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Item does not contain fulltext OBJECTIVE: To investigate if oxygen delivery index during cardiopulmonary bypass (DO(2)I) was more strongly associated with acute kidney injury (AKI), the higher the patient's preoperative pulse pressure (PP). DESIGN: Retrospective cohort of 1064 patients undergoing cardiac surgery. SETTING: Single academic healthcare center. PARTICIPANTS: Adult patients undergoing coronary artery bypass grafting, valve, aortic, or combined surgery requiring cardiopulmonary bypass. INTERVENTIONS: Hemoglobin, arterial oxygen saturation, and pump flow recorded no fewer than every 30 min were extracted from the patients' perfusion records, and DO(2)I was calculated. The AKI was assessed from the pre- and postoperative creatinine and urine output values using the Acute Kidney Injury Network criteria. The sample was stratified in 5 categories of progressively higher PP. The patient characteristics and intraoperative variables were evaluated in univariate analysis for a relationship with AKI. The significant risk factors from the univariate analysis then were evaluated in a multivariate analysis and assessed for logistic fit with respect to AKI. PRIMARY OUTCOME: The AKI assessed as a binary outcome. MEASUREMENTS AND MAIN RESULTS: Age, body surface area, DO(2)I, history of heart failure, and baseline creatinine were associated significantly with AKI, as was an interaction term between the PP category and DO(2)I (p = 0.0067). The higher the PP category, the stronger the observed association between DO(2)I and AKI, and the higher the variability in the predicted risk of AKI dependent on DO(2)I. CONCLUSIONS: A lower DO(2)I during cardiopulmonary bypass appeared more strongly associated with a higher likelihood of developing AKI, the higher the patient's preoperative pulse pressure. 01 november 2022

Dealing with the class imbalance issue in the data is a big problem when creating fraud detection systems since valid transactions exceed fraudulent transactions by a large degree. Fraudulent transactions generally make up less than 1% of all transactions. This is a crucial field of research because it can be challenging to discern between a positive instance (a fraudulent case), and it gets tougher when more data are collected and a smaller percentage of such cases are represented. Eight distinct sampling techniques and two classifiers were used in this investigation, and the results of each methodology are reported. The results of this study point to favourable outcomes for sampling methods based on SMOTE. The best F1 score score obtained was with SMOTE sampling strategy on Random Forest classifier at 0.867.

Supplementary Data from Dual Inhibition of Akt/Mammalian Target of Rapamycin Pathway by Nanoparticle Albumin-Bound–Rapamycin and Perifosine Induces Antitumor Activity in Multiple Myeloma

Mesothelioma patient molecular profile from biopsy: A) Immunohistochemical staining of phosphatase and tensin homolog (PTEN); B) Single-nucleotide polymorphism on PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2)

Supplementary Figure legend

Purpose: This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies.Experimental Design:nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m2. Additional doses were 56.25, 100, 150, and 125 mg/m2.Results: Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m2 [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m2 (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m2. Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration–time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m2, except for a relatively low AUC at 125 mg/m2. nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1.Conclusions: The clinical dose of single-agent nab-rapamycin was established at 100 mg/m2 weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies. Clin Cancer Res; 19(19); 5474–84. ©2013 AACR.

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound–rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM. Mol Cancer Ther; 9(4); 963–75. ©2010 AACR.

A) Association of PBMC 4EBP1 T70 levels with serum rapamycin concentrations; B) Association of PBMC S6K T389 levels with serum rapamycin concentrations

Health jurisdictions have seen a near-disappearance of respiratory syncytial virus (RSV) during the first year of the coronavirus disease 2019 (COVID-19) pandemic. Over this corresponding period, we report a reduction in RSV antibody levels and live virus neutralization in sera from women of childbearing age and infants between May to June 2020 and February to June 2021, in British Columbia (BC), Canada. This supports that antibody immunity against RSV is relatively short-lived and that maintaining optimal antibody levels in infants requires repeated maternal viral exposure. Waning immunity may explain the interseasonal resurgence of RSV cases observed in BC and other countries.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

