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Inverse problems occur in many scientific fields. Albeit grid search, where points of a regular grid are tested as possible solutions, is a straightforward and robust method to numerically solve inverse problems, it is computationally intensive and becomes prohibitive when the problem has a high dimensionality. Heterogeneous clusters are a viable and cost-effective solution to exploit the combined computational power of multiple available computers. In this paper, we present a computing framework that supports efficient grid search for inverse problems on heterogeneous clusters. Scheduling the workload on such systems might be challenging, especially when nodes are comprised of CPUs and GPUs with different computational speeds. The framework dynamically schedules computations on the processing elements of the cluster according to a selected performance index, which is determined at run-time. The framework is extensible, as it allows easy integration of additional inverse problems.

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

Die chronisch-obstruktive Lungenerkrankung (COPD) ist eine chronisch-entzündliche Erkrankung der Atemwege und des Lungenparenchyms mit vielfältigen systemischen Manifestationen. Exazerbationen der COPD sind wichtige Ereignisse im Krankheitsverlauf, da sie mit einer erhöhten Sterblichkeit, einer schwerwiegenden Beeinträchtigung der gesundheitsbezogenen Lebensqualität, einer beschleunigten Verschlechterung der Lungenfunktion, einer erheblichen Einschränkung der körperlichen Aktivität und einer erheblichen wirtschaftlichen Belastung verbunden sind. Telemedizin ist der Einsatz von Kommunikationstechnologien zur Übertragung medizinischer Daten über kurze oder lange Strecken und zur Erbringung von Gesundheitsdienstleistungen. Die Notwendigkeit, persönliche Termine während der COVID-19-Pandemie einzuschränken, hat zu einem raschen Anstieg der telemedizinischen Dienste geführt. In der vorliegenden Literaturübersicht über veröffentlichte randomisierte kontrollierte Studien mit Ergebnissen zum Einsatz digitaler Hilfsmittel bei akuten Exazerbationen der COPD versuchen wir, die Wirksamkeit der Telemedizin bei der Erkennung, Vorbeugung und Verringerung von COPD-Exazerbationen sowie bei der Verbesserung anderer klinisch relevanter Ergebnisse zu klären und gleichzeitig die spezifischen telemedizinischen Interventionen im Detail zu beschreiben.

Background COPD patients have an increased risk of cardiovascular disease and venous thromboembolism. Methods This study aimed to investigate whether patients with stable COPD have a prothrombotic state compared to COPD-free smokers. We conducted an observational study comparing levels of: D-dimers, INR, aPTT, coagulation factors; fibrinogen, FII, FV, FVII, FVIII, FIX, FX and coagulation inhibitors; protein S, proteins C and antithrombin between stable COPD patients and control subjects. Results A total of 103 COPD patients and 42 controls with similar age, sex, current smoking status, comorbidity burden and cardiovascular risk met the inclusion criteria. Compared to controls, COPD patients had higher levels of D-dimers (median (interquartile range): 360 (230–600) ng·mL−1 versus 240 (180–400) ng·mL−1, p=0.001), fibrinogen (mean±sd: 399±82 mg·dL−1 versus 346±65 mg·dL−1, p, Patients with stable COPD exhibit increased levels of key coagulation factors and decreased levels of coagulation inhibitors, namely protein S and antithrombin, compared to COPD-free smokers, indicating a prothrombotic state in stable COPD https://bit.ly/2VmR1PP

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.

Introduction: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. Aim: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO­VID-19 wave. Methods: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March–April 2020) and the corresponding period of the 2 previous years (2018–2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. Results: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491–0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502–0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). Discussion/Conclusion: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.

PURPOSE In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473 ). METHODS We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B). RESULTS Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed. CONCLUSION In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

PURPOSE Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression. PATIENTS AND METHODS Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382 ). 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI. RESULTS Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUVhetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUVtotal) was seen at the time of progression, as measured by 18F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI. CONCLUSION We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.

Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial. Patients and Methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen deprivation therapy were randomly assigned to receive pTVG-AR on one of two treatment schedules over one year, and with or without GM-CSF as a vaccine adjuvant. Patients were followed for 18 months. Primary objectives were safety and immune response. Secondary objectives included median time to PSA progression, and 18-month PSA-PFS (PPFS). Results: Forty patients were enrolled at three centers. Twenty-seven patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event before the 18-month time point. No grade 3 or 4 adverse events were observed. Of 30 patients with samples available for immune analysis, 14 (47%) developed Th1-type immunity to the AR LBD, as determined by IFNγ and/or granzyme B ELISPOT. Persistent IFNγ immune responses were observed irrespective of GM-CSF adjuvant. Patients who developed T-cell immunity had a significantly prolonged PPFS compared with patients without immunity (HR = 0.01; 95% CI, 0.0–0.21; P = 0.003). Conclusions: pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings, and will be prospectively evaluated in future trials. See related commentary by Shenderov and Antonarakis, p. 5056

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Introduction: Asthma and bronchiectasis appear to be two related diseases and in their complex inflammatory interaction, the cysteinyl leukotriene/cysteinyl leukotriene receptor 1 (cysLT/cysLTR1) axis appears to play an important role given its involvement also in the neutrophilic pathway. To our knowledge, few studies have been conducted so far to evaluate the role of the leukotriene cysLT/cysLTr1 axis in the management of clinical and inflammatory outcomes within a population of patients with severe asthma and bronchiectasis. The aim of our study was to verify in this population the effect of leukotriene receptor antagonist (LTRA) therapy in clinical and inflammatory control before and after 6 months of introduction of biologic therapy. Methods: We retrospectively enrolled, from eight different severe asthma centers’ outpatients, 36 atopic patients with the simultaneous presence of non-cystic fibrosis (non-CF) and non-allergic bronchopulmonary aspergillosis (non-ABPA) bronchiectasis and severe asthma. The first biological injection was performed at baseline (T0 time). Patients who were already taking LTRA therapy at time T0 were recorded, and no new prescriptions were made. We observed our population over a 6-month period (T1 time). At the baseline we collected the following data: baseline characteristics, clinical history, high resolution computed tomography and bronchiectasis-related parameters and skin prick test. At both times T0 and T1 we collected the following data: asthma control test (ACT), asthma control questionnaire (ACQ), immunoglobulin E (IgE) level, blood count, fractional exhaled nitric oxide 50 (FeNO 50) and flow-volume spirometry. The study was retrospectively registered. Results: Our population had a mean age of 59.08 ± 11.09 and 50% were female. At T1, patients on LTRA therapy had a significantly lower FeNO value (33.03 ± 23.61 vs. 88.92 ± 77.96; p = 0.012). We assessed that the value of ΔFeNO (FeNO 50 T1 − FeNO 50 T0) and the number of unplanned specialist visits allowed a discrimination of 66.7% in the presence of LTRA therapy. We also verified how low FeNO values at time T1 were statistically significant predictors of LTRA therapy (ODD = 9.96 (0.94–0.99); p = 0.032). Conclusion: The presence of LTRA in therapy in a population of severe asthmatics with coexisting non-ASBPA bronchiectasis and non-cystic fibrosis, acting simultaneously on the T helper type 2 (TH2) pathway and probably on the neutrophilic component of bronchiectasis, would allow a further amplification of the beneficial effects of biological therapy, leading to a reduction in the number of unplanned visits to specialists.

447 Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by a lack of (a) prospective studies, (b) rigorous approaches to assess and define clinical complete response (cCR), and (c) integration of novel therapies. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance. Patients not achieving cCR were recommended to undergo cystectomy. Coprimary endpoints included (1) cCR rate and (2) association between cCR and 2-year outcomes. The key secondary endpoint was the impact of pre-specified baseline genomic alterations on outcomes. Additional biomarkers to refine patient selection were also explored. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%). Median follow-up is 27 months. 72/76 patients underwent clinical restaging and a cCR was achieved in 33/76 (43%; 95% CI: 32%, 55%). One cCR patient opted for immediate cystectomy (ypTaN0M0). Outcomes are summarized in the Table. Baseline ERCC2, ATM, FANCC, or RB1 alterations were not, but tumor mutational burden ≥ 10 mutations/mb was, significantly associated with the composite endpoint of ypT0 (immediate cystectomy) or 2-year bladder-intact metastasis-free survival (BIMFS). On landmark analysis, VI-RADS (Vesical Imaging–Reporting and Data System) score (3-5 versus 1-2) on restaging MRI (central blinded review) was associated with inferior BIMFS (HR 4.5; p =

179 Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease >90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577 .

