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Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8–4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Background: Safety net hospitals treat a large burden of uninsured, or Medicaid insured patients, and have been linked to worse outcomes across several medical and surgical conditions. Currently, there is limited data on the effect of safety net burden on outcomes of inpatient cardiopulmonary resuscitation (CPR) for patients that suffered in-hospital cardiac arrest (IHCA) in the US. Hypothesis: Patients that experience IHCA in high burden safety net hospitals (HBH) will have worse outcomes compared to low burden safety net hospitals (LBH). Methods: Using the National Inpatient Sample database, from 2008 – 2018, we identified patients aged ≥ 18 years who experienced IHCA, using International Classification of Diseases (ICD) codes. Hospitals’ safety net burden was calculated from the proportions of Medicaid and uninsured patients using previously published methodology and categorized into LBH and HBH. Multivariate regression models were used to estimate the odds of key clinical outcomes Result: From 2008 to 2018, an estimated 555,016 unweighted adult hospitalizations underwent CPR for IHCA, out of which 19.2 % occurred at LBH and 55.2 % occurred at HBH. Compared with LBH, patients at HBH on average were younger 62 years ± 20 vs 67 years ± 17), less likely to be of White race, and more likely to be in the lowest median household income. On multivariate regression analysis, HBH was associated with lower chances of survival to hospital discharge (aOR 0.88; 95% CI 0.85 – 0.96) and lower odds of routine discharge (aOR 0.6; 95% CI 0.47 – 0.75)), compared to LBH. Patients who suffered IHCA in safety net hospitals with medium and large hospital bed size (aOR 0.96; 95% CI 0.94 – 0.98) and those publicly owned (aOR 0.95; 95% CI 0.92 – 0.98) were less likely to survive to hospital discharge. Median household income of patients in the 26 th – 100 th quartile and hospital location in the Midwest and Southern region were associated with better odds of hospital survival. Conclusion: Our study suggests that patients who experience IHCA at HBH had lower rates and odds of in-hospital survival and also less likely to be routinely discharged home. Patients’ income level and hospital-level characteristics appear to contribute to survival.

Myocardial infarction (MI) secondary to thrombolytic therapy in the setting of acute ischaemic stroke (AIS) is a rare but severe complication. This phenomenon has been well documented in the past with recombinant tissue-type plasminogen activator, also known as Alteplase. However, there are no documented reports of MI secondary to Tenecteplase (TNKase), an alternative thrombolytic agent rapidly gaining favour in managing AIS. We report a male patient in his 50s who received TNKase for an AIS and subsequently developed an inferolateral ST elevation MI.

7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 109/L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), WBC count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]

7018 Background: MF is a life-limiting malignancy characterized by marrow fibrosis, splenomegaly, and progressive cytopenias. JAK2 inhibitors can reduce spleen volume, which is considered a surrogate for disease response. For example, ≥10% SVR on ruxolitinib (RUX) is associated with improved OS among patients with platelet (PLT) counts ≥100×109/L. RUX cannot be administered at full dose in patients with lower PLTs, and it is not known whether the association between SVR and OS persists in such patients. PAC is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated SVR benefit vs BAT (including RUX) in PERSIST-2, which enrolled MF patients with PLTs ≤100×109/L. Here we present a retrospective landmark OS analysis of the relationship between SVR and OS on PERSIST-2. Methods: This analysis includes PERSIST-2 patients who were alive and on study at the start of the 12-week SVR window (study week 10) on PAC 200 mg BID or BAT. Spleen volume was assessed radiographically (MRI or CT). OS was evaluated among SVR responders vs non-responders within each treatment arm using different SVR thresholds (≥35%, ≥20%, ≥10%, > 0%) and a landmark analysis methodology. OS was compared using the log-rank test. Results: Among patients on PAC (n = 89), any SVR ( > 0%) at 12 weeks was significantly associated with improved survival (HR = 0.08 [95% CI: 0.01, 0.51], P = 0.0007). Among all SVR response thresholds, SVR ≥10% demonstrated the greatest separation in OS curves between responders vs. non-responders on PAC, with no deaths on study among 65 responders compared to 5 deaths among 24 non-responders (HR = 0.0 [95% CI: 0.0, 0.14], P < 0.0001). By contrast, SVR did not predict OS benefit on BAT (n = 84), including RUX (n = 39). For example, 11% (3/28) of patients on BAT who achieved SVR ≥10% died compared to a similar number (14%, 8/56) of non-responders (HR = 0.63 [95% CI: 0.17, 2.37], P = 0.49). Of the 28 patients on BAT who achieved SVR ≥10%, 23 (82%) were treated with RUX. Among these 23 patients, most patients were receiving low-dose RUX at the time of the landmark: 78% were on ≤10 mg BID and 43% were on £5 mg BID. By contrast, the median relative dose intensity on PAC was 100% (200 mg BID) through week 12 among both SVR ≥10% responders and non-responders. Conclusions: In MF patients with PLTs ≤100×109/L, achieving SVR on full-dose PAC was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on RUX, albeit at low doses. As PAC can be given at full dose regardless of PLT count, it is possible that PAC may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction. Clinical trial information: NCT02055781 .

