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TPS3650 Background: A total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone in those with locally advanced rectal cancer. Recent data indicate that optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to improve complete response rates. The use of FOLFIRINOX has shown to improve response and outcomes compared to CRT and surgery alone. Data have also shown that patients with clinical complete response (cCR) after TNT may be managed with a watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to improve cCR rates has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. We designed this NCI-sponsored study of chemotherapy intensification to address this and to increase cCR rates, provide opportunity for organ preservation, and survival outcomes. Methods: In this multigroup randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX (control arm)) or triplet chemotherapy (FOLFIRINOX (experimental arm)) for 3–4 months. LCRT in both arms involve 4500 cGy in 25 fractions over 5 weeks +900 cGy boost in 5 fractions with a fluoropyrimidine. Patients will undergo assessment 8–12 (±4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include overall survival, organ preservation time, time to distant metastasis, and adverse event rates. This study has accrued 587 patients as of January 2025, and is investigating exploratory correlatives (e.g., ctDNA). Support: U10CA180821, U10CA180882, U24 CA196171. https://acknowledgments.alliancefound.org. Clinicaltrials.gov ID: NCT05610163. Clinical trial information: NCT05610163 .

Objective Raynaud phenomenon (RP) is often the initial clinical manifestation of systemic sclerosis (SSc), but some patients develop other manifestations first. To help elucidate the diversity of SSc presentation in its early stages, we describe the initial clinical manifestations and antinuclear antibody (ANA) profiles of patients in two early SSc cohorts. Methods All patient data in the Genetics vs Environment in Scleroderma Outcomes Study (GENISOS) and Collaborative National Quality and Efficacy Registry (CONQUER) cohorts were reviewed. Both studies enrolled patients within five years of the first non‐RP symptom. Results In GENISOS and CONQUER, respectively, 194 (44.2%) of 439 and 292 (31.1%) of 938 patients had a non‐RP initial symptom, most commonly puffy fingers/hands. Black patients had a non‐RP symptom before RP more commonly than patients in other race and ethnicity categories. Non‐RP first patients were more likely than RP first patients to have diffuse cutaneous involvement and joint contractures at enrollment and had a higher prevalence of RNA polymerase III antibody positivity. Conclusion In two large US cohorts, >30% of patients began to manifest SSc with puffy fingers/hands or other symptoms, without the “warning sign” of RP as their initial symptom. These patients presented with more severe skin and musculoskeletal disease on average, highlighting the importance of early recognition. The most common autoantibody associated with this presentation was RNA polymerase III. These results should be considered in efforts to recognize SSc in its earliest stages. Puffy fingers/hands, even in the absence of RP, should prompt consideration of early SSc and testing for ANA and SSc‐associated autoantibodies, including RNA polymerase III.

Abstract Introduction: Trastuzumab emtansine (T-DM1) is a standard therapeutic agent for advanced stages of HER2-positive breast cancer, known to improve survival rates. However, it is associated with side effects including fatigue, anemia, and mild-to-moderate bleeding. We present a rare case of pulmonary arteriovenous malformations (PAVMs) potentially linked to T-DM1 therapy, with clinical manifestations resembling hereditary hemorrhagic telangiectasia (HHT). Case Presentation: A 57-year-old female presented with chronic hypoxia on 3 L/min nasal oxygen. Her history included two years of worsening exertional dyspnea and hypoxemia during T-DM1 therapy for HER2-positive breast cancer, diagnosed 10 years earlier. She underwent bilateral mastectomy and was treated with T-DM1 and anastrozole. Echocardiography suggested a right-to-left shunt, while right heart catheterization excluded pulmonary hypertension. Subsequent CT angiography revealed small peripheral PAVMs, confirmed by Tc-99m MAA scintigraphy with a 30% right-to-left shunt. Lab results showed PaO2 at 52 mmHg, HCO3 at 20.3 mmol/L, O2 saturation at 86.4%, and PCO2 at 31 mmHg. Pulmonary function tests indicated restrictive lung volumes and severe diffusion impairment (FVC: 2.66 L, FEV1: 2.06 L, FEV1/FVC: 77.5%, TLC: 3.99 L, DLCO-SB: 20.7% predicted). Following discontinuation of T-DM1, patient experienced slight improvement in telangiectasias and dyspnea over three months but continued to require 10-15 L/min of oxygen during exertion. Arterial blood gas analysis showed a PaO2 of 56.4 mmHg, HCO3 of 20.7 mmol/L, resting O2 saturation of 88.4%, PCO2 of 26.8 mmHg, and PaO2 of 180.9 mmHg on 100% oxygen via a non-rebreather mask, indicating a persistent right-to-left shunt. Discussion: Arteriovenous malformations (AVMs) are abnormal artery-vein connections linked to HHT, with PAVMs present in 80-90% of HHT cases, leading to right-to-left shunts. This patient's prolonged T-DM1 therapy appears associated with PAVMs and HHT-like symptoms. While T-DM1 has been linked to pulmonary and portal hypertension, as well as cerebral AVMs, this is the first report associating it with PAVMs, possibly through disruption of endothelial function and HHT pathways like ALK1 and ENG. Diagnosing PAVMs can be challenging due to their often-asymptomatic nature; however, in this case, they were identified through repeated CT imaging and Tc-99m MAA scintigraphy. Embolization, a typical intervention for PAVMs, was not feasible due to the small size of the malformations. The patient's condition improved after discontinuing T-DM1, suggesting a potential link between the drug and PAVMs. Understanding the mechanisms by which T-DM1 induces vascular abnormalities is crucial for developing targeted interventions and improving patient outcomes.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