In modern trials, traditional planning target volume (PTV) margins for postoperative prostate radiation therapy have been large (7-10 mm) to account for both daily changes in patient positioning and target deformation. With daily adaptive radiation therapy, these interfractional changes could be minimized, potentially reducing the margins required for treatment and improving adjacent normal-tissue dosimetry.A single-center retrospective study was conducted from March 2021 to November 2021. Patients receiving conventionally fractionated postoperative radiation therapy (PORT) for prostate cancer with pretreatment and posttreatment cone beam computed tomography (CBCT) imaging (pre-CBCT and post-CBCT, respectively) were included (248 paired images). Pretreatment and posttreatment clinical target volumes (pre-CTVs and post-CTVs) were contoured by a single observer on all CBCTs and verified by a second observer. Motion was calculated from pre-CTV to that of the post-CTV, and predicted margins were calculated with van Herk's formula. Adequate coverage of the proposed planning target volume (PTV) margin expansions (pre-PTV) were verified by determining overlap with post-CTV. In a smaller cohort (25 paired images), dosimetric changes with the proposed online adaptive margins were compared with conventional plans in the Ethos emulator environment.The estimated margins predicted to achieve ≥95% CTV coverage for 90% of the population were 1.6 mm, 2.0 mm, and 2.2 mm (x-, y-, and z -xes, respectively), with 95% of the absolute region of interest displacement being within 1.9 mm, 2.8 mm, and 2.1 mm. After symmetrically expanding all pre-CTVs by 3 mm, the percentage of paired images achieving ≥95% CTV coverage was 97.1%. When comparing adaptive plans (3-mm margins) with scheduled plans (7-mm margins), rectum dosimetry significantly improved, with an average relative reduction in V40Gy[cc] of 59.2% and V65Gy[cc] of 79.5% (where V40Gy and V65Gy are defined as the volumes receiving 40 Gy and 65 Gy or higher dose, respectively).Online daily adaptive radiation therapy could significantly decrease PTV margins for prostatic PORT and improve rectal dosimetry, with a symmetrical expansion of 3 mm achieving excellent coverage in this cohort. These results need to be validated in a larger prospective cohort.

Background Extranodal natural killer/T-cell lymphoma is a rare, aggressive non-Hodgkin lymphoma that is treated upfront mostly with L-asparaginase containing regimens. Relapsed extranodal natural killer/T-cell lymphoma is associated with a poor prognosis, and there is no established standard of care. Case presentation We report the case of a 72 year-old white male with a distant extranasal relapse of extranodal natural killer/T-cell lymphoma that has been managed successfully with a combination of radiation and immune checkpoint blockade with pembrolizumab. Pseudoprogression with new skin and bone lesions on positron emission tomography imaging was encountered during this Caucasian patient’s immunotherapy and was successfully managed with supportive care and continuation of immune checkpoint blockade. Conclusions The patient has been in complete clinical, radiologic, and molecular remission for close to 3 years and has not had any immune-related adverse effects. Pseudoprogression is a clinical challenge that can be encountered while patients are treated with immunotherapy, and astute clinical acumen is needed for accurate management. We believe this is the longest duration of response to immune checkpoint blockade in relapsed extranodal natural killer/T-cell lymphoma reported to date in literature. There is a strong biologic rationale in combining radiation with immunotherapy. The optimal timing, dose, and duration of radiation combined with immunotherapy in extranodal natural killer/T-cell lymphoma need to be prospectively evaluated.

