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A Case of Leptospirosis Induced Acute Respiratory Distress Syndrome
No full textINTRODUCTION: Leptospirosis is an infection that is often overlooked due to its low incidence in the United States, especially in cooler climates. It is also underdiagnosed due to its mild clinical course in many patients. We present a case of severe leptospirosis in a patient presenting with sepsis and multiorgan involvement. CASE: A 66-year-old female with a past medical history of hyperlipidemia presented with a five-day history of fatigue, chills, nausea, and vomiting. She was found to be tachycardic, tachypneic, febrile, and hypoxic initially requiring 2 liters via nasal cannula. Her preliminary workup was significant for hyponatremia, acute kidney injury, transaminitis, hyperbilirubinemia, and thrombocytopenia. Urinalysis and creatinine kinase were consistent with rhabdomyolysis. Her chest x-ray was unremarkable, with computed tomography (CT) abdomen and pelvis showing tree-in-bud nodules in the lung bases. She was started on antibiotics, however continued to worsen and was admitted to the medical intensive care unit. Her oxygen requirements continued to escalate, up to 30 liters via heated high-flow nasal cannula. CT chest showed interval worsening of diffuse lung disease with bilateral ground glass opacities and septal thickening concerning for acute respiratory distress syndrome (ARDS). Her PaO2/FiO2 ratio was 146, suggestive of moderate severity ARDS. An extensive workup by multiple specialties did not reveal the cause of her overall clinical picture, with respiratory viral panel, legionella, autoimmune liver panel, and multiple myeloma testing all negative. On hospital day four, it was noted that the patient was a gardener and had recently cleaned out rat traps around her garden. Antibiotics were changed to ceftriaxone and azithromycin due to concern for leptospirosis, with a positive IgM confirming the high clinical suspicion of our infectious disease team. She completed antibiotic therapy with continued improvement in her oxygen requirements, creatinine, thrombocytopenia, and bilirubin. A repeat chest x-ray done one week after discharge showed no abnormality. DISCUSSION: This patient presented with a constellation of symptoms classic for icteric leptospirosis, including jaundice, renal failure, thrombocytopenia, and ARDS. In addition, she was found to have known risk factors of rodent and contaminated soil exposure while gardening. Of note, this patient was originally on ampicillin-sulbactam and changed to ceftriaxone once there was suspicion for leptospirosis. Placing leptospirosis on the differential as well as taking a detailed social history in similar cases may allow for earlier diagnosis and more targeted antibiotic therapy
TCT-1083 Association of Weekend Admission With Clinical Outcomes and Invasive Management in ST-Elevation Myocardial Infarction: A National Cohort Analysis
No full textBackground: ST-elevation myocardial infarction (STEMI) requires urgent revascularization to improve outcomes. The “weekend effect”—worse outcomes for weekend admissions—has been observed across various conditions, but its impact on all-comer STEMI hospitalizations remains unclear. Prior studies have focused on those receiving prompt PCI; less is known about overall access and outcomes. This study assesses whether weekend admission independently affects treatment and clinical outcomes in all STEMI admissions. Methods: We analyzed the 2017–2022 National Inpatient Sample for adults (≥18 years) with a primary STEMI diagnosis. Weekend admission was identified via the AWEEKEND variable. The primary outcome was in-hospital mortality. Secondary outcomes included cardiogenic shock, AKI, vasopressor use, sepsis, CVA, ICU admission, cardiac arrest, PCI and CABG (within 24h or overall), and mechanical circulatory support. Weighted logistic regression adjusted for patient and hospital factors. Results: Among 1.5 million STEMI admissions (25.9% weekend), weekend admission was linked to higher mortality (aOR 1.026), shock, AKI, sepsis, CVA, ICU use, and arrest (all p \u3c 0.05). Odds of PCI within 24h, CABG, and any revascularization were lower (all p \u3c 0.001). No differences were found in bleeding, ECMO, or balloon pump use. Impella use was slightly lower. [Formula presented] Conclusion: Weekend STEMI admission remains associated with worse outcomes and reduced revascularization. System-wide strategies are needed to close these gaps. Categories: CORONARY: Acute Coronary Syndrome
