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The Lancet. Oncology Jul 2024The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.
BACKGROUND
The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.
METHODS
ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
FINDINGS
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
INTERPRETATION
Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
FUNDING
The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).
Topics: Humans; Male; Female; Child; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Sirolimus; Rhabdomyosarcoma; Child, Preschool; Vincristine; Young Adult; Cyclophosphamide; Adult; Dactinomycin; Irinotecan; Infant; Progression-Free Survival; Forkhead Box Protein O1
PubMed: 38936378
DOI: 10.1016/S1470-2045(24)00255-9 -
Oral Oncology Jun 2024This retrospective study aimed to determine the optimal metronomic chemotherapy duration (MTCD) as adjuvant therapy for patients with locally advanced nasopharyngeal...
BACKGROUND
This retrospective study aimed to determine the optimal metronomic chemotherapy duration (MTCD) as adjuvant therapy for patients with locally advanced nasopharyngeal carcinoma (LANPC).
METHODS
This study involved LANPC patients treated with metronomic chemotherapy (MTC) using a 5-FU prodrug (S1, capecitabine, or tegafur) from May 2013 to September 2020. The optimal MTCD threshold was established using X-tile Bioinformatics software. The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) were compared between short-term and long-term groups using propensity score matching (PSM).
RESULTS
A total of 546 patients were analyzed. MTCD was an independent prognostic factor for OS, PFS, and DMFS (all P < 0.05). Patients were categorized into long-term (>3 months) and short-term (≤3 months) MTCD groups. After a median follow-up of 48 months, significant differences were observed in 4-year OS (97.0 % vs. 87.1 %; P < 0.01), PFS (84.6 % vs. 70.9 %; P < 0.01), DMFS (87.3 % vs. 78.8 %; P < 0.01), and LRRFS (95.3 % vs. 87.4 %; P < 0.01) between the long-term and short-term groups. In the PSM-matched cohort of 196 patients per group, the long-term group demonstrated superior 4-year OS and LRRFS (97.3 % vs. 87.1 %, P < 0.01; 95.2 % vs. 90.0 %, P < 0.05). No significant differences in acute toxicities were observed between the groups (P > 0.05).
CONCLUSION
Extended MTC with a 5-FU prodrug (>3 months) may benefit NPC patients. Further prospective studies are needed to validate these findings.
PubMed: 38936007
DOI: 10.1016/j.oraloncology.2024.106908 -
Current Opinion in Gastroenterology Jun 2024The burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a...
PURPOSE OF REVIEW
The burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a causal factor for PDAC and examined clinical manifestations of PDAC-associated acute pancreatitis.
RECENT FINDINGS
Recent findings detail the timing of acute pancreatitis before and after PDAC occurrence, further solidifying the evidence for PDAC-associated acute pancreatitis and for acute pancreatitis as a causal risk factor for PDAC. The risk of PDAC remains elevated above the general population in patients with distant history of acute pancreatitis. PDAC risk also increases with recurrent acute pancreatitis episodes, independent of smoking and alcohol. Mechanisms linking acute pancreatitis to PDAC include inflammation and neutrophil infiltration, which can be attenuated by suppressing inflammation and/or epigenetic modulation, thus slowing the progression of acinar-to-ductal metaplasia. Clinical presentation and management of acute pancreatitis in the context of PDAC are discussed, including challenges acute pancreatitis poses in the diagnosis and treatment of PDAC, and novel interventions for PDAC-associated acute pancreatitis.
SUMMARY
PDAC risk may be reduced with improved acute pancreatitis prevention and treatment, such as antiinflammatories or epigenetic modulators. Increased acute pancreatitis and PDAC burden warrant more research on better diagnosis and management of PDAC-associated acute pancreatitis.
PubMed: 38935270
DOI: 10.1097/MOG.0000000000001051 -
The Journal of Hand Surgery Jun 2024The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109...
PURPOSE
The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109 patients, as well as to characterize risk factors for poor oncologic and functional outcomes.
METHODS
We analyzed data from 109 consecutive patients who had definitive surgical treatment for soft tissue sarcoma of the hand performed between 1996 and 2019 by a single surgeon at a sarcoma center. Primary outcomes included functional outcome (assessed by Musculoskeletal Tumor Society scores), disease-free survival (DFS), and overall survival (OS). We compiled descriptive data and used a multivariable linear model to identify factors associated with functional outcomes. Kaplan-Meier methods were used to estimate 5- and 10-year DFS and OS.
