Objective Responses in Metastatic Pleomorphic Rhabdomyosarcoma Treated with Combination of Doxorubicin and Pembrolizumab: A Case Series.

Introduction: Pleomorphic rhabdomyosarcoma is a rare subtype of rhabdomyosarcoma, a soft tissue sarcoma with skeletal muscle differentiation. Although rhabdomyosarcoma is typically seen in the pediatric population, the pleomorphic variant most frequently presents in adulthood and is characteristically aggressive with no currently established treatment regimen in the setting of metastatic disease. There has been growing interest in the application of immune checkpoint inhibitors alongside conventional chemotherapeutic agents in the treatment of pleomorphic rhabdomyosarcoma. Case Presentation: In the present case series, we report 2 patients with metastatic pleomorphic rhabdomyosarcoma treated with combination doxorubicin and pembrolizumab who had confirmed objective responses. Of note, these 2 patients had variable PD-L1 status - negative and low positive. Duration of treatment response was notable at 14 months and 9 months, respectively, with the first patient remaining on maintenance pembrolizumab therapy and the second patient subsequently achieving complete response with third-line trabectedin. Both patients are currently undergoing routine interval imaging with no evidence of disease at this time. Conclusion: This report highlights and discusses the potential role of PD-1 blockade in the treatment of pleomorphic rhabdomyosarcoma and also discusses burgeoning immunological data that may explain the clinical responses seen in these 2 cases.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

Gaps in Adolescent and Young Adult Cancer Education in Oncology Fellowship Training.

Purpose: Adolescents and young adults (AYAs, 15-39 years) with cancer experience disparities in care and outcomes compared with older/younger patients. AYAs receive care from medical and pediatric oncologists, however, little is known about the extent of training fellows receive. This needs assessment evaluating current AYA oncology (AYA-O) education in pediatric and medical oncology fellowship programs to identify knowledge gaps for curricular development. Methods: An anonymous, cross-sectional, web-based survey developed by pediatric and medical oncologists was sent to medical (n = 178) and pediatric (n = 119) hematology/oncology program directors (PDs) at 251 sites in the United States. PDs were asked to participate and distribute the survey to their fellows. Survey questions addressed current AYA curriculum, provider comfort, and priorities for future AYA educational content. Results: Participants from 69/251 programs responded (program response rate = 27%), including 51 PDs (32 pediatric, 19 medical oncology) and 58 fellows (33 pediatric, 25 medical oncology). Eighty-five percent of PDs (44/51) reported lacking formal AYA curricula. Of these, 80% (35/44) offer some topic-specific lectures, while 20% (9/44) provide little/no education for any topics. For nearly all topics, at least 45% of combined respondents reported little/no education. Respondents believe AYA topics are important for inclusion in future curricula. The most important topics for inclusion reported were oncofertility (82%), survivorship (78%), and communication (77%). Conclusions: There are large and actionable gaps in AYA-O education during fellowship training. Efforts are underway to develop AYA-O curriculum to provide both medical and pediatric oncology fellows with the knowledge and skills required to provide optimal AYA care.

PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study.

OBJECTIVES: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

Exploring the Dorian Gray Trait: Unveiling the Complexities of Perceived Aging and Self-Image.

The concept of the "Dorian Gray Trait," inspired by Oscar Wilde's renowned literary work, delves into the intricate interplay between self-perception, the fear of aging, and the pursuit of eternal youth. This article explores the psychological dimensions of this trait, wherein individuals harbor an intense preoccupation with maintaining their youthful appearance, often at the cost of their overall well-being. By examining the underlying factors that drive this phenomenon, including societal pressures and personal anxieties, we aim to shed light on the broader implications for mental health and self-image.

Topiramate Monotherapy for Civilian Posttraumatic Stress Disorder: A Controlled Pilot Study.

Objective: To assess the efficacy, safety, and tolerability of topiramate for the treatment of posttraumatic stress disorder (PTSD) in civilians.Methods: This 12-week double-blind, randomized, placebo-controlled study enrolled 72 outpatients (aged 19-64 years) with a DSM-IV-TR diagnosis of non-combat-related PTSD and a score ≥ 50 on the Clinician-Administered PTSD Scale (CAPS). The primary efficacy endpoint, percent change in total CAPS score, and secondary efficacy measures were assessed by analysis of covariance. Safety assessments included monitoring of vital signs, physical examinations, clinical laboratory parameters, electrocardiograms, and adverse events (AEs). The study was conducted from October 2001 to March 2004.Results: The intent-to-treat (ITT) population (N = 68; mean age = 35 years; 87% women; 74% White) showed greater percent reduction in total CAPS scores with topiramate versus placebo (39.5% vs 29.5%), but the difference was not statistically significant (P = .31). Similarly, higher reductions with topiramate versus placebo were seen in the CAPS subscale scores for symptoms of reexperiencing (43.6% vs 34.8%), avoidance/numbing (38.3% vs 30.6%), and hyperarousal (36.6% vs 21.4%). However, these differences were not statistically significant. Six patients in the topiramate arm had a final CAPS score < 20, whereas only 2 in the placebo arm achieved the result (P = .075). The median final topiramate daily dose was 100 mg/d (range, 25-400 mg/d), and mean ± SD treatment duration was 55 ± 32 days, showing the tolerability of the medication. In topiramate-treated patients, treatment-emergent AEs included paresthesia, headache, fatigue, and insomnia; treatment-limiting AEs included influenza-like symptoms, agitation, cognitive problems not otherwise specified, and somnolence. However, a higher rate of AE-related discontinuation was seen in the placebo group than in the treatment group (26% vs 18%).Conclusions: In this 12-week civilian PTSD study, topiramate improved the primary and secondary outcome measures at a higher rate than did placebo, but the difference did not reach statistical significance. Further adequately powered studies may be warranted.Trial Registration: Clinical Trials.gov identifier: NCT00208130.Prim Care Companion CNS Disord 2023;25(5):23m03555. Author affiliations are listed at the end of this article.

