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Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age < 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and < 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725

A growing body of research has begun to link exposure to environmental contaminants, such as heavy metals, with a variety of negative health outcomes. In this paper, we sought to review the current research describing the impact of certain common contaminant metals on cardiovascular (CV) health. We reviewed ten metals: lead, barium, nickel, chromium, cadmium, arsenic, mercury, selenium, zinc, and copper. After a literature review, we briefly summarized the routes of environmental exposure, pathophysiological mechanisms, CV health impacts, and exposure prevention and/or mitigation strategies for each metal. The resulting article discloses a broad spectrum of pathological significance, from relatively benign substances with little to no described effects on CV health, such as chromium and selenium, to substances with a wide-ranging and relatively severe spectrum of CV pathologies, such as arsenic, cadmium, and lead. It is our hope that this article will provide clinicians with a practical overview of the impact of these common environmental contaminants on CV health as well as highlight areas that require further investigation to better understand how these metals impact the incidence and progression of CV diseases.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Radioligand therapy (RLT) with [177Lu]Lu-DOTA-TATE is a standard of care for adult patients with somatostatin-receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Taking advantage of this precision nuclear medicine approach requires diligent monitoring and surveillance, from the use of diagnostic SSTR-targeted radioligand imaging for the selection of patients through treatment and assessments of response. Published evidence-based guidelines assist the multidisciplinary healthcare team by providing acceptable approaches to care; however, the sheer heterogeneity of GEP-NETs can make these frameworks difficult to apply in individual clinical circumstances. There are also contradictions in the literature regarding the utility of novel approaches in monitoring and surveilling patients with GEP-NETs receiving RLT. This article discusses the emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving RLT for GEP-NETs; additionally, it documents our own best practices. This allows us to offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making.

Abstract Introduction Retroperitoneal schwannomas are extremely rare, slow growing, benign, neurogenic tumors. Their diagnosis is challenging and often incidentally found upon evaluation of vague symptoms. Extrinsic compression to nearby organs or nerves may cause pain and paresthesia. Vulvar pain as a presenting symptom of a retroperitoneal schwannoma is reported in the literature in a case with pudendal nerve involvement. Here we present a case report of a patient who presented with vulvar burning and lower urinary tract irritative symptoms which was found to have a large infra-hepatic retroperitoneal schwannoma. Objectives In this report we show case how performing a detailed neurological evaluation and having a good understanding of the vulvar, perineal, and lower extremity dermatomal innervation have assisted in early diagnosis and treatment of a large retroperitoneal schwannoma. Methods A 65-year-old menopausal woman presented to her primary provider for a 3-month-history of worsening vulvar burning sensation associated with urinary burning, frequency, and nocturia. The pain is worse at night and when sitting for more than an hour. The patient endorsed low back pain that radiated like pins down her anterior thighs. The patient underwent evaluation by her referring provider to rule out a urinary tract infections and vaginitis. She was treated with vaginal estrogen tablets with partial relief for a working diagnosis of Urogenital Syndrome of Menopause. Patient was then referred to Gynecology due to inadequate relief. A detailed pelvic examination revealed normal labia majora and minora with no erythema or swelling. The Vestibule, Bartholin and Skene glands were non tender. Q-tip testing provoked burning sensation in the left and right labia minora on the medial and lateral aspect as well as the labia majora. Pelvic Floor evaluation elicited left pelvic floor tenderness and bilateral ischial spine pain concerning for Pudendal neuralgia. Also, noted paresthesia overlying the left lower extremity at the L3 and L4 distribution at the medial thigh (Figure-1) The patient underwent a bilateral pudendal block with total resolution of her vulvar pain for 24 hours and hence, lumbar and pelvic nerve entrapment was suspected. Magnetic Resonance Imaging was requested. Evaluation revealed a 3.3x4.4cm left ovarian mass and uterine fibroids that could potentially explain L2-L5 radiculopathy. The Lumbar MRI noted a cystic mass in the right mid abdomen for which further evaluation with CT scan was recommended. (Image-1). Referral to Surgical Oncology and Gyn oncology was sought. Epithelial ovarian cancer tumor markers were normal. Catecholamine studies were nonrevealing except for unexplained increase in dopamine levels. Results Surgical excision of the retroperitoneal and ovarian tumor revealed a left ovarian Fibroma and Schwannoma with Cystic Degeneration, confirmed with Immuno-peroxidase studies for S100 and SOX10. The patient had an uncomplicated post-operative course and remains asymptomatic with total resolution of her urinary and vulvar burning symptoms. Conclusions This a case report of vulvar and urethral paresthesia caused by an exceedingly rare tumor located high in the retroperitoneum. Diagnosis was aided by detailed history, comprehensive gynecological, and neurodermatomal evaluation. Appropriate imaging and timely referral led to early diagnosis and treatment, resulting in symptom resolution. Disclosure No.

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]

Abstract Purpose This scoping review summarises five decades of research on gender bias in subjective performance evaluations of medical trainees. Method A medical librarian searched PubMed, Ovid Embase, Scopus, Web of Science and Cochrane DBSR in June 2020. Two researchers independently reviewed each abstract to determine if it met inclusion criteria (original research article investigating gender bias in subjective medical trainee evaluations by staff). References from selected articles were also reviewed for inclusion. Data were extracted from the articles, and summary statistics were performed. Results A total of 212 abstracts were reviewed, and 32 met criteria. Twenty (62.5%) evaluated residents, and 12 (37.5%) studied medical students. The majority of studies on residents were Internal Medicine ( n = 8, 40.0%) and Surgery ( n = 7, 35.0%). All studies were performed in North America and were either retrospective or observational. Nine (28.0%) were qualitative, and 24 (75.0%) were quantitative. The majority of studies were published in the last decade ( n = 21, 65.6%). Twenty (62.5%) studies documented gender bias, of which 11 (55%) found that males received higher quantitative performance evaluations and 5 (25%) found that females received higher evaluation scores. The remaining 4 (20%) reported gender differences in qualitative evaluations. Conclusions Most studies detected gender bias in subjective performance evaluations of medical trainees, with a majority favouring males. There is a paucity of studies on bias in medical education with a lack of standardised approach to investigating bias.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������