RESULTS
Patients had a median age of 36 years at presentation. Median follow-up was 6.1 years among patients alive at the end of follow-up. The median Musculoskeletal Tumor Society score was 29; functional outcome was worse among patients with high-grade tumors or complications. Among the 107 patients who became disease-free, there were four local recurrences (one with metastasis), six distant recurrences, and one death without recurrence. All local recurrences were deep tumors (two myxofibrosarcoma and two myxoinflammatory fibrosarcoma). Estimated 5- and 10-year DFS rates were 89% (95% confidence interval [CI]: 83% to 96%) and 88% (95% CI: 80% to 95%). There were seven deaths, and the estimated 5- and 10-year OS rates were 95% (95% CI: 90% to 100%) and 92% (95% CI: 84% to 100%). Larger tumor size and higher stage at diagnosis were associated with shorter DFS and OS in univariable analyses; low event rates precluded multivariable analysis of survival.
CONCLUSIONS
Aggressive disease-specific surgical and multidisciplinary treatment can yield long DFS and OS, and good functional outcomes. However, complications and high-grade tumors are associated with worse functional scores.
TYPE OF STUDY/LEVEL OF EVIDENCE
Prognostic II.
PubMed: 38934989
DOI: 10.1016/j.jhsa.2024.05.003 -
Developmental Psychology Jun 2024Counterfactual outcomes (i.e., events that did not happen) vary in their closeness to reality. Whereas some are viewed as distant possibilities, others are seen as...
Counterfactual outcomes (i.e., events that did not happen) vary in their closeness to reality. Whereas some are viewed as distant possibilities, others are seen as close, barely unrealized outcomes. Here, we investigate whether young children distinguish between two kinds of counterfactual closeness: one based on proximity and the other on ability. In two experiments, 4-7-year-olds (total = 304) saw stories where two agents lost a race against a competitor. One of the losing racers finished just behind the winner (proximity), whereas the other losing racer was much faster than the winner (ability) but lost after tripping on a stone. When asked which racer almost won the race, children across the full age range predominantly picked the racer who finished in second place, close behind the winner. However, when asked which racer easily could have won and when asked which racer should have won, children at older ages picked the fastest racer. Together, these findings show that children's understanding of proximity-based closeness is already present at Age 4, earlier than children were previously thought to grasp counterfactual closeness. Moreover, the findings suggest young children have differentiated concepts of counterfactual closeness and do not conflate the two kinds of closeness. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
PubMed: 38934903
DOI: 10.1037/dev0001774 -
The Journal of Clinical Endocrinology... Jun 202417α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare subtype of congenital adrenal hyperplasia (CAH) caused by homozygous or compound heterozygous pathogenic...
BACKGROUND
17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare subtype of congenital adrenal hyperplasia (CAH) caused by homozygous or compound heterozygous pathogenic variants in the CYP17A1 gene.
PURPOSE
This study aimed to identify and characterize pathogenic variants in individuals with 17-OHD, and to classify and validate the pathogenicity of novel variants.
METHODS
Variants were identified via targeted long-read sequencing (TLRS) of the entire CYP17A1 gene in enrolled 17-OHD patients. The American College of Medical Genetics and Genomics guidelines were employed to assess the pathogenicity of novel variants. A minigene splicing assay was utilized to determine the impact of variants on RNA splicing.
RESULTS
This study encompassed 26 patients with 17-OHD, detecting two trans pathogenic variants per patient using the TLRS method. A total of 20 pathogenic variants in the CYP17A1 were identified, with variant c.985_987delinsAA being the most frequent (28/52 alleles), followed by variant c.1459_1467del (4/52 alleles). Five novel variants including c.280T>C, c.470T>A, c.636_637del, c.866A>G, and c.1095del, were classified as pathogenic/likely pathogenic ones according to ACMG criteria. The minigene assay revealed c.866A>G in exon 5 causes a frameshift due to a 104 base pair deletion, while c.470T>A generates two transcripts, with vast majority spliced like the wild-type, and a small fraction lack 35 base pairs in the 5' flank of exon 3.
CONCLUSION
The TLRS can determine the cis/trans orientation of two distant variants. Five novel pathogenic variants were reported, broadening the spectrum of CYP17A1 pathogenic variant. The variant c.866A>G, located deep in exon, affects gene function through mechanisms of aberrant splicing.