247 Background: The mainstay of therapy in metastatic prostate cancer is androgen receptor (AR) signaling inhibition. However, the emergence of early castration resistance or neuroendocrine transformation is associated with poor prognosis. Reliable biomarkers are needed to identify these patients and guide selection of clinical therapy. Methods: mRNA was isolated from EpCAM-positive circulating tumor cells (CTCs) isolated from patients with CSPC, CRPC, or NEPC to measure expression of KLK2, KLK3 (PSA), TMPRSS2, FOLH1 (PSMA), synaptophysin ( SYP), and chromogranin ( CHGA). Post-hoc retrospective analysis of an institutional review board–approved prospective cohort (N = 98) was performed to identify patterns of gene expression. Samples were considered AR+ if 3 of 4 AR pathway genes ( TMPRSS2, KLK2, KLK3, and FOLH1) were positive, and were considered NE+ if either or both SYP or CHGA were positive. Blood samples from two prospective clinical trials of men with mCRPC treated with abiraterone and enzalutamide, respectively, were analyzed to confirm results. Longitudinal samples were collected from 17 patients (6 NEPC and 11 Adenocarcinoma) and cell free DNA was isolated and sequenced using a novel targeted exon panel. Results: AR and/or NE positive patients were found to have a median overall survival (OS) of 8.58 months as compared to a median OS of 29.6 months in the AR and NE negative population (p

526 Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, a topoisomerase-I inhibitor, via a proprietary hydrolyzable linker. SG received accelerated FDA approval in April 2021 in pts with mUC who previously received PT-based therapy and a CPI based on the primary analysis of the pivotal TROPHY-U-01 Cohort 1 study. With 9.1 mo median (med) follow-up, SG monotherapy demonstrated a 27% objective response rate (ORR) and med overall survival (OS) of 10.9 mo in 113 pts with locally advanced or mUC progressing after receiving at least a PT-based therapy and a CPI (Tagawa, et al. J Clin Oncol. 2021). Here we report updated Cohort 1 outcomes. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase 2 study. Cohort 1 pts (≥18 y) had progression of mUC following PT (as first-line metastatic therapy or as (neo)adjuvant therapy with recurrence/progression ≤12 mo) and CPI, had ECOG PS 0-1, and creatinine clearance ≥30 mL/min. Pts received 10 mg/kg of SG intravenously on D1 and D8 of 21-D cycles. The primary endpoint was ORR per central review by RECIST 1.1. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), OS, and safety. Results: As of July 26, 2022, med follow-up was 10.5 mo (range, 0.3-40.9) for treated pts (N=113). As previously reported, pts (78% men; med age, 66 y; 66% with visceral metastases, 34% liver), were heavily pretreated with a med of 3 prior therapies (range, 1-8). Med time since last prior therapy was 1.5 mo (range, 0-60.0). At data cutoff, per central review, ORR was 28% (95% CI, 20.2-37.6); CBR was 38% (95% CI, 29.1-47.7), med DOR was 6.1 mo (95% CI, 4.7-9.7, n=32) and med PFS was 5.4 mo (95% CI, 3.5-6.9). Med time to response was 1.6 mo (range, 1.2-5.6) and med OS was 10.9 mo (95% CI, 8.9-13.8). DOR, PFS, and OS rates (95% CI) at 12 mo were 30% (13.6-48.8), 14% (7.2-23.3), and 45% (35.4-53.8), respectively, with 7 (6%) pts still receiving SG at 12 mo. In pts who received prior enfortumab vedotin (n=10) and prior PT in the (neo)adjuvant setting (n=39), results were consistent with the overall population. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 65% of pts and were similar to prior reports; the most common Grade ≥3 TRAEs were neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%). One treatment-related death occurred due to febrile neutropenia-related sepsis. Conclusions: At 10.5-mo med follow-up, the response rate remains high in pts with heavily pretreated mUC, including pts with visceral metastases, prior EV therapy and prior (neo)adjuvant PT therapy. No new safety signals were observed. These data support the use of SG in pts with mUC who received PT and a CPI and further evaluation of SG in earlier lines of therapy. Clinical trial information: NCT03547973 .

Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease characterized by airflow limitation that is not completely reversible. The fixed-dose combination of salmeterol and fluticasone propionate (SFC) has been approved as a treatment for COPD patients with a history of recurrent exacerbations and significant symptoms despite regular bronchodilator therapy. In the present study, we evaluated the change in FEV1, mMRC dyspnea score and satisfaction in COPD patients with at least one comorbidity versus those without comorbidities treated with a fixed-dose SFC via the Elpenhaler® device for 12 months. Methods: A 12-month multicenter prospective, observational study (NCT02978703) was designed. Data were collected during the enrollment visit (V0) and six (V1) and twelve months (V2) after the initiation of treatment with Elpenhaler® SFC. The evaluation of the efficacy of the fixed-dose SFC was performed by assessing the change in lung function and dyspnea as expressed by FEV1 and the mMRC dyspnea scale score in COPD patients with and without comorbidities. Results: In total 1016 patients were enrolled, following usual daily clinical practice. A statistically significant improvement was observed in FEV1 in the total study population between visits V0, V1 and V2, with a change from the baseline at V1 0.15 ± 0.22 L and at V2 0.21 ± 0.25 L (p &lt, 0.0001 for both comparisons). This improvement was exhibited regardless of the COPD severity at the baseline, being more noticeable in GOLD 2020 groups B and C. Similarly, a significant improvement was observed in mMRC dyspnea scale values between successive visits (p &lt, 0.0001). In patients without comorbidities, there was a significant improvement in FEV1 of 0.19 ± 0.24 L at V1 and 0.28 ± 0.27 L at V2 (p &lt, 0.0001 for both comparisons), as well as in the mMRC dyspnea score (p &lt, 0.0001). In patients with at least one comorbidity, a corresponding but smaller improvement in FEV1 was observed (0.11 ± 0.34 L at V1 and 0.20 ± 0.42 L at V2, p &lt, 0.0001 for both comparisons and in the mMRC score (p &lt, 0.0001). In the multiple linear regression analysis BMI, GOLD 2020 groups, mMRC and the presence of comorbidities at the baseline were significant factors for the change of FEV1 between V0 and V2. Conclusions: COPD patients treated for twelve months with SFC via the Elpenhaler® device showed significant improvement in lung function and dyspnea at 6 and 12 months, irrespective of the presence of comorbidities.

BackgroundWe previously reported a pilot clinical trial using a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP), given over 12 weeks either concurrently or in sequence with pembrolizumab, in patients with mCRPC. We report here the final analysis of this trial following two additional treatment arms in which patients with mCRPC were treated beyond 12 weeks until progression.MethodsPatients with mCRPC were treated with pTVG-HP and pembrolizumab every 3 weeks (Arm 3, n=20), or pTVG-HP every 2 weeks and pembrolizumab every 4 weeks (Arm 4, n=20). The primary objectives were safety, 6-month PFS, median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations.ResultsTreatment was without unexpected toxicity, and only 1 grade 4 event (hyperglycemia) was observed. Immune related adverse events (irAE) > grade 1 included adrenal insufficiency, hepatitis, colitis, thyroid dysfunction, pancreatitis, pneumonitis, and rash, occurring in 42% of patients overall. 10/25 patients with measurable disease experienced any decrease in tumor volume from baseline, with 1 confirmed PR and no CR. 23/66 (35%) experienced any PSA decline from baseline. Overall median TTP was 5.4 months (95% CI; 5.3–8.1 months); median TTP for Arm 3 was 5.3 months compared to 8.0 months for Arm 4. Overall, 41.7% of patients had no radiographic progression at 6 months (29.9% Arm 3, 57.9% Arm 4). Median overall survival was 22.9 months. IFNγ and/or granzyme B immune response to PAP was detected in 2/20 patients in Arm 3 and 6/20 patients in Arm 4. Cytokines associated with immune activation and CD8+ T cell recruitment were augmented in the plasma of patients at weeks 6 and 12. Increased IFNγ in the sera at week 6 trended with prolonged TTP (p=0.010) and overall survival (p=0.025). The development of irAE was associated with a prolonged TTP (HR=0.25, p=0.003).ConclusionsPD-1 pathway inhibitors have demonstrated little clinical activity to date as monotherapies for mCRPC. Our findings demonstrate that combining PD-1 blockade with tumor-targeted T-cell activation using pTVG-HP is safe, can augment tumor-specific T cells, and result in objective changes with longer time to progression than what has been observed in previous trials. The association of progression or survival with increased IFNγ, irAE, and vaccine schedule suggests T cell activation by vaccination is critical to the mechanism of action of this combination. This study suggests this approach should be further evaluated in randomized clinical trials for patients with advanced mCRPC.AcknowledgementsFunding for this trial was from a 2014 Movember Prostate Cancer Foundation Challenge Award and Madison Vaccines, Inc.Trial RegistrationNCT02499835Ethics ApprovalThis trial was reviewed and approved by the University of Wisconsin Human Subjects’ Review Committee (IRB), protocol 2015–0453. All participants provided IRB-approved written informed consent before taking part.