TCT-1082 Impact of Weekend Admission on Outcomes in STEMI Patients Undergoing Early Percutaneous Coronary Intervention: A National Retrospective Cohort Study
No full textBackground: ST-elevation myocardial infarction (STEMI) is a time-sensitive emergency requiring rapid reperfusion, usually via percutaneous coronary intervention (PCI). Despite improvements in door-to-balloon times, concerns remain about the “weekend effect,” where patients admitted on weekends may experience delays and worse outcomes. Limited data exist on whether this effect persists among STEMI patients undergoing PCI within 24 hours. This study evaluated whether weekend admission independently impacts in-hospital outcomes in this population. Methods: We used the 2017–2022 National Inpatient Sample (NIS) to identify adults with a primary diagnosis of STEMI who underwent PCI within 24 hours. The exposure was weekend admission (AWEEKEND). The primary outcome was in-hospital mortality. Secondary outcomes included cardiogenic shock, acute kidney injury (AKI), vasopressor use, sepsis, CVA, ICU admission, arrest, CABG, IABP, Impella, and ECMO. Of 117,462 patients, 28,632 (24.4%) were weekend admissions. We used survey-weighted logistic regression to adjust for patient, clinical, and hospital factors. Results: Weekend admission was associated with higher mortality (aOR 1.204; CI 1.124–1.29; p \u3c 0.001), cardiogenic shock (aOR 1.189), AKI (aOR 1.163), vasopressor use (aOR 1.138), sepsis (aOR 1.136), CVA (aOR 1.302), ICU admission (aOR 1.17), and cardiac arrest (aOR 1.215). No differences were found for transfusion, GI bleeding, CABG, Impella, or ECMO. [Formula presented] Conclusion: Weekend admission was independently associated with worse outcomes despite early PCI, suggesting persistent disparities in STEMI care. Categories: CORONARY: Acute Coronary Syndrome
Debio 0123, a highly selective WEE1 inhibitor, in combination with carboplatin (C) and etoposide (E), in patients (pts) with recurrent small cell lung cancer (SCLC): Determination of recommended dose (RD) from a phase 1 escalation
No full textBackground: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, allowing mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Debio 0123 is in clinical development in solid tumors, as monotherapy and in combination with different therapeutic agents. Debio 0123 has shown manageable safety profile and initial signals of antitumor activity. SCLC is an aggressive disease that carries a high mutational burden and genomic instability. Debio 0123 has shown to significantly improve the antitumor activity of DNA damaging agents, C + E, in preclinical SCLC models. Methods: This Phase 1 study (NCT05815160) is evaluating Debio 0123 in combination with C + E in pts with recurrent SCLC after first line of platinum-based chemotherapy. Of note, pts with stable brain metastasis were eligible. In the dose escalation, pts who had a chemotherapy-free interval (CFI).45 days since the last dose of platinum chemotherapy, received escalating doses of Debio 0123 (D1–3 and D8–10) in combination with standard C (AUC5) on D1 and E (100 mg/m2) on D1-3 in 21-day cycles. Results: Dose escalation data (cut-off date Oct 24th, 2024) are presented. Overall, 16 pts were treated (44% female, mean age 63.3 years). Using a Bayesian Logistic model-guided dose escalation, tested doses of Debio 0123 ranged from 200-400 mg. The RD was selected at 200 mg. At this dose level, 3/10 pts experienced a dose-limiting toxicity. The treatment was considered well tolerated with a manageable overall safety profile, in line with that expected for the chemotherapy combination. Most frequent Debio 0123 -related toxicities are shown in Table 1. PK data showed Debio 0123 plasma levels increasing proportionally with the dose. Debio 0123 CSF/ plasma ratio was ~40%, suggesting that Debio 0123 crosses the blood brain barrier. At 200 mg, confirmed partial responses (PR) occurred in 4/9 evaluable pts overall, and in 4/7 pts in the subgroup with CFI.90 days, including pt with intracranial response; 4 pts had SD of which 2 had tumor shrinkage of . 