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and > 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

PURPOSE Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Introduction There have been several studies of Moyamoya disease (MMD) with concurrent autoimmune (AI) disease. It has been proposed that there may be a causal or synergistic effect of autoimmune and inflammatory conditions in patients with MMD. As such, in the present study we seek to characterizethe surgical outcomes of adults and children with MMD and coexisting AI conditions. Methods A systematic review was performed of published studies reporting patient level data of Moyamoya disease and concomitant autoimmune disease. Relevant studies were identified using Preferred reporting Items for Systematic Reviews and Meta‐Analysis criteria. Results A total of 149 studies were included, encompassing 257 patients. Of the 257 patients with concurrent AI and MMD, 107 (88 females, 19 males) underwent surgery. The average age was 31.3 years (Range 5–65; SD 12.5). Five cases presented with hemorrhagic symptoms, 87 ischemic, and 15 were unspecified. The most commonly associated AI conditions were Graves’ disease (71 cases, 66.4%), Lupus (17 cases, 15.9%), and T1DM (6 cases, 5.6%).Follow‐up was reported in 25 cases and was an average of 17.8 months. Surgical outcomes were reported in 82 cases; 63 (76.8%) improved, 7 (8.5%) were stable, 9 (10.9%) developed a new deficit, and 3 (3.7%) died at most recent follow up. Eight patients (7.5%) had disease progression. 63 (58.8%) patients were treated with additional autoimmune therapy although this therapy did not lead to any difference in outcomes. Twenty patients (18.7%) required additional supportive medical therapy (eg: aspirin, statins). Conclusions Moyamoya disease may be multifactorial. Patients with concomitant AI and Moyamoya disease may be at increased risk and warrant additional surveillance or intervention. The ideal therapy for these patients remains to be understood. These findings warrant further study into optimal diagnostic and therapeutic techniques for concomitant MMD and AI conditions.

Introduction Moyamoya disease was first described in the 1950’s. After over six decades, however, the underlying etiology of Moyamoya still remains unknown. It has been postulated that underlying inflammatory or autoimmune (AI) processes may play a role in the development of this condition. In order to further investigate this hypothesis, we studied the clinical and epidemiological attributes of patients with concurrent Moyamoya disease and AI condition(s). Methods A systematic review was performed including studies reporting patient level data of Moyamoya disease and concomitant autoimmune disease. Relevant studies were identified using Preferred reporting Items for Systematic Reviews and Meta‐Analysis criteria. Results There were 739 results of which 149 were included in this study. The first reports of concurrent Moyamoya and AI occurred in 1991 and involved 2 cases of Moyamoya and associated Graves’ disease. These patients were treated with antithyroid medication alone and showed improvement. Altogether, our search yielded a total of 257 patients (192 females, 48 males, 17 unspecified). A total of 158 cases were reported as “Moyamoya Disease” and 99 were reported as “Moyamoya Syndrome/Vasculopathy.” Most cases were ischemic (175 ischemic, 15 hemorrhagic) in nature. Bilaterality of the disease was reported in 130 cases, unilaterality in 34 cases. The most commonly reported ethnicity was Chinese (26 cases), followed by Japanese (17 cases), and Korean (17 cases). The most common co‐presenting AI conditions were Graves’ disease (150 cases, 58.4%), Lupus (26 cases, 10.1%), antiphospholipid syndrome (19 cases, 7.4%), Type 1 Diabetes (19 cases, 7.4%), and Multiple Sclerosis (7 cases, 2.7%). Conclusions There are numerous reports describing patients diagnosed with Moyamoya in addition to coexisting AI conditions. Our study shows that the demographic characteristics of co‐presentation align with the common autoimmune (female predominance) and Moyamoya (high east Asian prevalence) attributes. These results warrant further investigation into a possible causal or synergistic relationship between Moyamoya and AI disease.