PubMed: 38934795
DOI: 10.1210/clinem/dgae414 -
Indian Journal of Dental Research :... Jan 2024Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth...
Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth decade, and is predominant in males. Clinically, they present as an asymptomatic macular or nodular growth. The prognosis is impacted by the size of the tumour and distant metastases. Patients with distant metastases have a 5-year survival rate of less than 30%, constituting metastasis as the major cause of melanoma-related fatality. Currently, the mainstay of treatment for metastatic melanoma is immunotherapy due to the inoperable state, radioresistant nature of the tumour and high chances of cytotoxicity in chemotherapy. A senile male patient, who was diagnosed with oral malignant melanoma of the maxillary buccopalatal gingiva with distant metastasis to the liver and the prostate, is reported here. Although metastasis to the liver is common among malignant melanomas, in this case metastasis to the prostate gland highlights the rarity.
Topics: Humans; Male; Melanoma; Prostatic Neoplasms; Mouth Neoplasms; Liver Neoplasms; Gingival Neoplasms; Aged
PubMed: 38934760
DOI: 10.4103/ijdr.ijdr_376_23 -
MSystems Jun 2024Hypersaline ecosystems display taxonomically similar assemblages with low diversities and highly dense accompanying viromes. The ecological implications of viral...
UNLABELLED
Hypersaline ecosystems display taxonomically similar assemblages with low diversities and highly dense accompanying viromes. The ecological implications of viral infection on natural microbial populations remain poorly understood, especially at finer scales of diversity. Here, we sought to investigate the influence of changes in environmental physicochemical conditions and viral predation pressure by autochthonous and allochthonous viruses on host dynamics. For this purpose, we transplanted two microbiomes coming from distant hypersaline systems (solar salterns of Es Trenc in Spain and the thalassohaline lake of Aran-Bidgol lake in Iran), by exchanging the cellular fractions with the sterile-filtered accompanying brines with and without the free extracellular virus fraction. The midterm exposure (1 month) of the microbiomes to the new conditions showed that at the supraspecific taxonomic range, the assemblies from the solar saltern brine more strongly resisted the environmental changes and viral predation than that of the lake. The metagenome-assembled genomes (MAGs) analysis revealed an intraspecific transition at the ecotype level, mainly driven by changes in viral predation pressure, by both autochthonous and allochthonous viruses.
IMPORTANCE
Viruses greatly influence succession and diversification of their hosts, yet the effects of viral infection on the ecological dynamics of natural microbial populations remain poorly understood, especially at finer scales of diversity. By manipulating the viral predation pressure by autochthonous and allochthonous viruses, we uncovered potential phage-host interaction, and their important role in structuring the prokaryote community at an ecotype level.
PubMed: 38934645
DOI: 10.1128/msystems.00538-24 -
Biochemical Society Transactions Jun 2024Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of...
Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of neuronal function is evident in the morphology of their plasma membrane (PM), by far the most intricate of all cell types. Yet, within the neuron lies an organelle whose architecture adds another level to this morphological sophistication - the endoplasmic reticulum (ER). Neuronal ER is abundant in the cell body and extends to distant axonal terminals and postsynaptic dendritic spines. It also adopts specialised structures like the spine apparatus in the postsynapse and the cisternal organelle in the axon initial segment. At membrane contact sites (MCSs) between the ER and the PM, the two membranes come in close proximity to create hubs of lipid exchange and Ca2+ signalling called ER-PM junctions. The development of electron and light microscopy techniques extended our knowledge on the physiological relevance of ER-PM MCSs. Equally important was the identification of ER and PM partners that interact in these junctions, most notably the STIM-ORAI and VAP-Kv2.1 pairs. The physiological functions of ER-PM junctions in neurons are being increasingly explored, but their molecular composition and the role in the dynamics of Ca2+ signalling are less clear. This review aims to outline the current state of research on the topic of neuronal ER-PM contacts. Specifically, we will summarise the involvement of different classes of Ca2+ channels in these junctions, discuss their role in neuronal development and neuropathology and propose directions for further research.
PubMed: 38934485
DOI: 10.1042/BST20230819 -
The American Journal of Surgical... Jun 2024The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined...
The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.
PubMed: 38934254
DOI: 10.1097/PAS.0000000000002264