20 %. mPFS at the RD (n=10) was 7.2 months. Conclusions: Debio 0123 combined with C + E is well tolerated, with a manageable safety profile, up to 200 mg; this combination led to promising antitumor activity in pts with recurrent SCLC after prior platinum-based therapy with CFI . 45 days. Further investigation of Debio 0123 at 200 mg in pts with a CFI . 90 days is ongoing. Clinical trial information: NCT05815160
Initial phase 1 dose escalation data for emiltatug ledadotin (Emi-Le), a novel B7-H4- directed dolasynthen antibody-drug conjugate
No full textBackground: B7-H4 is a transmembrane protein over-expressed in breast (BC), ovarian (OC), endometrial (EC), and adenoid cystic carcinoma type 1 (ACC-1) cancers, with limited expression in healthy tissues. Emi-Le (XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect. Methods: The Phase 1 trial is investigating Emi-Le monotherapy in adult patients (pts) with advanced/metastatic TNBC, HR+/HER2- BC, OC, EC and ACC-1. In dose escalation, eligible pts received Emi-Le at doses of 7.2-115 mg/m2 per cycle, with all collected data informing the recommended doses for the expansion (EXP) portion of the trial. Tumors were evaluated retrospectively for B7-H4 expression by IHC, with the preliminary high cutoff set at TPS≥70. Results: As of December 13, 2024, 130 pts were dosed. Across all tumor types, median age of pts was 55; median 4.5 prior lines of therapy (range 0-15). B7-H4 status was evaluated for 103 pts, with 44% determined to be B7-H4 TPS high. Overall, Emi-Le was generally well tolerated. The most common TRAEs were transient AST increase (38%, G3 14%), proteinuria (31%, G3 9%), nausea (29%, G3 1%) and fatigue (28%, G3 0%). The only G3 TRAEs in ≥5% of pts were AST increase and proteinuria. No G4 or 5 TRAEs were reported. No observed dose-limiting treatment-related neutropenia, neuropathy, ocular toxicity, interstitial lung disease or thrombocytopenia. TRAEs leading to discontinuation were observed in 2.3% of pts. Clinical activity was correlated with both dose and B7-H4 expression. For pts treated with doses ranging from 38.1-67.4 mg/m2 per cycle (intermediate dose range), the confirmed ORR in evaluable pts with high B7-H4 expression was 23% (6/26), including a 23% (3/13) confirmed ORR in evaluable pts with TNBC, with all 13 pts having previously received at least one topoisomerase-1 inhibitor (topo-1) ADC. At doses ≥76.2 mg/m2 per cycle (high dose range), the confirmed ORR in evaluable pts with high B7-H4 expression was 22% (2/9), with 78% (7/9) having ≥30% reduction in target lesions. Of the 8 pts with confirmed responses at doses ≥38.1 mg/m2, 5 had reduction in target lesions \u3e 60%, including 1 CR. All 4 pts with high B7-H4 expression treated at the initial EXP dose of 67.4mg/m2 Q4W had tumor reductions and were on treatment with durations of ≥16 weeks as of data cutoff. Conclusions: Based on the initial reported data, Emi-Le appears to have encouraging clinical activity and tolerability in a heavily pretreated population. Further clinical development is ongoing in the EXP portion of the trial at a dose of 67.4 mg/m2 Q4W in pts with advanced/metastatic TNBC who have received 1-4 prior lines of systemic therapy, including at least one topo-1 ADC. Dose exploration is ongoing to identify a potential second higher EXP dose
298MO Clinical activity of emiltatug ledadotin (Emi-Le), a B7-H4-directed ADC, in patients with TNBC who received at least one prior topoisomerase-1 inhibitor (Topo-1) ADC