The p53 tumor suppressor mutations resulting in loss of function control tumor proliferation in 50% of human cancers. TP53 missense and nonsense mutations are present in about 50% and 7-12% of the p53 driven cancer, respectively. To date there is no effective treatment for rescuing p53 function in cancers harboring p53 nonsense mutations. We have developed a new potent strategy combining mRNA with a tumor selective nanocarrier, to rescue of p53 tumor suppressor functions as potential therapeutic approach in cancers. ADGN-531 contains proprietary p53-mRNA complexed with proprietary short amphipathic peptides that form stable neutral nanoparticles. ADGN-531 was evaluated on 20 different cancer cell lines harboring different types of p53 mutations. In-vivo efficacy of IV-administered ADGN-531 nanoparticles (weekly, 0.5 & 1.0mg/kg) was evaluated on colorectal SW403 (p53 nonsense/KRASG12V), osteosarcoma SaOs2 (p53 null) and lung H358 (p53 null/KRASG12C) mouse xenografts. Sensitivity to Veliparib (PARPi) following ADGN-531 treatment was evaluated on PARPi resistant SUM-149PT and OVCAR-8 and PARPi sensitive MDA-MB436 cells. ADGN-531/AMG-510 synergy was evaluated on H358 and M-PACA cells and H358 mouse xenograft. ADGN-531 markedly delay the growth of a large panel of cancer cells harboring p53-missense or nonsense mutations, by rescuing p53 transcriptional activity and subsequent expression of its target proteins. ADGN-531 induces cell cycle arrest in G1 due to p21 upregulation and apoptosis following BAX and PUMA activation. ADGN-531 mediated p53 function rescue is directly correlated to the type of p53 mutation in the cancer cells. ADGN-531 induces 80% cell proliferation inhibition in p53 null/nonsense cells and 20 to 50% in p53 missense cells. IV-administration of ADGN-531 resulted in dose responsive tumor growth inhibition. ADGN-531 (1.0mg/kg) induces 40-60% tumor regression SaOs2, SW403 and H358 xenografted mouse model. We demonstrated a synergistic combination between ADGN-531/AMG-510 a KRASG12C inhibitor in human lung carcinoma. ADGN-531 (0.5mg/kg, weekly)/AMG-510 (10mg/kg, daily) induces about 80% tumor regression, higher than with either single agents. We demonstrated that ADGN-531 mediated p53 rescue markedly improves (200 fold) and restores the sensitivity of ovarian and breast cancer cells to Veliparib. ADGN-531 treatments are well tolerated, no sign of clinical toxicity or inflammatory response was detected after single or repeated administrations. ADGN-531 is effective in rescuing P53 functions both in vitro and in vivo. Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy or in combination together with other therapies for potent combinatorial cancer treatment. Citation Format: Gilles Divita, Audrey Grunenberger, Elodie Czuba, Khadidja Boularache, Melanie Guidetti, Veronique Josserand, Neil Desai. p53 rescue of tumor suppressor function with ADGN-531 causes tumor regression both as single agent and in combination with PARPi and KRASG12Cinhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 550.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel’s discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

Health jurisdictions have seen a near-disappearance of Respiratory Syncytial Virus (RSV) during the first year of the COVID-19 pandemic. Over a corresponding period, we report a reduction in RSV antibody levels and neutralization in women and infants one year into the COVID-19 pandemic (February - June 2021) compared to earlier in the pandemic (May - June 2020), in British Columbia (BC), Canada. This supports that humoral immunity against RSV is relatively short-lived and its establishment in infants requires repeated viral exposure. Waned immunity in young children may explain the inter-seasonal resurgence of RSV cases in BC as seen also in other countries.

Aim/objectives/background To standardize the practice of stereotactic body radiation therapy (SBRT), the American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) cooperatively developed the practice parameter for SBRT. SBRT is a treatment technique that delivers radiation dose to a well-defined extracranial target in 5 fractions or less and usually employs a higher dose per fraction than used in conventional radiation. Methods The ACR-ASTRO Practice Parameter for the Performance of Stereotactic Body Radiation Therapy was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. Results Given the complexities of SBRT, a separate document was created to develop a technical standard for the medical physics of SBRT (ACR-AAPM Technical Standard for Medical Physics Performance Monitoring of Stereotactic Body Radiation Therapy). Workflow, qualifications and responsibilities of personnel, specifications, documentation, quality control/safety/improvement, simulation/treatment, and follow-up were addressed in this practice parameter. Conclusions This practice parameter assists practitioners in providing safe and appropriate SBRT treatment and care for patients when clinically indicated. As technologies and techniques continue to evolve, this document will be reviewed, revised and renewed accordingly to a 5 year or sooner timeline specified by the ACR.

Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Background: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. Objective: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. Design, setting, and participants: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometa-static), metachronous oligometastatic (5 lesions), or de novo metastatic (metastasis at diagnosis) disease. Outcome measurements and statistical analysis: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). Results and limitations: The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined. Conclusions: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration. Patient summary: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

INTRODUCTION AND OBJECTIVE:Metastasis-directed radiation therapy (MDRT) may improve oncologic and quality of life outcomes in patients with metastatic cancer, but data on its use in metastatic blad...

Purpose: Primary central nervous system lymphoma (PCNSL) is an aggressive disease with many tools for management that may be subject to resource barriers. This study compares the treatment patterns and survival outcomes among PCNSL patients treated at a safety-net hospital versus a tertiary academic institution.Methods:We retrospectively reviewed records of PCNSL patients from 2007-2020 (n = 95) at a public safety-net hospital (n = 33) and a private academic center (n = 62) staffed by the same university. Demographics, treatment patterns, and outcomes were analyzed.Results:Compared to the tertiary academic center, patients at the safety-net hospital were significantly younger, more commonly Black or Hispanic, and had a higher proportion of presenting patients with HIV. The safety-net hospital cohort was significantly less likely to receive induction chemotherapy (67% vs 86%, p = 0.003) than those at the academic center. Safety-net hospital patients were significantly less likely to receive autologous stem cell transplant (ASCT) consolidation (0% vs. 44%, p = 0.001) and had higher rates of consolidative WBRT (35% vs 15%, p = 0.001). Younger age and receiving consolidation were associated with improved progression-free survival (PFS, p = 0.001) and overall survival (OS, p = 0.001). Hospital location had no statistical effect on PFS (p = 0.725) or OS (p = 0.226) on age-adjusted analysis. Conclusions:Our study showed significant treatment differences between a public safety-net hospital and an academic cancer center reflecting access disparities. Despite variable treatment patterns, survival outcomes were not different. Further research is needed to determine optimal treatments for an orphan disease like PCNSL and it will be essential to advocate for equitable access in resource-limited settings.

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.

Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials.Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom.Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival.Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.

Purpose Hydrogel spacers reduce rectal dose toxicity during prostate cancer radiation therapy. Current products require magnetic resonance imaging (MRI) for visualization during treatment planning, but MRI incompatibility and cost have prompted alternatives using computed tomography (CT). This case series evaluates the addition of iodinated contrast to hydrogel as such an alternative. Methods and materials Three patients underwent rectal hydrogel spacer placement with iodinated contrast modification. CT was performed within 1 hour of injection and again 1 week later. MRI was obtained at the time of the second CT. Hydrogel delineation was compared between CT and MRI and between paired CT scans. Results Spacer enhancement was visible on CT immediately after hydrogel placement (mean Hounsfield units, 122; range, 52-193) but not at the second CT 1 week later (mean Hounsfield units, 8; range, −8 to 29). Delineated spacer volume did not significantly differ between immediate postprocedure CT and MRI ≥1 week later in 2 patients (patient 1: 16.6 vs 15.5 cm3; patient 2: 12.6 vs 14.7 cm3; paired t-test, P = .81). Conclusions CT visualization of rectal hydrogel admixed with contrast is feasible and allows delineation of interface with rectum/prostate.

