Citations

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.

LBA2 Background: Radiation with sensitizing fluoropyrimidine (5FUCRT) is a standard curative intent treatment for LARC. It improves disease-free survival (DFS) by decreasing pelvic recurrence but has short- and long-term toxicity. The PROSPECT trial compares FOLFOX chemotherapy with selective use of 5FUCRT (intervention) to 5FUCRT (control) for neoadjuvant treatment prior to TME for LARC. Methods: Eligible patients (pts) had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Pts with distal, T4 tumors, threatened radial margins or > 4 enlarged lymph nodes were ineligible. Pts were randomized 1:1 without blinding. Pts in the control group received 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. Pts in the intervention group had 6 cycles of mFOLFOX6 followed by restaging. If tumor regression was > 20%, then TME was performed without radiation; if < 20%, 5FUCRT was given before TME. DFS was the 1°outcome, defined as time from randomization to any recurrence or death, analyzed in the per-protocol population. One interim analysis was conducted with α spending = 0.001. Noninferiority (NI) of the intervention could be claimed if the upper limit of the 2-sided 90.2% confidence interval (CI) of the DFS hazard ratio did not exceed 1.29 (NI margin). Secondary endpoints included overall survival (OS), local recurrence free survival, R0 resection, pathologic complete response (CR), and toxicity. Results: From June 2012 to December 2018, 1194, pts were randomized and 1128 initiated protocol-assigned treatment. Median age was 57, 34.5% were women and 61.9% had clinically positive nodes. 53 of 585 pts in the intervention group (9%) received preop 5FUCRT. DFS was analyzed after 227 events and median follow-up of 58 months. Conclusions: FOLFOX chemotherapy with selective use of 5FUCRT is non-inferior to 5FUCRT for neoadjuvant treatment of LARC prior to low anterior resection with TME. Patients and physicians have alternative strategies for management of LARC. Clinical trial information: NCT01515787 . [Table: see text]

PURPOSE The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions. METHODS PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N–, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL). RESULTS From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point. CONCLUSION For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.

Abstract Introduction Vasectomy is a highly effective, permanent method of contraception. Poor compliance rates have been observed for patients in obtaining their post-vasectomy semen analyses (PVSA). Few studies have looked at associations with low compliance. Objective The objective of our study was to identify compliance rates of post-vasectomy semen analysis and to identify associations that may increase or decrease the rates of compliance. Methods We studied 111 patients between November 2018 and April 2022 who underwent vasectomy at a single institution. Only patients who underwent vasectomy for fertility-related reasons were included in our final analysis. We excluded any patients who had undergone previous vasectomy or vasectomy reversal. Variables analyzed included age, relationship status, presence of primary care provider, anxiety diagnosis, and race. Variables were obtained via chart review which included but was not limited to reviewing notes, summary diagnostic pages, problem lists, and medication lists. All analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Categorical data were described with the number and percentage of patients. Continuous data were described with the median, minimum, and maximum. Associations of race and anxiety diagnosis with PVSA were explored using Fisher’s exact test. All p-values were two-sided at the 5% significance level without adjustment for multiple testing. Results Our cohort included 111 men who underwent vasectomy with exclusion of 1 patient who underwent vasectomy for non-fertility reasons. The median age of vasectomy was 38 years (range 26-59 years). Of 110 patients, 83 (75%) returned for PVSA. There were 103 (94%) married patients. Additional cohort characteristics can be seen in Table 1. As shown in Table 2, African American patients were less likely to return for PVSA than either white patients (14% vs. 79%, p&lt;0.001) or Hispanic patients (14% vs. 100%, p=0.015). we did not find evidence of difference between white and Hispanic patients (p=0.58). Patients with an anxiety diagnosis were more likely to undergo PVSA compared to patients without an anxiety diagnosis (p&lt;0.001). Conclusions Patients in our cohort of African American race were significantly less likely to undergo PVSA compared to white and Hispanic patients. This suggests an opportunity for improved counseling in the African American population. We do recognize a disparity in the number of white patients studied (n=95) versus African American (n=7) and Hispanic (n=5) patients. Additionally, patients with an anxiety disorder were more likely to undergo PVSA compared to patients without an anxiety disorder. The prevalence of anxiety disorder in our cohort is somewhat high relative to the overall population in the United States. This could be due to questionnaires used at our institution and the timeliness of those questionnaires. Personality traits could also lead to confounding in anxiety diagnoses. Overall, a 75% rate of PVSA speaks to an opportunity for better counseling regarding PVSA, especially in particular populations such as the African American population. Disclosure No

Abstract Introduction The presence and extent of penile calcifications is an important factor in disease management of Peyronie’s Disease (PD). Calcified plaques may necessitate plaque excision and grafting (E&G) in addition to other therapies or surgeries. PD pathology such as corporal septal involvement, multifocal calcifications, and circumferential corporal calcification can be difficult to assess on color doppler ultrasound (CDDU) due to device limitations. Computed tomography (CT) can be utilized for further characterization of PD. Objective The objective of our study was to review patients who underwent CT imaging for characterization of their Peyronie's Disease. Methods Twenty-three patients with a diagnosis of PD were retrospectively evaluated between 2017 and 2021. Patients underwent CDDU examination with artificial erection and were evaluated based on erectile function, plaque dimension, hourglass deformity, plaque septal involvement, and suspected calcification status. Patients with CDDU examination suggestive of calcification or significant complexity underwent non-contrast CT scan for 3-dimensional evaluation of the plaque prior to surgical discussion. CT complexity was defined as concern for multifocal calcified plaques (&gt;2), partial/complete circumferential corpus cavernosum involvement, or septal involvement. Results All 23 patients had concerning findings on initial examination for calcified plaque which led to their CT evaluation; 9 of 23 (39.1%) patients had exam findings with hourglass deformity. On CT evaluation, calcification was confirmed in 22 of 23 patients (95.7%). Plaque dimensions on CT scan ranged from 0.4 x 0.2 x 0.5 cm to 4.0 x 2.0 x1.7 cm. Many of these measurements were approximations due to circumferential calcified plaque. A classic “gull-wing” appearance was noted in 6 of 23 (26%) patients; 12 of 23 (52.2%) of patients had septal involvement on CT; 8 of 23 patients (34.8%) had significant multifocal disease; 8 of 23 patients (34.8%) decided to proceed with surgical correction via E&G (n = 3), IPP with E&G (n =1), or via IPP with manual remodeling via Wilson technique (n = 4). Conclusions Non-contrast penile CT scan identifies calcification well in patients with Peyronie's Disease. CT allows for increased accuracy of surgical planning especially when evaluating for multifocal disease, circumferential plaque and/or septal involvement. These elements are critical for for providing accurate surgical recommendations and preoperative discussions. Disclosure No