Citations

6036 Background: E3311 is a phase II randomized study of intermediate risk HPV+ OPC patients who underwent TOS by credentialed surgeons and were then treated by pathology-guided, deintensified post-operative treatment. Recent retrospective population data suggest that time to post-operative radiotherapy (PORT) > 6 weeks is associated with worse progression-free survival (PFS). Methods: We retrospectively analyzed demographics, pathologic characteristics, and oncologic outcomes in E3311 by time to initiation of PORT (short vs long, exploring both 6 and 7 weeks postop as the cutpoint). Binary and categorical variables were compared using a chi-square test (or a Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. PFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test, which was stratified by intermediate- (Arms B/C) vs high-risk (Arm D). Results: Among 321 evaluable patients, the median time to initiation of PORT was 5.1 weeks (range 0.7-15.7); 5.0 (0.7-15.7) for Arm B, 5.1 (2.4-7.0) for Arm C, 5.6 (3.6-7.9) for Arm D. No significant difference in PFS or OS was observed whether PORT commenced by 6 or 7 weeks postoperatively, compared with longer time to initiation of PORT (p = 0.62 and 0.65, p = 0.30 and p = 0.41, respectively). 3-yr PFS rates were 93.5% (95% CI: 89.4%, 96.0%) among those treated ≤6 weeks, and 91.2% (95% CI: 81.4%, 95.9%) among those treated > 6 weeks; 3-yr OS rates were 96.1% (95% CI: 92.7%, 98.0%) among those treated ≤6 weeks, and 94.1% (95% CI: 84.9%, 97.8%) among those treated > 6 weeks. No significant differences in outcomes were observed between intermediate risk treatment arms (deintensified (50Gy) or standard dose (60Gy) RT). Additional demographic and pathologic characteristics, including primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between those with short vs long time to PORT, whether 6 or 7 weeks was used as the cutpoint. There were more T2 tumors in those treated > 7 weeks postop (84% vs. 49%, p = 0.007). PS = 1 patients were more numerous among those with shorter time to PORT (10% vs 0%, with the 7 week cutpoint). Conclusions: In contrast to retrospective NCDB data, intermediate- and high-risk HPV+ OPC patients enrolled on E3311 had favorable 3-yr PFS and OS rates that were not significantly worse when adjuvant therapy was started > 6 wks or > 7wks. These results argue against a survival advantage for initiation of PORT within 6 or 7 weeks for early-stage HPV+ OPC managed with high-quality transoral resection. The optimal time window to initiate PORT in HPV+ OPC patients remains to be determined. Clinical trial information: NCT01898494 .

TPS4199 Background: Tumor Treating Fields (TTFields) therapy is a locoregional antimitotic treatment approved for newly diagnosed and recurrent glioblastoma GBM and pleural mesothelioma. TTFields (150 kHz) therapy, with/without chemotherapy, had antiproliferative and anticlonogenic activity in pancreatic cancer cell lines, and reduced tumor volume and weight more than chemotherapy alone in in vivo models. TTFields therapy with gemcitabine and nab-paclitaxel (GnP) was well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) in the phase 2 PANOVA study (NCT01971281). LAPC prognosis remains poor despite available therapies, which can negatively impact quality of life (QoL). As such, there remains a need for effective and tolerable treatments. Methods: PANOVA-3 (EF-27, NCT03377491) is a prospective, randomized, phase 3 study investigating the efficacy and safety of TTFields therapy with GnP in patients with LAPC, with a planned enrollment of 556 patients. Key inclusion criteria are: a diagnosis of unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region and assigned 1:1 to treatment groups to receive TTFields therapy + GnP or GnP alone. GnP will be administered at a standard dose per standard of care. TTFields therapy (150 kHz, 18h/day) will be delivered by the NovoTTF-200T System until local disease progression per RECIST v1.1. Usage will be tracked by the device. Follow-up will be performed every 4 weeks and computed tomography scans of the chest and abdomen will be taken every 8 weeks until disease progression. Patients will be followed every month until death. The primary endpoint is overall survival and key secondary endpoints include QoL, pain-free survival, and puncture-free survival, which will be compared between treatment groups. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Guidance around usage, lifestyle integration and prevention and management of skin adverse events will be provided by Device Support Specialists and field personnel. Usage information will be provided to patients and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches aim to optimize patient usage and outcomes. The trial is currently recruiting at 149 sites, globally. The DMC last reviewed the trial in August 2022, and suggested that the trial continue as planned. Clinical trial information: NCT03377491 .

