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Antibody–drug conjugates (ADCs) are reshaping the therapeutic approach to advanced gastrointestinal cancers by integrating tumor-specific monoclonal antibodies with potent cytotoxic payloads to improve targeted tumor cell destruction while minimizing systemic exposure. Compared to traditional chemotherapy, trastuzumab deruxtecan has significantly improved objective response rates and overall survival in HER2-positive gastric and gastroesophageal junction tumors after trastuzumab-based therapy. This supports its role as an important second-line or later treatment option. The ongoing advancement of ADCs targeting CLDN18.2, TROP2, and CEACAM5 indicates that this therapeutic category will continue to expand across gastrointestinal neoplasms. Nonetheless, these advancements are accompanied by a specific and clinically significant toxicity profile. Hematologic suppression, gastrointestinal side effects, hepatotoxicity, and notably interstitial lung disease (ILD) are essential consequences that may need inpatient assessment and care. Interstitial lung disease (ILD), although uncommon, may be severe or lethal if not identified immediately and treated swiftly with medication cessation and corticosteroids. In hospitalized patients, distinguishing ADC-related toxicity from infection or disease progression is often difficult owing to overlapping clinical manifestations, requiring meticulous evaluation and interdisciplinary cooperation. As ADCs are integrated into earlier treatment lines and across a broader patient population, hospital systems must evolve to ensure prompt identification, consistent management protocols, and efficient collaboration between oncology and inpatient teams. This study analyzes the mechanisms, clinical effectiveness, and safety profile of ADCs in gastrointestinal oncology, pointing out the importance of institutional preparedness to safely incorporate these medicines into standard clinical practice. These features also align ADC therapy with personalized medicine by emphasizing biomarker-guided patient selection and individualized toxicity monitoring.

Inflammatory myofibroblastic tumors (IMTs), originating from mesenchymal cells, are rare neoplasms with intermediate biological potential. Despite being predominantly benign, they can progress to locally aggressive disease and may recur over time. IMTs are predominantly seen in the pediatric population, making our case of IMT in an older adult even rarer. A 67-year-old female with a 42-pack-year smoking history presented with cough, fever, and progressively worsening exertional dyspnea. Imaging studies, including chest X-ray followed by chest computed tomography, identified a right lower lobe lung nodule without evidence of metastasis. Subsequent evaluation with robotic bronchoscopy and endobronchial ultrasound revealed densely cellular reactive lung tissue on lymph node biopsy. Ultimately, the patient underwent a robotic-assisted right lower lobectomy. Final pathology confirmed the diagnosis of an IMT. IMTs are characterized by the presence of spindle cells associated with dense monomorphic inflammatory cells. It has been found that IMT arises from chromosomal rearrangements that aberrantly activate various kinase signaling pathways. This understanding of the molecular mechanisms underlying IMT development has elucidated the neoplastic nature of the disease and has also been pivotal in distinguishing IMT from other inflammatory pseudotumors. Surgical resection remains the cornerstone of treatment, with targeted therapies offering promising results for unresectable or advanced cases. IMTs pose a multifaceted challenge in clinical practice due to their diverse clinical manifestations, histopathological variability, and unclear etiopathogenesis, underscoring the need for continued research and a multidisciplinary approach to optimize patient outcomes.

Background The prognostic significance of an adverse acid–base milieu despite venoarterial extracorporeal membrane oxygenation support in patients with cardiogenic shock remains poorly defined. We examined metabolic and respiratory disturbances in the ELSO (Extracorporeal Life Support Organization) Registry among patients who received venoarterial extracorporeal membrane oxygenation support for refractory cardiogenic shock. Methods Arterial blood gas acid–base values at 24 hours following venoarterial extracorporeal membrane oxygenation initiation were analyzed, with patients classified by pH, arterial partial pressure of carbon dioxide, and bicarbonate. Multivariable logistic regression and exploratory machine learning analyses were used to assess predictors of in‐hospital mortality. Results Among 15 144 adult patients, 74.6% (10 860) had neither respiratory nor metabolic acidosis, 13.1% (1909) had isolated respiratory acidosis, 11.6% (1684) had isolated metabolic acidosis, and 0.7% (100) had combined acidosis. In‐hospital mortality occurred in 7719 (51.0%) patients and increased incrementally across patients with lower pH (adjusted odds ratio [OR], 2.03 with each 0.1‐unit decrease in pH, using 7.4 as a reference point [95% CI, 1.82–2.26]), bicarbonate (adjusted OR, 1.93 per each 5‐mEq/L <24 mEq/L [95% CI, 1.76–2.12]) or base excess (adjusted OR, 1.90 per each 5‐mEq/L <0 mEq/L [95% CI, 1.75–2.07]) (all P <0.01). Mortality varied significantly, being highest for the low‐pH metabolic acidosis cluster (adjusted OR, 1.90 [95% CI, 1.70–2.12], P <0.01). Conclusions Survival decreased progressively with worse acidemia or metabolic acidosis despite 24 hours of hemodynamic support with venoarterial extracorporeal membrane oxygenation among patients with cardiogenic shock. Our findings emphasize the prognostic significance of metabolic parameters as potentially modifiable risk factors and underscore the need for early recognition and interventions to mitigate severe metabolic derangements.

