximab predicted better OS.Outcomes of patients with PCNSL treated with HD-MTX based therapy are comparable to reported literature however a large proportion of patients do not undergo required treatment despite the curable nature of disease., Supplementary Information: The online version supplementary material available at 10.1007/s12288-022-01557-7., Competing Interests: Conflict of interestWe have no conflict of interest to declare., (© The Author(s), under exclusive licence to Indian Society of Hematology and Blood Transfusion 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: Advanced Hodgkin Lymphoma has a higher probability of relapse and recurrence. Classical clinicopathological parameters including the International Prognostic Score (IPS) have not been reliable in predicting prognosis or tailoring treatment. Since FDG PET/CT is the standard of care in staging Hodgkin Lymphoma, this study attempted to evaluate the clinical utility of baseline metabolic tumor parameters in a cohort of advanced Hodgkin lymphoma (stage III and IV)., Methods: Histology-proven advanced Hodgkin Patients presenting to our institute between 2012-2016 and treated with chemo-radiotherapy (ABVD / AEVD) were followed up till 2019. Quantitative PET/CT and clinicopathological parameters were used to estimate the Event Free Survival (EFS) in 100 patients. Kaplan-Meier method with log-rank test was used to compare the survival times of prognostic factors., Results: At a median follow-up of 48.83 months (IQR:33.31-63.05 months), the five-year-EFS was 81%. Of the 100 patients, 16 had relapsed (16%) and none died at the last follow-up. On Univariate analysis, among non-PET parameters bulky disease (P=0.03) and B-symptoms (P=0.04) were significant while among PET/CT parameters SUV max (p=0.001), SUV mean (P=0.002), WBMTV2.5 (P<0.001), WBMTV41% (P<0.001), WBTLG2.5 (P<0.001) and WBTLG41% (P <0.001) predicted poorer EFS. 5-year EFS for patients with low WBMTV2.5 [<1038.3 cm3] was 89% and 35% for patients with high WBMTV2.5 [≥1038.3 cm3] (p <0.001). In a multivariate model, only WBMTV2.5 (P=0.03) independently predicted poorer EFS., Conclusion: PET-based metabolic parameter (WBMTV2.5) was able to prognosticate and complement the classical clinical prognostic factors in advanced Hodgkin Lymphoma. This parameter could have a surrogate value for prognosticating advanced Hodgkin lymphoma. Better prognostication at baseline translates to tailored or risk-modified treatment and hence higher survival., Competing Interests: Authors declare no conflict of interest.

The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed that in situ hydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs. In vivo gamma scintigraphy of 99m Tc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application.

Glioblastoma (GBM) has poor median survival due to its resistance to chemoradiotherapy, which results in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is upregulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies compared to expression levels in primary GBM biopsies. Importantly, although it has been reported to be a cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse populations of GBM cell lines generated from an in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radiosensitized primary and, importantly, relapse GBM cells by inhibiting the recruitment of phosphorylated DNAPKcs (also known as PRKDC), subsequently downregulating the recruitment of phosphorylated histone H2AX (γH2AX) and 53BP1 (also known as TP53BP1). This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The aim of present study was to investigate the anticancer mechanisms of 3,3'-diselenodipropionic acid (DSePA), a redox-active organodiselenide in human lung cancer cells. DSePA elicited a significant concentration and time-dependent cytotoxicity in human lung cancer cell line A549 than in normal WI38 cells. The cytotoxic effect of DSePA was preceded by an acute decrease in the level of basal reactive oxygen species (ROS) and a concurrent increase in levels of reducing equivalents (like GSH/GSSG and NADH/NAD) within cells. Further, a series of experiments were performed to measure the markers of intrinsic (Bax, cytochrome c and caspase-9), extrinsic (TNFR, FADR and caspase-8) and endoplasmic reticulum (ER) stress (protein ubiquitylation, calcium flux, Bip, CHOP and caspase-12) pathways in DSePA treated cells. DSePA treatment significantly increased the levels of all the above markers. Moreover, DSePA did not alter the expression and phosphorylation (Ser15) of p53 but caused a significant damage to mitochondria. Pharmacological modulation of GSH level by BSO and NAC in DSePA treated cells led to partial abrogation and augmentation of cell kill respectively. This established the role of reductive stress as a trigger for the apoptosis induced by DSePA treatment. Finally, in vitro anticancer activity of DSePA was also corroborated by its in vivo efficacy of suppressing the growth of A549 derived xenograft tumor in SCID mice. In conclusion, above results suggest that DSePA induces apoptosis in a p53 independent manner by involving extrinsic and intrinsic pathways together with ER stress which can an interesting strategy for lung cancer therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: There is lack of consensus on management of adolescent and young adult (AYA) Hodgkin lymphoma with respect to chemotherapy approach (adult or pediatric). Hence we sought to evaluate the efficacy and safety of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) chemotherapy in AYA Hodgkin lymphoma. Patients and Methods: It is a retrospective, observational, single-center study. From January 2013 to December 2016, all consecutive patients with AYA (15-25 years, all stages) were analyzed. The primary endpoint of the study was event-free survival (EFS). Secondary endpoints were complete response rates (CR) and overall survival (OS). Results: A total of 220 patients (70% men) with median age 20 years were evaluated. A significant proportion of patients had adverse features such as stage III/IV disease (63%), bulky disease (63%), extranodal involvement (37%), and marrow involvement (22%). After two cycles and end of therapy, 77% patients achieved complete response. Primary progressive disease was seen in 6% patients. With a median follow-up of 2.6 years, 19 (8.6%) patients relapsed, 1 patient developed second malignancy, and 6 patients died. Three-year EFS and OS were 81.3% and 97%, respectively. Bleomycin-induced lung injury was seen in 16% patients. On multivariate analysis stage at presentation, bone marrow involvement, partial response at interim positron emission tomography and International prognosis score (IPS) >3 were predictors of poor EFS. Conclusion: ABVD is an effective and safe regimen in AYA Hodgkin lymphoma. Advanced disease with high IPS (>3) score needs an early escalation approach to escBEACOPP regimen.