TPS3640 Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients (pts) with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated it as a primary endpoint. Collaborating with a multidisciplinary oncology team and pt groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation and improve quality of life for pts. Methods: In this Alliance for Clinical Trials in Oncology randomized phase II trial (1:1), up to 312 pts with microsatellite stable LARC, clinical stage T4N0, any T, N+ or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Pts will be randomized to receive neoadjuvant long course CRT (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks (w) + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Pts will undergo assessment 8-12 w post-TNT completion for the primary endpoint of cCR per previously validated criteria and recommended WW and surveillance if cCR is achieved or TME if an incomplete response is noted. Secondary objectives include time-to event outcomes (disease-free and overall survival, organ preservation time and time to distant metastasis) and adverse effects. Statistical power, based on cCR, incorporates a one-sided alpha = 0.048 and power = 90% yielding 312 patients (156 per arm). Biospecimens including archival tumor tissue, matched / normal blood samples and serial rectal MRI will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and is actively recruiting. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov ID: NCT05610163 Clinical trial information: NCT05610163 .

3531 Background: Homologous recombination deficient (HRD) colorectal cancer (CRC) has improved overall survival (OS) when exposed to DNA damaging agents (DDA) oxaliplatin (OX) and irinotecan (IR). However, this OS benefit is only observed in HRD mutated CRC. Low expression of wild type (WT) BRCA1 RNA displays prolonged OS in ovarian cancer; this finding has not been investigated in CRC or outside BRCA. We investigate if low expression of WT HR genes is associated with prolonged OS in response to DDA. Methods: A total of 12,860 CRC patients tumor biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Patients with HRD mutations and MSI-H were excluded (N = 935). 11,925 patients were included in the analysis. A total of 11 core ( BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B) and 7 related ( BAP1, WRN, DNMT3A, ERCC1, FANCA, FANCF, RECQL4) HR genes were analyzed. Samples were classified by RNA expression percentiles within the studied cohort. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first of OX or IR to last contact. Results: OS benefit is seen in low RNA expression (bottom 10%) compared to high expression (top 10%) of all core WT HR genes except RAD51B, BARD1 and BRCA2 in response to IR. We observe a progressively longer OS with lower associated RNA expression in response to DDA. OS of nearly 7 years was observed in low expressing BRCA1 and RAD51 following IR exposure and 4.5-year OS benefit when compared to high expression of these genes. OS benefit in response to OX was less robust but significantly prolonged in BRCA1 and BRIP1 (Table). Patients harboring HRD mutations had similar OS to WT HR RNA low (bottom 10%) in response to OX (HR = 0.75; p = 0.1) and IR (HR = 0.82; p = 0.36). Conclusions: Here we report a novel subclass of CRC defined as patients with low RNA expressing WT HR genes that exhibit differential sensitivity to DDA. Significantly longer survival is noted in CRC with low expression BRCA1, RAD51 and BLM, while post-OX survival was significantly prolonged with low expression of BRCA1, BRIP1 and FANCA. Further characterization of sensitive HR genes will better predict DDA sensitivity and impact treatment sequencing. [Table: see text]

Abstract A false pituitary tumor describes pituitary enlargement due to intracranial hypotension. Reported previously primarily in the neurological literature, we present this case referred to endocrinology for evaluation of a pituitary mass. A 24-year-old male was referred to endocrinology for evaluation of pituitary enlargement without a hypo-enhancing lesion on magnetic resonance imaging (MRI). The main symptom reported was headache that was worse in the standing position and in the afternoon. He had no symptoms or signs of pituitary mass-effect, or hormone excess or deficiencies. Past medical history was relevant for a history of nerve schwannoma status post resection with subsequent spinal fusion. Biochemical evaluation of pituitary hormones was normal. Upon review of his pituitary MRI, other abnormalities seen were suggestive of intracranial hypotension. Based on his history and imaging findings, he was diagnosed with intracranial hypotension causing a “false pituitary tumor” rather than pituitary enlargement or abnormality. Further evaluation revealed multiple spinal leaks that were patched. His symptoms subsided within a few days of repair. Endocrinologists should be aware of the possible misdiagnosis of a pituitary mass due to intracranial hypotension.