Purpose The treatment paradigm for uterine clear cell carcinoma is often linked to serous carcinoma. This study compares oncologic outcomes between women with uterine clear cell and serous carcinoma. Methods and Materials We reviewed 114 women with stage I–II uterine clear cell carcinoma (n = 17, 15%) or serous carcinoma (n = 97, 85%) who underwent hysterectomy and salpingo-oophorectomy at our institution from April 1992 to December 2011; 86 (76%) had stage IA, 14 (12%) had stage IB, and 14 (12%) had stage II disease. Median followup was 57 months. Results Patients with uterine clear cell and serous carcinoma did not differ significantly by age ≥60 years, stage, or rate of lymphovascular invasion. There was no difference in the number of patients with clear cell or serous histology who received adjuvant radiotherapy (71% vs. 84%, respectively; p = 0.31); however, significantly fewer patients with clear cell histology received adjuvant chemotherapy (35% vs. 67%, respectively; p = 0.02). At 5 years, there were no significant differences in disease-free survival (94% vs. 84%, respectively; p = 0.27), disease-specific survival (100% vs. 92%, respectively; p = 0.20), or overall survival (100% vs. 89%, respectively; p = 0.34). The differences in chemotherapy utilization did not impact pattern of relapse, specifically peritoneal spread (7% vs. 6%, respectively; p = 0.92) or other distant sites (0% vs. 9%, respectively; p = 0.17). Conclusions Oncologic outcomes and recurrence patterns of women with stage I–II uterine clear cell carcinoma compared favorably with those of women with serous carcinoma, despite significantly less adjuvant chemotherapy use. Potential reduction in adjuvant therapy in women with clear cell carcinoma should be studied prospectively.

11574 Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare and aggressive sarcoma. nab-Sirolimus is an albumin-bound intravenous (IV) mTOR inhibitor (mTORi) approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The AMPECT trial (NCT02494570) was the first prospective study in advanced malignant PEComa. In exploratory biomarker analyses, TSC1 or TSC2 alterations were associated with response. We report data from the final analysis of AMPECT patients, who were naïve to mTORi, and in patients with malignant PEComa with prior mTORi exposure treated with nab-sirolimus in an expanded access program (EAP) (NCT03817515). Methods: In AMPECT, patients with malignant PEComa naïve to mTORi received nab-sirolimus (100 mg/m2 IV days 1 and 8 of every 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Other endpoints included duration of response (DOR) and disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) at ≥12 weeks. In the EAP, patients with malignant PEComa and prior mTORi exposure received the same dose of nab-sirolimus as in AMPECT. Responses and DCR were evaluated post hoc via electronic medical record review. Genetic profiling, including TSC1 or TSC2 status, was assessed in both protocols, but no specific mutation criteria were required for enrollment. Results: Data include 47 total efficacy-evaluable patients, 31 in AMPECT and 16 with malignant PEComa and prior mTORi exposure treated in the EAP from July 2019–July 2021. Prior mTORi on the EAP included sirolimus, everolimus, temsirolimus, or sapanisertib; 12 patients had exposure to 1 prior mTORi and 4 to ≥2 prior mTORi, and 50% had had progressive disease as best response on mTORi. In AMPECT, ORR was 39% (12/31 patients), and DCR was 71%. Median DOR was not reached after 3 years of follow-up. On the EAP, 4/16 patients (25%) achieved PR (DOR range: 1.3+–25.2+ months, 3 ongoing), and 8/16 (50%) had SD as best response; the DCR was 63% (10/16). Of patients with known TSC1 or TSC2 inactivating alterations in the combined datasets (n = 23), 57% had a response (AMPECT, 64%; EAP, 44%). There were no Grade 4 or 5 treatment-related adverse events on either protocol Conclusions: nab-Sirolimus provided durable responses in mTORi-naïve patients with malignant PEComa and clinical benefit in an expanded access protocol for patients with malignant PEComa with prior mTORi therapy. Although AMPECT and the EAP cannot be directly compared, response rates showed similar trends regardless of prior mTORi exposure and in patients with TSC1 or TSC2 alterations. Based on the emerging biomarker results, a tissue-agnostic study in patients with TSC1 and TSC2 alterations has been initiated (NCT05103358). Clinical trial information: NCT02494570, NCT03817515.

