Citations

ImportancePathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).ObjectiveTo examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.Design, Setting, and ParticipantsThe study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.InterventionsParticipants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.Main Outcomes and MeasuresThe presence of DCIS and EFS, DRFS, and LRR.ResultsThe study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.Conclusions and RelevanceThe analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.Trial RegistrationClinicalTrials.gov Identifier NCT01042379.

ObjectiveTo describe people with gout who were diagnosed with coronavirus disease 2019 (COVID‐19) and hospitalized and to characterize their outcomes.MethodsData on patients with gout hospitalized for COVID‐19 between March 12, 2020, and October 25, 2021, were extracted from the COVID‐19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID‐19 outcomes including oxygenation or ventilation support and death.ResultsOne hundred sixty‐three patients with gout who developed COVID‐19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre‐COVID‐19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID‐19‐related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities.ConclusionThis cohort of people with gout and COVID‐19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID‐19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.

Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl − secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl − secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD.

Abstract Background and study aims Adenoma recurrence is one of the key limitations of endoscopic mucosal resection (EMR), which occurs in 15 % to 30 % of cases during first surveillance colonoscopy. The main hypothesis behind adenoma recurrence is leftover micro-adenomas at the margins of post-EMR defects. In this systematic review and meta-analysis, we evaluated the efficacy of snare tip soft coagulation (STSC) at the margins of mucosal defects to reduce adenoma recurrence and bleeding complications. Methods Electronic databases such as PubMed and the Cochrane library were used for systematic literature search. Studies with polyps only resected by piecemeal EMR and active treatment: with STSC, comparator: non-STSC were included. A random effects model was used to calculate the summary of risk ratio and 95 % confidence intervals. The main outcome of the study was to compare the effect of STSC versus non-STSC with respect to adenoma recurrence at first surveillance colonoscopy after thermal ablation of post-EMR defects. Results Five studies were included in the systematic review and meta-analysis. The total number patients who completed first surveillance colonoscopy (SC1) in the STSC group was 534 and in the non-STSC group was 514. The pooled adenoma recurrence rate was 6 % (37 of 534 cases) in the STSC arm and 22 % (115 of 514 cases) in the non-STSC arm, (odds ratio [OR] 0.26, 95 % confidence interval [CI], 0.16–0.41, P = 0.001). The pooled delayed post-EMR bleeding rate 19 % (67 of 343) in the STSC arm and 22 % (78 of 341) in the non-STSC arm (OR 0.82, 95 %CI, 0.57–1.18). Conclusions Thermal ablation of post-EMR defects significantly reduces adenoma recurrence at first surveillance colonoscopy.

ObjectiveSome patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID‐19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID‐19 ARDS in this population and to create a simple risk score calculator for use in clinical settings.MethodsData were derived from the COVID‐19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID‐19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier.ResultsThe study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67‐0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%‐83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator.ConclusionWe were able to predict ARDS with good sensitivity using information readily available at COVID‐19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID‐19 disease progression.

Introduction Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. Methods and analysis This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients’ patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. Ethics and dissemination This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. Trial registration number NCT04509115 .

TPS7586 Background: EO2463 is a therapeutic vaccine designed to activate existing commensal bacteria-specific memory T cells that cross-react with B cell markers in order to drive anti-tumor immune activity against B-cell malignancies. The four microbial-derived, synthetically produced peptides contained in EO2463 (OMP72, OMP64, OMP65, and OMP66), correspond to cytotoxic CD8 T cell HLA-A2 restricted epitopes, and exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), respectively. In pre-clinical models, these peptides can generate strong immune responses and specifically stimulate cross-reactive cytotoxic CD8 T cells to recognize the chosen B cell targets. EO2463 also contains a CD4 helper peptide referred to as universal cancer peptide 2, derived from the human telomerase reverse transcriptase catalytic subunit. The present study is a first-in-human clinical trial of this microbiome-derived peptide therapeutic cancer vaccine approach in patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: This four-cohort phase 1/2 trial will investigate EO2463 monotherapy, and combinations of EO2463/lenalidomide (EL), EO2463/rituximab (ER), and EO2463/lenalidomide/rituximab (ER2), for treatment of patients with FL and MZL. Cohort 1 is a safety lead-in dose-finding in patients with relapsed/refractory (RR) disease, with a 3-by-3 design to establish the recommended phase 2 dose (RP2D) for EO2463 monotherapy and to confirm the safety of the RP2D for combination schedules of EL, and ER2. After the recommended EO2463 monotherapy dose is established, cohorts 2, 3, and 4 will open to accrual. Cohort 2 will investigate EO2463 monotherapy in patients with newly diagnosed FL/MZL who are not in need of treatment; cohort 3 will investigate EO2463 monotherapy, followed by ER in patients with limited tumor burden who need treatment, and cohort 4 will further investigate EL, followed by ER2 in the RR setting. EO2463 will be administered SC 4 times at 2-week intervals, followed by continued booster administrations every 4 weeks for 9 (Cohorts 2 and 3) or 12 (Cohorts 1 and 4) months. Inclusion/exclusion criteria, and the design and schedule of the intense immune and safety monitoring will be presented. The safety lead-in dose-finding is currently ongoing, and no safety concerns have been observed thus far. Clinical trial information: NCT04669171.

2027 Background: Breast cancer related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5-8% of breast cancer patients with overall survival (OS) measured in weeks without treatment. As new treatments prolong survival with breast cancer, the risk of developing BC-LMD may be increasing. We hypothesized that the rate of BC-LMD diagnosis increased significantly with time. We also predicted that OS with BC-LMD had changed with time and in relationship to molecular subtype and treatment following BC-LMD diagnosis. Methods: With approval of the local Scientific Research Committee and IRB, we conducted a retrospective analysis of medical records for patients treated or diagnosed with breast cancer at MCC from 2011-2020. Patient demographics, tumor characteristics, treatments, and outcomes were collected. Kaplan Meier survival curves were used to determine median overall survival (OS), progression of disease, and differences by molecular subtype. Univariate and multivariate analyses were used to determine characteristics of primary tumors and treatments which affected OS. Results: Of the 133 cases identified, significantly more were diagnosed between 2016-2020 than 2011-2015 (p < 0.01). Significant increases were seen in HER2+ and TNBC patients (p < 0.05) but not for ER/PR positive (HR+) disease (p = 0.058). HER2+ LMD associated with longest overall survival (OS; 7mths) followed by HR+ disease (3mths) and TNBC with the shortest OS (2mths). Systemic metastases preceded BC-LMD diagnosis in 72% of cases and CNS metastases in 85% of cases. HER2+ disease also conferred increased survival after CNS metastases were diagnosed until progression to LMD (8mth vs 2mth for HR+ and 1mth for TNBC LMD; p < 0.05). Positive impact on survival by HER2 targeted therapies may account for improved OS in this population. Other factors which increased OS generally were: WBRT, continuation of systemic therapy, delivery of intrathecal chemotherapy, and participation in clinical trials. Having TNBC and decision to defer treatment were associated with reduced OS. Conclusions: This study highlights the importance of identifying patients with BC-LMD early and with the intention to treat. Prospective clinical trials and population-based studies are needed to advance treatment of BC-LMD.