Importance Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

The central neural mechanisms affecting sympathetic neuronal discharge strategies supporting homeostatic adjustments in human muscle sympathetic nerve activity (MSNA) remain unclear. This study investigated the hypothesis that central alpha-2 adrenergic mechanisms affect sympathetic action potential (AP) discharge, recruitment, and latency patterns within human MSNA (peroneal nerve microneurography and continuous wavelet transform). An alpha-2 adrenergic agonist (dexmedetomidine) was infused in eight healthy male and female participants (5 females; 28 ± 7years). Data were recorded during a 5-minute resting control condition, a 10-minute intravenous dexmedetomidine loading dose (0.225 μg/kg), and a dexmedetomidine maintenance dose (~0.1 μg/kg/hr). Data are reported as mean (SD) for the 5-minute control condition and 2-minutes of the dexmedetomidine infusion when MSNA bursting activity was demonstrably reduced. Two-tailed paired t-tests were performed. Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg; P < 0.01) but did not affect heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.75). Dexmedetomidine reduced integrated MSNA burst frequency (14 ± 6 to 4 ± 3 bursts/min; P < 0.01), sympathetic AP frequency (75 ± 46 to 16 ± 14 AP/min; P < 0.01), APs per burst (5 ± 1 to 4 ± 1 AP/burst; P = 0.01), AP clusters per burst (3.5 ± 0.7 to 3.0 ± 0.7 clusters/burst; P = 0.03), and de-recruited the largest AP clusters (12 ± 3 to 7 ± 2 AP clusters; P < 0.01). Despite de-recruiting large AP clusters with short conduction times, dexmedetomidine elicited shorter sympathetic AP conduction times (1.18 ± 0.12 to 1.14 ± 0.13 s; P = 0.03). Six participants performed a Valsalva Maneuver (20 s, 40 mmHg mouth pressure) during the control condition and during the dexmedetomidine maintenance dose. Data are reported as mean (SD) change (Δ) from the 2-minute period preceding the Valsalva Maneuver to the Valsalva Maneuver for each condition. During the control condition, Valsalva Maneuver increased AP frequency (Δ 311 ± 317 AP/min; P = 0.048), recruited larger previously silent AP clusters (Δ 2 ± 1 AP clusters; P < 0.01), and elicited shorter AP conduction times (Δ ‑0.09 ± 0.07 s; P = 0.02). Compared to the control condition, Valsalva Maneuver performed during the dexmedetomidine maintenance dose condition elicited lesser increases in AP frequency (Δ 116 ± 189 AP/min; P vs. control = 0.02) and lesser recruitment of larger previously silent AP clusters (Δ 0 ± 1 AP clusters; P vs. control = 0.02). Dexmedetomidine did not affect the latency reduction elicited by Valsalva Maneuver (Δ ‑0.07 ± 0.14 s; P vs. control = 0.61). These data suggest that human central alpha-2 adrenergic mechanisms affect: i) sympathetic postganglionic neuronal discharge and recruitment patterns, and ii) synaptic delays within the sympathetic neurocircuitry influencing AP latency. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract Introduction Climacturia has been reported in up to 64% of patients following radical prostatectomy (RP). In 2017, a prospective multicenter, multinational, investigational pilot study was conducted examining outcomes using a novel surgical technique, the Mini-Jupette sling, for the management of men with post-RP erectile dysfunction (ED) and climacturia and/or minimal stress urinary incontinence (SUI). We sought to report the 5-year outcomes from this original cohort. Objective To assess long-term safety and efficacy of the mini-jupette sling in the treatment of ED and concomitant mild SUI and/or climacturia Methods We identified patients who were enrolled in the previous multicenter study with post-RP ED and climacturia and/or mild SUI (2 ppd) and underwent IPP insertion with simultaneous placement of a Mini-Jupette sling. Data including current ppd, improvement in climacturia, complications, need for revision of IPP or additional urinary incontinence surgery, and date of most recent follow-up were collected. Results Of the original 38 patients, 5 have since died and 10 were lost to follow-up with 23/38 (61%) patients available for evaluation of long-term outcomes. The average follow-up time was 59 months (SD= 8.8) with a mean age of 69 years (SD= 6.8). Most patients (n=21, 91%) had subjective improvement of SUI and climacturia. One patient with persistent bothersome incontinence underwent artificial urinary sphincter (AUS) placement in 2018 with no complications, while the other is still considering a repeat procedure due to minor but persistent SUI. The mean ppd decreased from 1.4 preoperatively to 0.3 at a mean 5 years of follow-up. Most patients reported satisfaction in their urinary symptoms with 91% and 73% reporting improvement in SUI and climacturia respectively, compared to 86% and 93% respectively in the original series. One (4.3%) patient had an IPP revision for pump malfunction. There were no device infections reported. Conclusions The Mini-Jupette sling appears to be a safe and effective procedure with durable improvements in SUI and climacturia at 5 years of follow-up. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus, Intuitive Surgical, Fidalis, Hims & Hers Health Inc

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D &lt;12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank&lt;0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity&lt;0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.