Introduction: Although in-person hospitalist presence, increasingly staffed by dedicated nocturnists, has become the norm overnight in the hospital, the scope of nocturnist practice and typical workload has not been defined. This study examines the clinical responsibilities and patient safety perceptions of hospitalists who work night shifts in the United States. Methods: In the fall of 2019, a cross-sectional, web-based survey was administered to physician and nurse practitioner/physician assistant (NP/PA) hospitalists who work night shifts. The questionnaire assessed night staffing structure, typical responsibilities, patient volume, perceptions of safety overnight, as well as demographic information. The survey was posted on the Society of Hospital Medicine (SHM) Hospital Medicine Exchange (HMX) Online Discussion Forum. Additionally, the survey was distributed by ‘snowball method’ by respondents to other night hospitalists. Responses were collected anonymously. Results: Of the 167 respondents, 157 reported working night shifts. There was at least one respondent from 32 different states. In addition to performing admissions to medicine services and covering inpatients, night hospitalists cover ICU patients, participate in RRT/Code teams and procedure teams, perform consults, participate in medical education, and take outpatient calls. Across institutions, there was a large distribution in numbers of patients covered in a night shift; however, patient volume fell into typical ranges: 5–10 admissions for physicians, 0–6 admissions for NP/PAs, and 25–75 patient cross-coverage census. When physicians perform more than five admissions per night, hospitalists were less likely to agree that they could provide safe care (88% vs. 63%, p = 0.0006). Conclusions: This is the first national study to examine the clinical responsibilities of hospitalists working overnight. Overnight responsibilities are heterogeneous across institutions. As hospitals are increasingly employing nocturnists, more research is needed to guide night staffing and optimize patient safety.

The risk of rectal toxicity during and after prostate cancer radiation therapy is common to all treatment regimens. Hydrogel rectal spacers are increasingly being used to mitigate this risk and to facilitate dose-escalation, but also may infiltrate the rectal wall, with unclear clinical implication. We present a case of significant infiltration associated with severe late rectal injury (grade 4) and further grade 3 to 4 sequelae (recto-urethral fistula and associated osteomyelitis requiring exenteration) after high-dose stereotactic body radiation therapy for localized prostate cancer. The injury's temporal pattern associated with the expected timing of gel dissolution and displacement of infiltrated rectal layers potentially toward high dose regions together suggest a contributing role of the infiltration to the injury. In light of the rapid increase of hydrogel rectal spacer utilization, we review the case's evolution, concerning imaging findings, and associated literature and make suggestions regarding treatment planning and endoscopic assessment in the setting of infiltration or expected injury.