Malignant Tourette's Syndrome in an Adult on Deep Brain Stimulation Presenting With Rhabdomyolysis.

Tourette's syndrome (TS) patients experiencing severe tics and behavioral disturbances can have a rare complication called rhabdomyolysis (RML), which is characterized by the breakdown of muscle tissue. The occurrence of RML poses a significant physical and emotional risk to patients with TS by impacting the quality of life and in some cases causing severe damage. In this case report, we present the first documented case of RML resulting from severe tics in an adult with a diagnosis of TS. The patient exhibited severe tics and self-injurious behaviors that led to elevated creatine kinase and a subsequent diagnosis of RML requiring hospitalization with a complex hospital course. The patient did not have neuroleptic malignant syndrome as his laboratory parameters improved with the decrease in severity of tics. Our case highlights the potential complication of RML because of severe tics independent of neuroleptic drug use in a patient with TS.

Exploring the Complex Relationship Between Antiepileptic Drugs and Suicidality: A Systematic Literature Review.

Objective: Compared to the general population, the risk of suicide is three times higher in patients with epilepsy and remains doubled for these patients even after adjusting for sociodemographic correlates of suicide in the absence of mental health comorbidities. Following the United States (US) Food and Drug Administration (FDA) alert prompting a black box warning regarding the association between suicidality and antiepileptic drugs (AEDs), several studies were conducted, the results of which have been ambiguous, with some demonstrating a positive association between suicidality and AEDs, while others did not. This systematic review of literature sought to study the relationship between suicidality and AEDs when used exclusively for treatment of epilepsy. Methods: A comprehensive literature search was conducted on PubMed without time limits using a predefined search language. The search results were then subjected to a systematic screening process. Eight out of a total of 443 articles satisfying predefined inclusion and exclusion criteria were included in the review for final data extraction. Results: Three studies found a significant association between suicide-related behavior and levetiracetam use in the treatment of epilepsy. One study reported a positive association of pregabalin use in patients with epilepsy under 40 years of age and high AED load with suicidality, independent of depression. The remaining four studies reported a significant association between positive family and personal history of psychiatric comorbidities and suicidality in epilepsy. Conclusion: Although there were several methodological limitations, this review found an association between levetiracetam use and mental health comorbidities and the occurrence of suicidality in epilepsy. Larger prospective, randomized studies that overcome the limitations of current studies are required to provide definitive evidence on the occurrence of suicidality in patients with epilepsy and AED use.

CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGN: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. RESULTS: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CONCLUSIONS: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.

A Rare Presentation of Narcolepsy With Cataplexy After Vaccines in a Genetically Susceptible Elderly Woman: A Case Report.

Observing cataplexy episodes during an office visit is extremely rare as they are usually triggered by laughter or emotional stress. Narcolepsy usually occurs in the younger population. We report a case of a 65-year-old Caucasian female with a past medical history of obesity who developed excessive daytime sleepiness, fatigue, and sleep attacks five weeks after getting influenza and pneumococcal vaccines. The presentation of cataplexy was atypical. Several episodes of cataplexy were observed during the office visit without any emotional trigger. Further workup, including polysomnography (PSG), was positive for obstructive sleep apnea, controlled with continuous positive airway pressure (CPAP) use. Later, she had PSG with CPAP use, which optimally controlled obstructive sleep apnea, followed by multiple sleep latency tests (MSLT) with CPAP use. It was positive for narcolepsy with a mean sleep latency of 1.6 minutes with sleep onset rapid eye movement (REM) in five out of five naps. Her cerebrospinal fluid (CSF) hypocretin level was extremely low at 50 pg/ml, usually seen in narcolepsy with cataplexy. She was also positive for human leukocyte antigen (HLA) DBQ1*06:02. The diagnosis of narcolepsy with cataplexy was made, which improved with medications for narcolepsy.