Subglottic stenosis (SGS) may arise from both mechanical and inflammatory airway injury. Patients with mast cell activation syndrome (MCAS) are uniquely vulnerable, due to both direct effects of systemic inflammation and indirect effects of repeated intubation for anaphylaxis that can converge to cause life-threatening airway compromise. We describe a sentinel case of a 34-year-old female with MCAS and multiple prior intubations who presented with progressive dyspnea. Flexible laryngoscopy revealed grade III SGS. She underwent urgent endoscopic intervention, including balloon dilation, carbon dioxide (CO 2 ) laser radial incisions, and steroid injection. Airway patency was restored, and postoperative care focused on optimizing systemic mast cell control with cromolyn, fexofenadine, montelukast, and omalizumab. Literature review supports a mechanistic role for mast cell mediators in airway fibrosis and impaired wound healing, compounding the effects of mechanical trauma in MCAS. This sentinel case highlights clinically significant risk of SGS in patients with MCAS. By integrating case findings with mechanistic insights, this report underscores the urgent need for interdisciplinary awareness, proactive airway evaluation, and research into surveillance and prevention strategies in MCAS and related disorders. Level of Evidence: Level V/Case Report and Narrative Review.

Background Level I trauma centers employ various orthopaedic call strategies based on resources and surgeon subspeciality availability. Objective We hypothesize when surgeons fellowship trained in trauma are solely on call that patient outcomes will be improved compared to a combined plan. Methods Retrospective cohort study from two 24-month time periods at an academic level one trauma center. The first cohort consisted of only trauma surgeons taking call. The second cohort consisted of a combination of trauma and other subspecialities taking call. The primary outcome analyzed was time from admission to operating room for hip, femoral shaft, distal femur, tibia shaft, pelvic ring and acetabulum fractures. Secondary outcomes analyzed included length of stay, 90 day incidence of reoperation, mortality, VTE and readmission. Results Eight hundred and fifty seven patients in the trauma cohort and 992 patients in the combined cohort met the inclusion criteria. The time from admission to index surgical procedure was significantly shorter in the trauma cohort (1.7 vs 2.4). Length of stay (8.95 vs 11 days) and 90 day mortality (1.8% vs 3.8%) was improved in the trauma cohort. There was no difference in 90 day rate of VTE, readmission or reoperation. Length of stay and time to OR in pelvic ring injuries and acetabulum fractures were doubled compared to the hybrid group. Conclusions Our findings suggest that when trauma fellowship trained surgeons are the only ones taking call patients have a shorter time from admission to index surgical procedure, length of stay and lower mortality rate.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (&lt;0.5), standard-low (0.5 to &lt;0.6), standard (0.6 to &lt;0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: &lt;0.5 (n=33), 0.5 to &lt;0.6 (n=131), 0.6 to &lt;0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of &lt;0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients &lt; 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients &lt; 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and &lt; 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients &lt; 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the &lt; 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients &lt; 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p&lt;0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p&lt;0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p&lt;0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, &gt; 1000/uL: 100% vs 57%, &gt; 2500/uL: 73% vs 19% and &gt; 3000/uL: 68% vs 14% (all p&lt;0.001). The absolute risk of Parkinsonism with ALC &gt; 3000 vs ≤ 3000/uL was 12% vs 1%, p&lt;0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p&lt;0.001. On multivariable analysis, peak ALC &gt; 3000/uL (OR: 12.7, p&lt;0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC &gt; 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of &gt; 2500/uL and &gt; 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.