Purpose/Objective(s) Bridging therapy (BT) with chemotherapy, targeted therapy, and/or radiation therapy (RT) is often administered to aid in tumor debulking or control symptomatic disease prior to CAR T-cell therapy (CAR-T). However, little is known about the optimal type of BT and the impact BT may have on patterns of failure. We sought to compare the patterns of failure in patients who received CAR-T for R/R NHL based on the type of BT received. We hypothesize that bridging RT decreases the risk of local recurrence in sites treated with RT prior to CAR-T therapy. Materials/Methods An IRB-approved single-institution retrospective review was performed of all R/R DLBCL patients who underwent CAR-T with axicabtagene ciloleucel and had PET/CT scans immediately before, D+30, and D+90 post-CAR-T available for review. PET/CTs were analyzed with response assessment per the Lugano classification. FDG-avid (Lugano 4 or 5) lesions on the pre-CAR-T scan were recorded as index lesions and compared to residual or new FDG-avid lesions on post-CAR-T scans. Results 20 patients met inclusion criteria, of whom 6 were treated with no BT, 8 with bridging chemotherapy, 5 with bridging RT (median 30 Gy in 10 fxs), and 1 with a Bruton's tyrosine-kinase inhibitor (BTKi). At last follow up, 13/19 (68%) were alive (4/6 with no BT, 5/7 with chemo, 3/5 with RT, 1/1 with BTKi) and 7/19 (37%) were without disease progression (2/6 with no BT, 4/7 with chemo, 1/5 with RT, 0/1 with BTKi); one patient was lost to follow up. 9 patients (45%) had metabolic complete response (CR) at D+30 and 8 (40%) at D+90. Based on type of BT received, D+90 CR rates were 50% for no BT, 57% for chemo, and 25% for RT. In analysis of patterns of failure, there were 67 total index lesions identified on pre-CAR-T PET/CT scans. Of those, 26 received no BT, 28 were treated with bridging chemotherapy, 7 with bridging RT, 6 with BTKi. On D+30 PET/CT, the rates of CR were 18/26 (69%) in lesions without BT, 21/28 (75%) in lesions treated with chemo, 6/7 (86%) in lesions with RT. By D+90, the rates of CR were 17/22 (77%) in lesions without BT, 18/22 (82%) in lesions treated with chemo, and 4/4 (100%) of lesions treated with RT. Of the 56 lesions noted on D+30 PET/CTs, 24 (43%) were index lesions on pre-CAR-T PET/CT, and only 8 (22%) of the lesions on D+90 PET/CT were initial index lesions. Conclusion Patients who require BT before CAR-T have higher relapse rates, likely reflecting more aggressive disease biology. Bridging RT to CAR-T appears to be safe and effective in providing local control, even at palliative doses, but may not impact overall outcomes. Radiating all sites of active disease pre-CAR-T may not improve outcomes as the predominant pattern of failure appears to be distant. However, these data suggest that bridging RT should be considered in sites where local control is a priority, such as symptomatic sites or sites where recurrence may cause significant morbidity. The optimal timing and combination strategies with RT and CAR-T for R/R DLBCL needs to be explored prospectively.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines (, Highlights • IR induces distinct DNA damage repair kinetics in prostate cancer PDEs and cell lines. • IR induces a distinct transcriptional program in prostate cancer PDE and cell lines. • DNA-PKcs inhibition blocks IR-induced DDR in prostate cancer PDE. • Inhibition of AR impairs NHEJ in prostate cancer PDEs.

High-dose SABR for prostate cancer offers the radiobiologic potency of the most intensified radiation therapy regimens but was associated with90% rates of ulceration of the anterior rectal wall on endoscopic assessment; this infrequently progressed to severe rectal toxicity in prior prospective series. A multi-institutional phase 2 prospective trial was conducted to assess whether placement of a perirectal hydrogel spacer would reduce acute periprostatic rectal ulcer events after high-dose (40 Gy) SABR.Eligible patients included men with stage ≤T2c localized grade group 1 to 3 prostate cancer, a prostate-specific antigen (PSA) level ≤15 ng/mL, American Urological Association Symptom Index = AUA-SI scores ≤18, and a gland volume ≤80 cmForty-four men were enrolled and 43 were eligible for protocol analysis. The median follow-up for surviving patients was 48 months. Acute periprostatic ulcers were observed in 6 of 42 patients (14.3%; 95% confidence interval, 6.0%-27%; P.001) at a median of 2.9 months posttreatment (range, 1.7-5.6 months). All ulcers (grade 1, 5 ulcers; grade 2, 1 ulcer) resolved on repeat anoscopy within 8 months of incidence. There were no grade ≥3 late gastrointestinal toxicities; the incidence of late grade-2 gastrointestinal toxicities was 14.3%, with a prevalence at 3 years of 0%. No toxicities greater than grade 3 occurred in any domain. Four-year freedom from biochemical failure was 93.8% (95% CI, 85.2%-100.0%).Temporary hydrogel spacer placement before high-dose SABR treatment for localized prostate cancer and use of strict dose constraints are associated with a significant reduction in the incidence of rectal ulcer events compared with prior phase 1/2 trial results.