Tocilizumab has been repurposed against the 'cytokine storm' in the setting of coronavirus disease 2019 (COVID-19). Our aim was to evaluate the efficacy of tocilizumab in the management of hospitalized COVID-19 patients. We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalized COVID-19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalization and differences in mortality in subgroups (ICU and non-ICU patients and patients receiving or not receiving concomitant corticosteroids). We included 52 studies (nine randomized controlled trials [RCTs] and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies, the use of tocilizumab was associated with a reduction in mortality; 11% in RCTs (risk ratio [RR] 0.89, 95% CI 0.82 to 0.96) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while no significant reduction was observed in observational studies. Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non-ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while that was not the case in the RCTs. Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalized patients with moderate-to-critical COVID-19.

Background Chronic obstructive pulmonary disease (COPD) is a multifactorial clinical condition, characterized by chronic progressive (or worsening) respiratory symptoms, structural pulmonary abnormalities, and impaired lung function, and is often accompanied by multiple, clinically significant comorbid disorders. In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) issued a new report on COPD prevention, diagnosis and management, aiming at personalizing the maintenance therapeutic approach of the stable disease, based on the patients’ symptoms and history of exacerbations (ABCD assessment approach). Our objective was to evaluate the implementation of GOLD suggestions in everyday clinical practice in Greece. Methods This was a cross-sectional observational study. Sixty-five different variables (demographics, vital sign measurements, COPD-related medical history parameters, comorbidities, vaccination data, COPD severity based on spirometry measurements, COPD stage based on the ABCD assessment approach, COPD treatments) were collected from 3615 nation-wide COPD patients (Greece). Results The mean age at the time of initial COPD diagnosis was 63.8 (± 10.2). Almost 60% of the subjects were classified into group B, while the remaining patients were falling into groups A (18%) and D (21%), and only a small minority of patients belonged to Group C, according to the ABCD assessment approach. The compliance of respiratory physicians to the GOLD 2017 therapeutic suggestions is problematic, especially when it comes to COPD patients belonging to Group A. Conclusion Our data provide valuable information regarding the demographic and medical profile of COPD patients in Greece, the domains which the revised ABCD assessment approach may show some clinical significance on, and the necessity for medical practitioners dealing with COPD patients to adhere closer to international recommendations for the proper management of the disease.

Smoking has been accounted for numerous adverse effects. We report a direct effect of smoking in a 73-year-old patient, a heavy smoker who presented to the emergency department with a 48-h history of productive cough and fever. Chest x-ray and chest CT revealed right lung infiltrates; however, they were not suggestive of the diagnosis, which was established through flexible bronchoscopy. The specific procedure concurrently contributed to the treatment of the patient.

Summary In Crete, as in the rest of the Ottoman Empire, patients who suffered from hernias and other diseases that required surgery made statements to the court of law that absolved the surgeons of liability in case of death as a result of the operation. These statements also included information about the medical condition concerned, the surgeon, the medical procedure and the fee to be paid. In this article, we discuss such statements of the period 1670–1760 from the town of Kandiye (mod. Heraklion). On one hand, we demonstrate that a critical analysis of the statements reveals a dynamic society, which actively overcomes its ideology of submission to God and religious prejudices when it comes to dealing with health issues. On the other hand, we argue that, as the statements were made before the official court of law, they constitute a facet of the Ottomanisation of Cretan society and its practices.

