Citations

AbstractEndometriosis is a complex gynecologic disorder characterized primarily by symptoms of pelvic pain, infertility, and altered quality of life. National and international guidelines highlight the diagnostic difficulties and lack of conclusive diagnostic tools for endometriosis. Furthermore, guidelines are becoming questionable at an increasingly rapid rate as new diagnostic techniques emerge. This work aims to provide a knowledge synthesis of the relevance of various diagnostic tools and to assess areas of improvement of conventional algorithms. MEDLINE and Cochrane Library databases were searched from January 2021 to December 2023 using relevant key words. Articles evaluating the diagnostic relevance and performance of various tools were included and independently reviewed by the authors for eligibility. Included studies were assessed using the GRADE and QUADAS‐2 tools. Of the 4204 retrieved articles, 26 were included. While anamnesis and clinical examination do contribute to diagnostic accuracy, their level of evidence and impact on the diagnostic process remains limited. Although imaging techniques are recommended to investigate endometriosis, ultrasonography remains highly operator dependent. Magnetic resonance imaging appears to exhibit higher sensitivities than ultrasound. However, concerns persist with regards to the terminology, anatomical definition of lesions, and accuracies of both ultrasound and magnetic resonance imaging. Recently, several biological markers have been studied and cumulative evidence supports the contribution of noncoding RNAs to the diagnosis of endometriosis. Marginal improvements have been suggested for anamnesis, clinical examination, and imaging examinations. Conversely, some biomarkers, including the saliva microRNA signature for endometriosis, have emerged as diagnostic tools which inspire reflection on the revision of conventional diagnostic algorithms.

Abstract Background It was reported that patients with Non-Alcoholic Fatty Liver Disease (NAFLD) were at increased risk of contracting severe infections requiring hospitalization which could end up with sepsis. However, data regarding the impact of comorbid NAFLD on the in-hospital outcomes of sepsis admission is scarce. Methods This nationwide retrospective observational study included 21,057,911 adult patients who were admitted into hospitals in the United States between 2000 and 2019 with a primary discharge diagnosis of sepsis. These patients were categorized according to the presence or absence of comorbid NAFLD. The twenty-year trend of nationwide NAFLD prevalence among sepsis inpatients was elucidated. Multivariate logistic regression analysis was used to analyze NAFLD's impact on in-hospital outcomes of sepsis. Results In the twenty-year study period, the prevalence of NALFD among sepsis inpatients trended up from 1.2% in 2000 to 4.2 % in 2019. While sepsis mortality had trended down, comorbid NAFLD in sepsis patients was consistently associated with a higher adjusted in-hospital all-cause mortality rate (adjusted odds ratio (OR), 1.45; 95% confidence interval (CI), 1.42-1.48), higher odds of developing septic shock, and multi-organ dysfunctions (including cardiovascular-, renal-, and hepatic dysfunction). They were more likely to be discharged to another acute hospital. The length of stay of sepsis patients with NAFLD who died in the hospital was significantly shorter than those without NAFLD. Conclusions Comorbid NAFLD is associated with higher in-hospital all-cause mortality and worse clinical outcomes in sepsis inpatients. Addressing this rising epidemic will be of paramount importance to improve sepsis in-hospital outcomes.

Abstract INTRODUCTION Tau‐positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS Using head‐to‐head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed “CenTauR” [CTR]). JPM is a statistical model that simultaneously models the relationships between head‐to‐head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION Preliminary findings using the JPM support the development and adoption of a universal scale for tau‐PET quantification. Highlights Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed “CenTauRs”. Tested a Centiloid‐like linear regression approach. Using five cohorts with head‐to‐head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

The nonalcoholic steatohepatitis clinical research network (NASH-CRN) system is commonly used for histologic assessment of disease activity and fibrosis in NASH. Despite this, the system does not fully capture the range of disease activity and fibrosis. As such, an expanded NAS (E-NAS) grading and staging system with a calculated E-NAS index was developed by our group. In this follow up study, we aim to revalidate the E-NAS system and compare its reliability to existing systems. Hematoxylin and eosin and trichrome stained sections from 40 liver biopsies were reviewed digitally by four hepatopathologists and assessed using the NASH-CRN and E-NAS systems as well as a modified Ishak fibrosis stage. The pathologist's gestalt impression of disease activity and fibrosis was scored on a Visual Analogue Scale (VAS), which ranged from 0 (no activity/fibrosis) to 100 (the worst activity/fibrosis ever seen). Inter-rater reliability was assessed, and Spearman correlation coefficients were calculated. The E-NAS index had higher inter-rater agreement versus the NAS score (ICC 0.70 vs 0.61). The inter-rater agreement for ballooning in the E-NAS system was also higher at 0.67 compared to the NAS (ICC 0.60). ICCs for fibrosis were comparable between all the systems assessed (0.78 to 0.88). Finally, the calculated E-NAS index was higher with increasing stage of fibrosis compared to the NAS suggesting that it associates better with fibrosis. In summary, the E-NAS system demonstrates substantial inter-rater reliability as well as improved correlation with disease activity VAS and fibrosis compared to the NAS score.