No full textBackground: Effective treatments for relapsed/refractory TNBC remain an unmet medical need. Standard-of-care single-agent chemotherapy has limited efficacy, with response rates of ∼5%, PFS ∼7 weeks. Emi-Le (XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect. Methods: The Phase I trial is investigating Emi-Le monotherapy in adult pts with select advanced/metastatic solid tumors, including TNBC. In dose escalation, eligible pts received Emi-Le at doses of 7.2-115 mg/m2. Tumors were evaluated retrospectively by IHC for B7-H4 expression with a preliminary high cutoff set at tumor proportion score (TPS) ≥70. Results: As of Dec 13, 2024, 130 pts were dosed with 4.5 median prior lines of therapy. 63 pts had TNBC, with a median of 4 prior lines (range 2-9) and 92% having previously received ≥1 topo-1 ADC. Among all 130 pts, the most common TRAEs were transient AST increase (38%, G3 14%), proteinuria (31%, G3 9%), nausea (29%, G3 1%) and fatigue (28%, G3 0%). The only G3 TRAEs in ≥5% of pts were AST increase and proteinuria. No G4 or 5 TRAEs were reported. No observed dose-limiting treatment-related neutropenia, neuropathy, ocular toxicity, interstitial lung disease or thrombocytopenia. In the 13 evaluable pts with TNBC and high B7-H4 expression dosed at 38.1-67.4 mg/m2 per cycle, prior lines of therapy ranged 3-8, and all had previously received at least one topo-1 ADC. The confirmed ORR in this population was 23% (3/13). All 3 confirmed responders had reduction in target lesions of \u3e60%. Of the 13 pts, 7 had received 3-4 prior lines; among these, the ORR was 29% (2/7). As of data cutoff, both responders were ongoing on treatment for \u3e16 weeks. Conclusions: Based on the initial reported data, Emi-Le appears to have encouraging clinical activity and tolerability in a heavily pretreated TNBC population with high B7-H4 expression who had previously received topo-1 ADCs. Further clinical development of Emi-Le is ongoing in the expansion portion of the Ph1 trial at a dose of 67.4 mg/m2 Q4W in pts with advanced/metastatic TNBC who have received 1-4 prior lines of systemic therapy, including at least one topo-1 ADC. Clinical trial identification: NCT05377996
Inflammatory bowel disease and risk of cancer: A nationwide study
No full textBackground: Inflammatory bowel disease (IBD), including Crohn\u27s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Existing research suggests that chronic inflammation, immune dysregulation, and prolonged use of immunosuppressive therapy may contribute to increased cancer risk in IBD. However, nationwide data on the prevalence and types of cancer in U.S. IBD patients remain limited. This study aimed to determine the frequency and associations of various cancers among individuals with IBD. Methods: We conducted a retrospective cross-sectional study using the 2016-2018 Nationwide Inpatient Sample (NIS), encompassing adult hospitalizations in the U.S. The NIS approximates 20% of hospital discharges nationwide. Patients with IBD were identified via ICD-10-CM codes. Statistical analyses were performed with SAS 9.4. We used chi-square tests for univariate analysis and multivariate logistic regression to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI). Statistical significance was set at p\u3c 0.05. Results: Out of 87,761,798 U.S. hospitalizations, 0.67% involved CD and 0.39% involved UC. Prevalence of pancreatic cancer was 0.16% in CD and 0.22% in UC. Melanoma skin cancer prevalence was 0.07%, while non-melanoma skin cancers (NMSC) including squamous cell, basal cell, and Merkel cell carcinomas were observed at 0.03% (p\u3c 0.0001). Notably, melanoma was more frequent in UC(0.13%) compared to CD(0.07%) or non-IBD (0.07%). Colon cancer occurred in 0.05% of IBD patients. Leukemia was documented in 0.51% of CD and 0.61% of UC hospitalizations. Barrett\u27s esophagus (BE) without dysplasia was seen in 0.76%, and BE with dysplasia in 0.01%. Esophageal malignancy prevalence was 0.03% in CD and 0.08% in UC. Multivariate regression indicated that UC was associated with a 51% higher melanoma risk than CD (aOR: 1.51, 95% CI: 1.22-1.85). BE