6514 Background: Tobacco use is a modifiable risk factor for adverse outcomes among patients diagnosed with cancer. Despite ASCO’s recommendation for assessment and treatment of tobacco use, integration into cancer care is suboptimal. Socioeconomic contexts influence access and utilization of tobacco treatment, but little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among cancer patients enrolled in clinical trials. Methods: The NCI Cancer Patient Tobacco Use Questionnaire (C-TUQ) was centrally administered to participants enrolled in 10 ECOG ACRIN clinical trials (9 therapeutic, 1 imaging). We examined associations of NSD with patient-reported rates of receiving brief tobacco cessation support (i.e., Ask, Assist (counseling)) and cessation (past 30d quit attempts and duration). NSD was measured using the national Area Deprivation Index (ADI) based on participant’s zip code. Associations between ADI (low, intermediate, and high) and tobacco variables were evaluated using logistic regression and ANOVA. Results: 740 patients, completing the C-TUQ between June 2017-October 2021, can be classified as 402 (54%) never smokers, 81 (11%) current smokers, and 257 (35%) former smokers. Patients were 70% male; 94% white; 3% Hispanic; mean age 58.8 (SD 9.0). Cancer diagnoses were 36% leukemia; 19% lymphoma, 18% prostate, 11% breast; 9% melanoma, 7% myeloma, and 0.5% head and neck. Patients were categorized into high (33%), intermediate (34%) and low (33%) disadvantaged neighborhoods. Patients in high (vs. low) disadvantaged neighborhoods were more likely to report being asked about smoking (OR = 3.90; 95% CI (confidence interval), 1.61 to 9.46; p = 0.0062) but less likely to report receiving counseling to help quit smoking (OR = 0.20; 95% CI, 0.06 to 0.73; p = 0.0234). Patients from high disadvantaged neighborhoods had the shortest quit duration, followed by patients from intermediate and low disadvantaged neighborhoods (mean = 145.78, 187.66, and 210.98 months, respectively, p = 0.0372). Conclusions: Greater socioeconomic neighborhood disadvantage was associated with increased assessment of tobacco use but decreased tobacco treatment referral, and the shortest quit duration. More research is needed to promote increased referral to tobacco treatment for individuals with cancer from disadvantaged neighborhoods to promote and sustain cessation.

e13554 Background: Quantitative 18F-NaF PET/CT imaging metrics have been shown to be prognostic in metastatic prostate cancer (mPC) patients. However, previous studies have shown conflicting results in which metrics could be prognostic. This study investigates if current methods from literature generalize to external datasets and explores which combination of features are necessary to for survival models to generalize across datasets. Methods: Imaging and progression-free survival (PFS) data from 118 patients with mPC from four separate prospective clinical trials were gathered retrospectively. Patients received 18F-NaF PET/CT imaging at baseline and at follow-up, between eight and thirteen weeks. TRAQinform IQ technology (AIQ Solutions) was used to identify, segment, and track individual lesions from baseline to follow-up. Eighty-four imaging features were extracted from each patient and sorted into baseline, follow-up, response, patient-level (no inter-lesion comparison), and intrapatient heterogeneity (comparisons between lesions). The data was split into two training and testing sets, 44 patients from one study and 73 patients from the remaining 3 studies. As they can utilize large number of inputs without overfitting, random survival forest (RSF) models were chosen to evaluate performance of feature sets in predicting PFS. Different combinations of features were used as inputs to RSF models to compare single timepoint features with response features and patient-level features with intrapatient heterogeneity features. The performance of the RSF models, together with other methods identified in literature, were evaluated in each dataset using Kaplan-Meier analysis for categorical variables and the c-index for continuous variables. Results: No patient-level imaging features highlighted by literature displayed significant association to PFS across all four clinical trials (c-index < 0.62 in at least one dataset). Other criteria from literature did not generalize across all datasets (P > 0.05). The RSF model trained with all features had high c-indices in all four datasets (range: 0.66-0.80). RSF models built with response features (min: 0.63) performed better on average than models built with features obtained from single timepoints (min: 0.55). Patient-level features (min: 0.56) were not sufficient in all testing scenarios as compared to intrapatient heterogeneity features (min: 0.63). Conclusions: The candidate imaging biomarkers from previous 18F-NaF PET/CT imaging studies of mPC patients did not generalize across all datasets. Incorporating response and heterogeneity features with single-timepoint and patient-level features resulted in RSF prediction models which were generalizable across all datasets. Use of such models hold promise for improving outcome prediction in mPC patients.

