Incorporating intensity modulated total body irradiation into a Children's Oncology Group trial: Rationale, techniques, and safeguards.

Historically, total body irradiation (TBI) has been delivered using static, parallel opposed photon beams (2D-TBI). Recently, centers have increasingly used intensity-modulated radiation therapy (IMRT) techniques for TBI. Relative to 2D-TBI, IMRT can reduce doses to critical organs (i.e., lungs and kidneys) while delivering myeloablative doses to the rest of the body, so it may decrease the risk of toxicity while maintaining oncologic outcomes. Despite these potential benefits, delivering TBI using IMRT introduces new challenges in treatment planning and delivery. We describe the extensive experience with IMRT-based TBI at Stanford University and City of Hope Cancer Center. These groups, and others, have reported favorable clinical outcomes and have developed methods to optimize treatment planning and delivery. A critical next step is to evaluate the broader adoption of this approach. Therefore, IMRT-based TBI will be incorporated into a prospective, multi-institutional Children's Oncology Group study with careful procedures and safeguards in place.

Heteronormative biases and distinctive experiences with prostate cancer among men who have sex with men: a qualitative focus group study.

BACKGROUND: Men who have sex with men (MSM) face many challenges and biases in healthcare. Within urology there is a need to better understand how prostate cancer impacts MSM given the unique ways in which side effects that accompany treatment may affect this population. The goal of this study is to explore the experience of MSM with prostate cancer to advance the existing literature in this area and inform implementation and delivery of clinical practice and policy guidelines. METHODS: Four focus groups were conducted with a semi-structured interview guide. Using a phenomenological qualitative approach consistent with grounded theory [1] and naturalistic inquiry principles we sought to better understand the direct experiences of MSM with prostate cancer. Audio transcriptions were thematically analyzed to identify themes that impact MSM throughout their prostate cancer journey. An iterative, team-wide classification process was used to identify, organize, and group common codes into higher-order categories and themes. RESULTS: Patient's choice of provider and their interactions with the healthcare system were strongly impacted by their sexual identities. Participants commented on navigating the heteronormative healthcare environment and the impact of assumptions they encountered. MSM experienced the sexual side effects of prostate cancer treatment in unique ways. Issues with erectile dysfunction and ejaculatory dysfunction had significant impacts on patient's sexual experience, with some describing being forced to explore new modes of sexual expression. Anejaculation was a theme that was distressing for many participants. The emotional impact of a prostate cancer diagnosis was significant in the men interviewed. Common themes included loss of identity and fear for future relationships. CONCLUSIONS: MSM have unique concerns after prostate cancer treatment that differ from men who don't identify as MSM. It is critical that providers familiarize themselves with the concerns of this patient population regarding prostate cancer treatment. An important step toward reducing heteronormative bias in prostate cancer care is to better understand the goals, identity, and sexual practices of MSM and to provide informed anticipatory guidance.

A prospective observational cohort study of covid-19 epidemiology and vaccine seroconversion in South Western Sydney, Australia, during the 2021-2022 pandemic period.

BACKGROUND: It is known that COVID-19 disproportionally adversely affects the immunocompromised, including kidney transplant recipients (KTR), as compared to the general population. Risk factors for adverse outcomes and vaccine seroconversion patterns are not fully understood. Australia was uniquely positioned to reduce initial case numbers during the 2021-2022 pandemic period due to its relative isolation and several significant public health interventions. South-Western Sydney Local Heath District was one of the predominant regions affected. METHODS: A single centre, prospective cohort study of prevalent renal transplant recipients was conducted between 25th July 2021 and 1st May 2022. Baseline characteristics, COVID-19 vaccination status, COVID-19 diagnosis and outcomes were determined from the electronic medical record, Australian vaccination register and Australian and New Zealand Dialysis and Transplant Registry. Assessment of vaccine-induced seroconversion was assessed with ELISA in a subpopulation. Analysis was performed using SPSS v.28. RESULTS: We identified 444 prevalent transplant recipients (60% male, 50% diabetic, median age 58 years (Interquartile range (IQR)21.0) and eGFR 56 ml/min/1.73m2 (IQR 21.9). COVID-19 was identified in 32% (n = 142) of patients, of which 38% (n = 54) required hospitalisation and 7% (n = 10) died. At least one COVID-19 vaccination was received by 95% (n = 423) with 17 (4%) patients remaining unvaccinated throughout the study period. Seroconversion after 2 and 3 doses of vaccine was 22% and 48% respectively. Increased COVID-19 related deaths were associated with older age (aOR 1.1, 95% CI 1.004-1.192, p = 0.040), smoking exposure (aOR 8.2, 05% CI 1.020-65.649, p = 0.048) and respiratory disease (aOR 14.2, 95%CI:1.825-110.930, p = 0.011) on multi-variable regression analysis. Receipt of three doses of vaccination was protective against acquiring COVID-19 (aOR 0.48, 95% CI 0.287-0.796, p = 0.005) and death (aOR 0.6, 95% CI: 0.007-0.523, p = 0.011), but not against hospitalisation (p = 0.32). Seroconversion was protective for acquiring COVID-19 on multi-variable regression independent of vaccination dose (aOR 0.1, 95%CI: 0.0025-0.523, p = 0.011). CONCLUSIONS: COVID-19 was associated with a high mortality rate. Older age, respiratory disease and prior smoking exposure may be risk factors for increased mortality. Vaccination of 3 doses is protective against acquiring COVID-19 and death, however not hospitalisation. Antibody response is protective for acquiring COVID-19, however seroconversion rates are low.