risk was significantly elevated in CD (aOR: 1.67, 95%CI: 1.55-1.79) and UC (aOR: 1.77, 95%CI: 1.62-1.93). Age over 75 significantly increased cancer risk (aOR: 1.99, 95%CI: 1.58-2.51). Additionally, Black patients (aOR: 1.20, 95%CI: 1.17-1.24) and smokers (aOR: 1.39, 95%CI: 1.20-1.61) showed higher odds of cancer. Conclusions: These findings highlight the need for vigilant, long-term surveillance of IBD patients to reduce gastrointestinal and melanoma cancer risks. Higher risk in specific demographics suggests the importance of tailored screening protocols. Further research on the potential for hematological malignancies in IBD is warranted to enhance understanding and improve patient care
Nautilus, a phase 1b/2 trial of combining oral HDAC inhibitor (HDACi) with MEK inhibitor (MEKi) in patients with NRAS-mutated metastatic melanoma (MM)
No full textBackground: Activating NRAS mutations occur in 15-20% of MM cases. The MEK inhibitor binimetinib has modest single agent activity with 15% objective response rate (ORR) and 2.8 month progression-free survival (PFS). Bocodepsin (OKI-179) is a novel Class Iselective, oral histone deacetylase inhibitor that was found to have synergistic efficacy with MEKi in preclinical models of NRAS-mutated melanoma. Cells displayed unrepaired double strandDNAbreaks and cellular apoptosis, while regressions were observed in xenograft models. Here we present the results of the phase 2 portion of a clinical trial of this combination in NRASmutantMM( NCT05340621). Methods: In this Phase 2 study, only patients with NRAS-mutant MM previously treated with immunotherapy were enrolled and treated with bocodepsin at the recommended phase 2 dose (300mgdaily, 4 days on, 3 days off, continuously) with binimetinib (45 mg twice daily, continuously). Primary endpoint was ORR, with secondary endpoints including safety and PK analyses. Results: As of 1/3/2025, 36 total patients were enrolled; 14 in phase 1b dose escalation and 22 in phase 2, including a total of 24 NRAS-mutant melanoma patients. Median age of NRAS-mutant MM patients was 69 years, and 47% of patients were males. Median numbers of prior therapies was 3 and LDH elevations were found in 41% of patients. There were no grade 3/4 toxicities seen in .10% of patients, including no episodes of high grade rash. Of the 20 evaluable patients with NRAS-mutant MM, ORR was 30%. The median PFS was 7.25 months (5-92 weeks). Conclusions: The combination of bocodepsin and binimetinib in patients with NRAS-mutant melanoma is tolerable with manageable AEs and no high grade rash. Initial response data in patients with NRAS-mutant melanoma are supportive of potential combinatorial activity of a MEK inhibitor and HDACi bocodepsin. Further investigation is crucial asMMpatients with disease progression after immunotherapy remain in need of rational therapeutic options. Thus, MEKi + HDACi warrants further study in a larger patient cohort
Proteogenomic characterization of antibody-drug conjugate target expression profiles in transcriptional subtypes of small cell lung cancer
No full textBackground: Small cell lung cancer (SCLC) is a highly lethal malignancy, and there is an urgent need for more effective therapies. Antibody-drug conjugates (ADCs), which combine the precision of monoclonal antibodies with the cytotoxic power of small molecules, represent a promising approach. Despite extensive research, the relationship between ADC target overexpression and the transcriptional profile of SCLC remains unclear. Our study aimed to elucidate how ADC target expression correlates with transcriptional subtypes of SCLC, potentially guiding the selection of ADCs based on molecular profiling. Methods: RNA-seq and tandem mass spectrometry data for 107 patients with matched SCLC tumors and normal adjacent lung tissue were obtained from the CPTAC SCLC cohort. SCLC subtypes were defined according to expression of four transcription factors: achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). ADC target expression for DLL3, SEZ6, B7-H3 (CD276), and Trop2 (TACSTD2) were