Radiology Gets Chatty: The ChatGPT Saga Unfolds.

As artificial intelligence (AI) continues to evolve and mature, it is increasingly finding applications in the field of healthcare, particularly in specialties like radiology that are data-heavy and image-focused. Language learning models (LLMs) such as OpenAI's Generative Pre-trained Transformer-4 (GPT-4) are new in the field of medicine and there is a paucity of literature regarding the possible utilities of GPT-4 given its novelty. We aim to present an in-depth exploration of the role of GPT-4, an advanced language model, in radiology. Giving the GPT-4 model prompts for generating reports, template generation, enhancing clinical decision-making, and suggesting captivating titles for research articles, patient communication, and education, can occasionally be quite generic, and at times, it may present factually incorrect content, which could lead to errors. The responses were then analyzed in detail regarding their potential utility in day-to-day radiologist workflow, patient education, and research processes. Further research is required to evaluate LLMs' accuracy and safety in clinical practice and to develop comprehensive guidelines for their implementation.

Serotonin Syndrome with Monotherapy of Low-Dose Sertraline in an Adult Patient with Autism Spectrum Disorder.

Serotonin syndrome, also known as serotonin toxicity, is associated with increased serotonergic activity in the central and the peripheral nervous system. The symptoms can range from mild to potentially life threatening. Given the widespread use of serotonergic agents, the number of cases is on the rise. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning, but still known cases with monotherapy of selective serotonin reuptake inhibitors are uncommon. Another known fact is that elevated whole blood serotonin, or hyperserotonemia, is one of the first biomarkers identified in autism spectrum disorder and is present in more than 25% of affected children. We present a case of a 32-year-old male with a history of autism spectrum disorder and depressive disorder who presented to the emergency department with restless agitation, neuromuscular excitability, and autonomic instability. He had been prescribed sertraline 50 mg which he had taken daily as prescribed for 4 days. On the fourth day, he presented to the emergency department with diffuse muscle stiffness, upper extremity tremors, ocular clonus, and inducible ankle clonus. He was diagnosed with probable serotonin syndrome utilizing Hunter's criteria. Patient's symptoms resolved within 24 hours with intravenous fluids, lorazepam, and discontinuation of sertraline. This case highlights the importance of a high degree of clinical suspicion in patients even on monotherapy of selective serotonin reuptake inhibitors in therapeutic doses, especially in children and adults with autism spectrum disorder. Due to preexisting hyperserotonemia, they may be more susceptible to serotonin syndrome than the general population.

The Midwest Sarcoma Trials Partnership: Bridging Academic and Community Networks in a Collaborative Approach to Sarcoma.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Sexual Dysfunction Among Adolescent and Young Adult Men Diagnosed with Cancer.

Purpose: Adolescent and young adult (AYA) cancer patients frequently demonstrate sexual dysfunction; however, there is a lack of data quantifying the severity and frequency. Methods: Males aged 18-39 years, diagnosed with cancer of any kind and who were scheduled to begin, were actively receiving, or had completed cancer treatment within 6 months, were offered validated surveys during their oncology appointment. These surveys included the International Index of Erectile Function (IIEF-6), Masturbation Erection Index (MEI), 36-Item Short Form Survey, and 5-point Likert scales to assess their desire and ability to engage in sex and masturbation. Results: Forty subjects completed the IIEF survey with a mean score of 17.7 ± 11, erectile dysfunction (ED) prevalence accordingly was 58%. Thirty-eight subjects completed the MEI with a mean score of 25.3 ± 5.3, ED prevalence was again 58%. Age and IIEF scores demonstrated a statistically significant (p < 0.05, n = 38) Pearson's correlation coefficient of 0.40, patients younger than 30 years had an ED prevalence of 72% (mean IIEF 13), whereas patients aged 30 years and older had an ED prevalence of 45% (mean IIEF 22). All treatment modalities had ED rates >30%: chemotherapy demonstrated the highest prevalence at 64% (mean IIEF 17), whereas radiation therapy had the lowest prevalence at 33% (mean IIEF 23). Conclusion: This study demonstrates that the prevalence of sexual dysfunction among male AYA patients undergoing treatment for cancer is high. AYA oncologists should discuss potential sexual health concerns when treating this population. The exact cause of ED (non-organic vs. organic) within this group should be explored further.

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial.

BACKGROUND: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. METHODS: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. RESULTS: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). CONCLUSIONS: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

T2* Imaging Assessment of Neoadjuvant Radiation Therapy Combined With Pharmacological Ascorbate in Extremity Soft-Tissue Sarcomas: A Pilot Study.

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T2*, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T2* maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T2* values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6. Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T2* measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68). Conclusion: T2* measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T2* mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV.

The Impact of TSC-1 and -2 Mutations on Response to Therapy in Malignant PEComa: A Multicenter Retrospective Analysis.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. RESULTS: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. CONCLUSIONS: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism.

The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.