Adrenal insufficiency in hemodialysis patients-An under-recognized problem: A case series.

Adrenal insufficiency is an uncommon disorder and presents with non-specific symptoms. Identifying adrenal insufficiency in patients with chronic kidney disease requiring dialysis is increasingly difficult as there is a significant overlap of the signs and symptoms of adrenal insufficiency with those seen in chronic kidney failure. We highlight this diagnostic uncertainty in a case series of three patients with chronic kidney disease requiring hemodialysis as renal replacement therapy from a single center identified as hypoadrenal. Steroid replacement improved symptoms and hemodynamic parameters. Increased vigilance for adrenal insufficiency in dialysis patients is necessary. It is likely under recognized in hemodialysis patients given their multi-morbidity.

radioGWAS links radiome to genome to discover driver genes with somatic mutations for heterogeneous tumor image phenotype in pancreatic cancer.

Addressing the significant level of variability exhibited by pancreatic cancer necessitates the adoption of a systems biology approach that integrates molecular data, biological properties of the tumors, medical images, and clinical features of the patients. In this study, a comprehensive multi-omics methodology was employed to examine a distinctive collection of patient dataset containing rapid autopsy tumor and normal tissue samples as well as longitudinal imaging with a focus on pancreatic cancer. By performing a whole exome sequencing analysis on tumor and normal tissues to identify somatic gene variants and a radiomic feature analysis to tumor CT images, the genome-wide association approach established a connection between pancreatic cancer driver genes and relevant radiomic features, enabling a thorough and quantitative assessment of the heterogeneity of pancreatic tumors. The significant association between sets of genes and radiomic features revealed the involvement of genes in shaping tumor morphological heterogeneity. Some results of the association established a connection between the molecular level mechanism and their outcomes at the level of tumor structural heterogeneity. Because tumor structure and tumor structural heterogeneity are related to the patients' overall survival, patients who had pancreatic cancer driver gene mutations with an association to a certain radiomic feature have been observed to experience worse survival rates than cases without these somatic mutations. Furthermore, the association analysis has revealed potential gene mutations and radiomic feature candidates that warrant further investigation in future research endeavors.

Phase 1 Study of Bortezomib, Fludarabine, and Melphalan, With or Without Total Marrow Irradiation, as Allogeneic Hematopoietic Stem Cell Transplant Conditioning for High-risk or Relapsed/Refractory Multiple Myeloma.

OBJECTIVE: We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. METHODS: Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). RESULTS: Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m 2 ; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m 2 ) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m 2 ), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. CONCLUSION: TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.

Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.

The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder that commonly manifests cardiovascular complications. We aimed to assess the prevalence of FD in a Chinese population with left ventricular hypertrophy (LVH) whilst implementing a gender-specific screening approach. Methods: Patients with LVH, defined as a maximum thickness of the left ventricular septal/posterior wall ≥ 13 mm, were considered eligible. All patients with hypertrophic cardiomyopathy (HCM) were excluded. Plasma α-galactosidase (α-GLA) enzyme activity was assessed using a dried blood spot test. Males with low enzyme activity underwent genetic testing to confirm a diagnosis of FD whereas females were screened for both α-GLA and globotriaosylsphingosine concentration and underwent genetic analysis of the GLA gene only if testing positive for ≥1 parameter. Results: 426 unrelated patients (age = 64.6 ± 13.0 years; female: male = 113:313) were evaluated. FD was diagnosed in 3 unrelated patients (age = 69.0 ± 3.5 years, female: male = 1:2) and 1 related female subject (age = 43 years). Genetic analyses confirmed the late-onset cardiac variant GLA c.640-801G>A (n = 3) and the missense variant c.869T>C associated with classic FD (n = 1). Cardiac complications were the only significant findings associated with the late-onset c.640-801G>A mutation, manifesting as mild or severe concentric LVH. In contrast, the classic c.869T>C mutation FD exhibited multisystemic manifestations in addition to severe concentric LVH. Conclusions: The prevalence of FD is lower in Chinese patients with LVH when HCM is excluded. The pathological variant c.640-801G>A remains the most common cause of late-onset FD, while the detection of FD in females can be improved by utilizing a gender-specific screening method.

The prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in post-irradiated patients with nasopharyngeal carcinoma (NPC) is unknown. MATERIALS AND METHODS: In a cross-sectional study, 31 NPC and 12 control patients completed questionnaires for GERD/LPR before esophageal manometry and 24-h pH monitoring. The DeMeester score and reflux finding score (RFS) were used to define GERD and LPR, respectively. Risk factors were identified. RESULTS: 51.6% of NPC and 8.3% of control patients, and 77.4% of NPC and 33% of control patients, were GERD-positive and LPR-positive, respectively. The GERD/LPR questionnaire failed to identify either condition in patients with NPC. No parameter differences in esophageal manometry or pneumonia incidence were noted between GERD/LPR-positive and GERD/LPR-negative patients. Post radiotherapy duration, high BMI, lack of chemotherapy, and dysphagia were positive risk factors for GERD/LPR. CONCLUSIONS: A high prevalence of GERD/LPR in patients with post-irradiated NPC exists, but reflux symptoms are inadequate for diagnosis.

Yttrium-90 Anti-CD25-BEAM-Conditioning for Autologous Hematopoietic Cell Transplantation in Peripheral T Cell Lymphoma.

Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemosensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCL. In this phase 1 clinical trial, we tested the addition of beta-emitting 90Y-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning for AHCT in patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5 and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure [median time of death 17 mo (range: 9-21 mo)] post-AHCT. Median follow-up was 24 mo (range: 9-26 mo) overall and 24 mo (range: 13-26 mo) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% CI: 34-77%) and 68% (95% CI: 42-84%), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.clinicaltrials.gov as # NCT02342782.

Establishing obstetrics-specific metrics and interventions for antimicrobial stewardship.

Background: To describe baseline antimicrobial stewardship (AMS) metrics and apply AMS interventions in an inpatient obstetrical population. Methods: From October 2018 to October 2019, our tertiary-care obstetrical center reviewed components of our AMS program, which included: (1) antimicrobial consumption data, (2) point prevalence surveys (PPS), and (3) prospective audit and feedback. We reviewed institutional data for antimicrobial consumption from the pharmacy database. Detailed point prevalence surveys were conducted for all antimicrobial prescriptions on two predefined dates each month. Daily audits and feedback assessed the appropriateness of all non-protocolized antimicrobials. Results: Our average antimicrobial length of therapy (LOT) was 12 days per 100 patient-days, where erythromycin (2.33), amoxicillin (2.28), and ampicillin (1.81) were the greatest contributors. Point prevalence surveys revealed that 28.8% of obstetrical inpatients were on antimicrobials, of which 11.2% were inappropriate. Protocolized antimicrobials were 62% less likely (p = 0.027) to be inappropriate. From 565 audited prescriptions, 110 (19.5%) resulted in feedback, where 90% of recommendations were accepted and implemented. The most common reasons for interventions include incorrect dosage, recommending a diagnostic test before continuing antimicrobials, and changing antimicrobials based on specific culture and sensitivity. Conclusions: Antimicrobial use in obstetrics is unique compared to general inpatients. We provide a baseline set of metrics for AMS at our obstetrical center intending to lay the groundwork for AMS programming in our discipline. Antimicrobial protocolization, as well as audit and feedback, are feasible interventions to improve antimicrobial prescribing patterns.

Historique: Décrire les mesures de gouvernance antimicrobienne (GAM) fondamentales et utiliser les interventions de GAM dans une population obstétricale hospitalisée. Méthodologie: D'octobre 2018 à octobre 2019, le centre obstétrical de soins tertiaires a révisé les éléments du programme de GAM, qui incluait : 1) les données sur la consommation d'antimicrobiens, 2) les enquêtes de prévalence ponctuelles (EPP) et 3) la vérification et la rétroaction prospectives. Les chercheurs ont examiné les données institutionnelles relatives à la consommation d'antimicrobiens dans la base de données de la pharmacie. Ils ont effectué des enquêtes de prévalence ponctuelles détaillées sur toutes les prescriptions d'antimicrobiens à deux dates déterminées chaque mois. Les vérifications et les rétroactions quotidiennes ont permis d'évaluer la pertinence de tous les antimicrobiens non protocolisés. Résultats: La durée du traitement antimicrobien moyen était de 12 jours sur 100 jours-patients, et l'érythromycine (2,33), l'amoxicilline (2,28) et l'ampicilline (1,81) étaient les plus utilisées. Les enquêtes de prévalence ponctuelles ont révélé que 28,8 % des patientes obstétricales hospitalisées prenaient des antimicrobiens, dont 11,2 % étaient inappropriés. Les antimicrobiens protocolisés étaient 62 % moins susceptibles d'être inappropriés (p = 0,027). Des 565 prescriptions vérifiées, 110 (19,5 %) ont donné lieu à des rétroactions, et 90 % des recommandations ont été acceptées et mises en œuvre. Les principales raisons d'intervenir incluaient une posologie inexacte, la recommandation d'un test diagnostique avant de poursuivre l'antimicrobien, ainsi que le changement d'antimicrobien d'après la culture et sensibilité spécifiques. Conclusions: L'utilisation d'antimicrobiens est unique en obstétrique par rapport aux autres patients hospitalisés. Les chercheurs fournissent la série de mesures de GAM de référence utilisée à leur centre obstétrical pour jeter les bases de la programmation de la GAM dans la discipline. La protocolisation des antimicrobiens, de même que la vérification et la rétroaction, est une intervention faisable pour améliorer les profils de prescription d'antimicrobiens.