TPS3166 Background: The forkhead box family transcription factor FOXP3 is essential for T regulatory cells (Tregs) development and immune suppressive function. Tregs are an integral component of the adaptive immune system and contribute to maintaining tolerance to self-antigens and preventing autoimmune diseases. In the context of cancer, however, Tregs contribute to tumor progression by suppressing antitumor immunity. To date inhibition of Treg-mediated immunosuppression tested in the clinic has lacked specificity. Targeting FOXP3 provides a selective approach to impair the immunosuppressive function of Tregs but targeting transcription factors has been a challenge using conventional drug modalities. AZD8701 employs next-generation antisense oligonucleotide (ASO) technology (Ionis Pharmaceuticals) to bind mRNA with high affinity and selectively reduce human Foxp3 mRNA expression levels. Foxp3-specific ASOs promote potent dose-dependent reductions in Foxp3 mRNA and protein in vitro. In preclinical models, AZD8701 induced Foxp3 knockdown results in Tregs with a reduced immunosuppressive capacity, loss of immunosuppressive markers, and increased markers of activation on CD8+ T-cells. AZD8701 reduces tumor growth as monotherapy in preclinical models and increased tumor inhibition is obtained by combining AZD8701 with a PD-L1 inhibitor. Methods: This is a Phase I multicenter study of AZD8701 alone or in combination with durvalumab in participants with selected advanced solid tumors. Eligible patients must have ECOG performance status 0 or 1, measurable target lesion per RECIST v1.1 and be diagnosed with selected tumor types as described below. Monotherapy and combination dose escalation phase is open for participants with head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), non-small-cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), gastroesophageal cancer, melanoma, cervical cancer, small-cell lung cancer (SCLC), and/or solid tumors that have demonstrated a response to prior programmed death-ligand-1 (PD-[L]1) treatment (as defined by duration of response > 18 weeks). Participants with NSCLC, HNSCC, TNBC, and ccRCC will be included in the pharmacodynamic cohort at the selected monotherapy dose and/or disease expansion cohorts. The primary objectives are to assess safety and tolerability and to determine the preliminary antitumor activity of AZD8701 (objective response rate) when administered as monotherapy or in combination with durvalumab. Secondary endpoints include, disease control rate, duration of response, progression free survival and overall survival, pharmacokinetics and pharmacodynamics (including changes in Foxp3 mRNA in paired tumor samples). The trial is currently recruiting. Clinical trial information: NCT04504669.

Brief abstract: Castleman's disease (CD) is an uncommon lymphoproliferative process that can present concurrent to other solid organ malignancy, especially in selected populations. Concomitant CD and renal cell carcinoma (RCC) are challenging in terms of diagnosis and treatment. Assessment of CD involvement is a crucial step in selecting the optimal treatment strategy. Here we report a case of metastatic RCC and concurrent CD treated with surgery and immunotherapy.

PURPOSE Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2–directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC. METHODS TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973 ) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety. RESULTS Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events. CONCLUSION SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

Author(s): Harris, Ruth; Barall, Michael; Ponce, David; Moore, Diane; Graymer, Russell; Lockner, David; Morrow, Carolyn; Funning, Gareth; Kyriakopoulos, Christos; Eberhart-Phillips, Donna | Abstract: The Rodgers Creek-Hayward-Calaveras-Northern Calaveras fault system in California dominates the hazard posed by active faults in the San Francisco Bay Area. Given that this fault system runs through a densely populated area, a large earthquake in this region is likely to affect millions of people. This study produced scenarios of large earthquakes in this fault system, using spontaneous (dynamic) rupture simulations. These types of physics-based computational simulations require information about the 3D fault geometry, physical rock properties, fault friction, and initial stress conditions. In terms of fault geometry, the well-connected multi-fault system includes the Hayward fault, at its southern end the Central and Northern Calaveras faults, and at its northern end the Rodgers Creek fault. Geodetic investigations of the fault system’s slip-rate pattern provide images of where the fault surfaces at depth are creeping or locked interseismically, and this helped us choose appropriate initial stress conditions for our simulations. A 3D geologic model of the fault system provides the 3D rock units and fault structure at depth, while field samples from rocks collected at Earth’s surface provide frictional parameters. We used this suite of information to investigate the behavior of large earthquake ruptures nucleating at various positions along this partially creeping fault system. We found that large earthquakes starting on the Hayward fault or on the Rodgers Creek fault may be slowed, stopped, or unaffected in their progress, depending on how much energy is released by the creeping regions of the Hayward and Central Calaveras faults during the time between large earthquakes. Large earthquakes starting on either the Hayward fault or the Rodgers Creek faults will likely not rupture the Northern Calaveras fault, and large earthquakes starting on either the Northern Calaveras fault or the Central Calaveras fault will likely remain confined to those fault segments.