In post-operative radiotherapy for prostate cancer, precisely contouring the clinical target volume (CTV) to be irradiated is challenging, because the cancerous prostate gland has been surgically removed, so the CTV encompasses the microscopic spread of tumor cells, which cannot be visualized in clinical images like computed tomography or magnetic resonance imaging. In current clinical practice, physicians' segment CTVs manually based on their relationship with nearby organs and other clinical information, but this allows large inter-physician variability. Automating post-operative prostate CTV segmentation with traditional image segmentation methods has yielded suboptimal results. We propose using deep learning to accurately segment post-operative prostate CTVs. The model proposed is trained using labels that were clinically approved and used for patient treatment. To segment the CTV, we segment nearby organs first, then use their relationship with the CTV to assist CTV segmentation. To ease the encoding of distance-based features, which are important for learning both the CTV contours' overlap with the surrounding OARs and the distance from their borders, we add distance prediction as an auxiliary task to the CTV network. To make the DL model practical for clinical use, we use Monte Carlo dropout (MCDO) to estimate model uncertainty. Using MCDO, we estimate and visualize the 95% upper and lower confidence bounds for each prediction which informs the physicians of areas that might require correction. The model proposed achieves an average Dice similarity coefficient (DSC) of 0.87 on a holdout test dataset, much better than established methods, such as atlas-based methods (DSC

Background Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. Objective To identify a potential ICE for men receiving PORT. Design, setting, and participants We performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance ( c ) indices were used to assess model discrimination. Results and limitations OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45–3.71; p p p c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. Conclusions While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. Patient summary We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.

Disease progression following salvage radiotherapy (SRT) for prostate cancer (PC) is common, and the time to biochemical recurrence (BCR) is heterogeneous.To describe the temporal distribution and clinical impact of BCR following SRT and model outcomes using patient age and time to BCR from SRT.A retrospective multi-institutional study included 547 consecutive men with lymph node-negative PC receiving SRT from 1985 to 2013. The median follow-up after SRT was 8.4 yr. Intervention All men received SRT with three-dimensional or intensity-modulated RT.BCR was defined as a rise in prostate-specific antigen (PSA) ≥0.2ng/ml above the PSA nadir followed by a sequentially equal or higher value. Additional outcomes included distant metastasis (DM), PC-specific mortality (PCSM), and overall mortality (OM). Cox proportional hazards models, a landmark analysis, and comparison of c-indices were used. Cumulative incidence curves were estimated from a Fine and Gray regression model.The estimated 10-yr cumulative incidence of BCR was 60%. Of the 274 men experiencing BCR, 149 (54%) had BCR within 18 mo of SRT. BCR ≤18 mo after SRT was associated with a higher risk of DM (hazard ratio [HR] 7.44, 95% confidence interval [CI] 4.91-11.3; p0.001), PCSM (HR 12.3, 95% CI 5.95-25.2; p0.001), and OM (HR 2.85, 95% CI 1.94-4.17; p0.001). We provide a model to estimate the cumulative incidence of DM and PCSM using age and time to BCR. The retrospective nature of our analysis limits our findings.A strikingly large proportion of men experience early BCR following SRT and are at higher risk of DM and PCSM. Novel predictive biomarkers are needed to identify men harboring micrometastatic disease to avoid potentially futile local therapies or allow for intensification of systemic therapies.Many men will develop biochemical recurrence of prostate cancer after salvage radiotherapy. Men with biochemical recurrence within 18 mo of salvage radiotherapy constitute a cohort at higher risk of distant metastasis and prostate cancer-specific mortality.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. A long natural history and an evolution in staging modalities and treatment options has complicated studies regarding its optimal management. As a result, there is great variety in the therapeutic approaches used for low-grade (grade 1–2) early-stage FL. Definitive radiation therapy (RT) to a generous involved site volume to 24 Gy remains the recommended treatment for patients with stage I or contiguous stage II disease, based on retrospective data demonstrating prolonged disease-free intervals and even cure. An alternative is an even lower-dose RT to 4 Gy, which results in high response rates, with less toxicity but inferior local control. Additionally, observation may be appropriate in selected cases. The use of immunochemotherapy may improve progression-free survival (PFS) when added to RT but does not appear to affect overall survival, so its use in combination with RT or alone remains under investigation. This chapter review focuses on current understanding of these issues in localized grade 1–2 FL.