4601 Background: Cretostimogene grenadenorepvec is a type-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the retinoblastoma pathway. Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mode of action. Cretostimogene monotherapy recently received Food and Drug Administration (FDA) Fast Track and Breakthrough Therapy Designations (BTD) in the BCG-Unresponsive, High-Risk, non-Muscle Invasive Bladder Cancer with Carcinoma in Situ (BCG-UR HR NMIBC with CIS) indication with a Complete Response (CR) at any time rate of 76%. This phase-2 study assessed the potential synergy between intravesical cretostimogene and pembrolizumab in patients with BCG-UR, HR NMIBC, with CIS, with or without Ta/T1 tumors. This combination has also received BTD from the FDA. Methods: 35 pts were treated with cretostimogene (1x1012 viral particles) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. Cretostimogene induction was given as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Pts with persistent CIS or high-grade Ta tumors at the 3mo assessment were eligible for re-induction. Pembrolizumab was administered for up to 24mo. Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12mo. The primary endpoint was CR at 12mo. Secondary endpoints included CR at any time, duration of response (DOR), CR at 24mo, cystectomy-free survival, and safety. Exploratory endpoints included analyses of baseline viral receptor expression, free E2F levels, PD-L1 status, urinary cytokine panels and measures of viral replication. Results: 30/35 pts are evaluable per protocol for the primary endpoint. Five pts discontinued prior to the 12mo time point. The CR rate in the Intention to Treat (ITT) population at 12mo and any time, was 57% (20/35) (95% CI 40-73%) and 83% (29/35) (95% CI 66-93%), respectively. Median DOR has not been reached but exceeds 21mo. The current CR rate in the ITT population at 24mo is 46% (16/35) (95% CI 29-63%). Three pts have yet to reach the 24mo time point. Cystectomy-free survival at 21mo is 80%. Complete data on the ITT and evaluable patient cohorts will be presented. Analyses of treatment-related adverse events (AE) are consistent with the individual agents and demonstrate no synergistic toxicity. Conclusions: The efficacy and safety of cretostimogene plus pembrolizumab for treatment of BCG-UR, HR NMIBC with CIS demonstrates best-in-class CR and DOR compared to current FDA-approved therapies, with an acceptable AE profile. Further investigation of this promising combination therapy is warranted and may serve to address a considerable unmet need. Clinical trial information: NCT04387461 .

Abstract Background Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. Methods In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60. Results Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. Conclusions Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment. Clinical Trials Registration EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

ABSTRACT Background The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial. Methods Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial (n = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake. Results Overall, 96% and 81.8% of participants (n = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups (P > 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P < 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS (P < 0.05). Conclusion HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group.

TPS5118 Background: Novel androgen receptor pathway inhibitors (ARPIs) improve overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in conjunction with testosterone suppression (TS) relative to TS alone. However, the duration of treatment required to derive clinical benefit is unclear, as is whether continuous treatment is requisite for optimal cancer outcomes. Favorable PSA declines have been associated with prolonged OS in clinical trials testing TS + ARPIs. We thus designed this single-arm Phase 2 trial to test the hypothesis that pts who achieve exceptional response to upfront TS + ARPI can suspend treatment, allowing for T recovery and improvement in quality of life while maintaining favorable clinical outcomes. Methods: Eligible pts had mHSPC by conventional imaging with PSA ≥ 5 ng/ml and T ≥ 150 ng/dl (or not known to have been hypogonadal) prior to starting treatment, have been receiving TS for 540-750 days and ARPI for ≥ 360 days, and have achieved PSA < 0.2 ng/ml (stable or falling for 3 consecutive measurements) with castrate T <50 ng/dl at the time of enrollment. Intermittent ADT for biochemical recurrence prior to mHSPC diagnosis, prior local therapy, prior radiation to metastatic sites, and up to 6 cycles of docetaxel in mHSPC are permitted. Pts who underwent surgical castration, received ARPI prior to mHSPC diagnosis, or are receiving experimental treatment for mHSPC or participating in a clinical trial that does not allow for TS or ARPI interruption are excluded. After enrollment, pts discontinue both TS and ARPI and are followed with PSA and T levels every 3 months, conventional CT/MRI and bone scan at least every 6 months, and FACT-P questionnaire for patient-reported outcomes every 6 months. Treatment re-initiation triggers are PSA increase to ≥ 5 ng/ml, radiographic change (progressive disease per modified RECIST 1.1 on CT/MRI or unconfirmed progressive disease per PCWG3 on bone scan), or symptoms attributable to prostate cancer. Subsequent management is per physician discretion. The primary endpoint is remaining treatment-free with eugonadal T (> 150 mg/dl) 18 months after the start of treatment interruption, with 75 pts to be enrolled to differentiate 18-month treatment free rates of 0.30 (null hypothesis) and 0.45 (alternative hypothesis). Secondary endpoints include time to eugonadal T, duration off treatment, and changes in patient-reported outcomes. Exploratory endpoints include radiographic progression-free survival, time to next treatment, OS, and correlation of tissue- and blood-based biomarkers with clinical endpoints. The study was activated in July 2022 and accrual is ongoing throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org , Veracyte Inc. Clinical trial information: NCT05241860 .