assessed at the transcriptomic and proteomic level. The correlation between transcriptional subtype and ADC target expression was determined using Pearson\u27s correlation coefficient. Results: In 107 SCLC tumors, subtypes corresponded to 66 (61.6%) ASCL1, 21 (19.6%) NeuroD1, 3 (2.8%) YAP1, and 17 (15.9%) POU2F3. The ASCL1 subtype was positively correlated with DLL3 (R2=0.93, p=9E-87) and SEZ6 (R2=0.85, p=2.9E-57), and negatively correlated with TROP2 expression (R2=-0.72, p=1.5E-34). The NEUROD1 subtype showed moderate positive correlation with DLL3 (R2=0.52, p=4.8E-14) and SEZ6 (R2=0.58, p=3.6E-18), and a moderate negative correlation with TROP2 (R2=-0.52, p=1.6E-14). The POU2F3 subtype did not demonstrate strong positive or negative correlations with ADC targets. The YAP1 subtype was negatively correlated DLL3 (R2=-0.72, p=1.1E-32) and SEZ6 (R2=-0.71, p=9.5E-33), and positively correlated with Trop2 expression (R2=0.85, P=7.5E-61). Conclusions: Our findings reveal that molecular subtypes of SCLC exhibit unique patterns of ADC target expression. These profiles are crucial for further research and could lead to the development of subtype-specific treatments that improve clinical outcomes for patients with SCLC
Combination casdatifan plus cabozantinib in previously treated patients with clear cell renal cell carcinoma: results from an expansion cohort of ARC-20 (NCT05536141)
No full textBackground: Hypoxia-inducible factor 2-alpha (HIF-2α) is highly dysreg_ulated in clear cell renal cell carcinoma (ccRCC), resulting in increased expression of proteins involved with angiogenesis, proliferation, and cancer cell survival. Casdatifan is an orally bioavailable small-molecule HIF-2α inhibitor that has demonstrated monotherapy activity in patients receiving 2L+ treatment for ccRCC. We investigated the safety and effi_cacy of casdatifan plus the anti-vascular endothelial growth factor recep_tor tyrosine kinase inhibitor (VEGFR-TKI) cabozantinib in previously treated patients with ccRCC in an expansion cohort (casdatifan plus cabozantinib) of the phase 1, open-label ARC-20 (NCT05536141) trial. Methods: Patients enrolled in the casdatifan plus cabozantinib expan_sion cohort were previously treated with immunotherapy (IO) alone or combined with anti-VEGF therapies. Casdatifan 100mg and cabozan_tinib 60mg were given orally once daily. Endpoints included the inci_dence of treatment-emergent adverse events (AEs) and objective response rate (ORR) by RECIST v1.1. The efficacy evaluable population was defined as patients who received any study treatment and achieved a minimum of 12weeks follow-up. This study is ongoing; data as of March 14, 2025, are reported. Results: Overall, 42 patients with a median (range) follow-up of 3.7 (1.1–9.1) months were enrolled. At the data cutoff date, prior treatment settings included adjuvant only (n=8/42) and locally advanced/meta_static (1 L n=29/42; 2 L n=5/42). Twenty-five (60%) patients had received prior IO alone, and 17 (41%) patients had received prior IO plus VEGFR-TKI treatment. All grade AEs occurred in 98% of patients, with the most common being anemia (69%) and fatigue (57%). Most common (\u3e 5%) grade ≥ 3 AEs were anemia (n=10 [24%]), hypona_tremia (n=4 [10%]), and hypoxia (n=3 [7%]). No casdatifan-related grade 4 or 5 AEs were observed. AEs leading to casdatifan only, cabozantinib only, or any study drug dose reductions occurred in 10 (24%), 16 (38%), and 22 (52%) patients, respectively. Two (5%) patients discontinued due to an AE related to casdatifan (hypoxia and drug hypersensitivity; n=1 each). For patients in the efficacy evaluable population (n=24), 1 (4%) patient achieved a complete response, and 10 (42%) patients achieved a partial response for a confirmed ORR of 45.8% (Table). Activity was seen across all IMDC risk groups. Conclusions: In previously treated patients with ccRCC, casdatifan 100mg plus cabozantinib 60mg had a manageable AE profile with promising clinical activity. These data support continued evaluation of this combination in the phase 3 PEAK-1 clinical trial