Abstract Glioblastoma (GBM) is a deadly brain cancer with near-universal recurrence despite maximal treatment for which new innovations are sorely needed. Immunotherapy has yet to make significant gains in GBM treatment despite revolutionizing other cancer therapies, due in part to GBM-mediated immune suppression. This immune derangement proceeds through several mechanisms, but increasing evidence points to critical roles for tumor-derived extracellular vesicles (EVs) and immunosuppressive myeloid cells as key factors in this process. In the present study, we demonstrate broad expression of TIGIT across myeloid cell populations in the GBM microenvironment, a finding recapitulated by conditioning healthy monocytes with GBM-derived EVs. Further, knockdown of TIGIT expression reduced the immunosuppressive polarization of monocytes, resulting in improvement in T cell function. This finding proceeded in an NLRP3-dependent manner, with substantial co-localization of TIGIT and NLRP3 expression prior to knockdown. These findings point to a novel role for TIGIT expression in diverse myeloid cells in the GBM microenvironment as a marker of immunosuppressive activity and further indicate a hierarchy of immunomodulatory protein activity in these myeloid cells, with TIGIT knockdown unmasking the pro-inflammatory activity of NLRP3. This study bolsters understanding of the immunosuppressive complexities of myeloid cells in the GBM microenvironment, while lending further support to prevention or attenuation of immunosuppressive myeloid cell activity as a means of restoring immune function in GBM. Graphical abstract (Created in BioRender. Asad, M. (2025) https://BioRender.com/euiljoq Key Points Tumor-mediated immune suppression is a key barrier to the development of effective immunotherapies for GBM. TIGIT is broadly expressed in myeloid cells within the GBM microenvironment and can be induced by GBM-derived extracellular vesicles. Knockdown of TIGIT reduces immunosuppressive polarization of monocytes and enhances T cell activity via NLRP3 signaling, implicating TIGIT expression as a targetable modifier of immunosuppressive activity in GBM-associated myeloid cells. Importance of the Study Glioblastoma (GBM) remains a formidable clinical challenge, with poor prognosis and limited response to current immunotherapies. This study uncovers a novel immunosuppressive axis involving TIGIT expression in myeloid cells, which are key players in the GBM tumor microenvironment. By demonstrating GBM-derived extracellular vesicles induce TIGIT in healthy monocytes and TIGIT knockdown diminishes immunosuppressive polarization in an NLRP3-dependent manner, this study highlights TIGIT as both a marker and modulator of immune dysfunction in GBM. These findings introduce a functional hierarchy of immunoregulatory proteins in tumor-associated myeloid cells, positioning TIGIT as a potential checkpoint target. Restoring immune activity by disrupting this axis could enhance the efficacy of immunotherapy in GBM. Thus, this research not only advances our understanding of tumor-induced immune suppression but also opens a promising therapeutic avenue to reinvigorate anti-tumor immunity in a cancer type historically resistant to immunotherapeutic approaches.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

ABSTRACTBackgroundDrug‐induced hypersensitivity syndrome (DiHS), or drug reaction with eosinophilia and systemic symptoms (DRESS), is a delayed and severe immune response to certain medications. We investigated vancomycin‐induced DiHS/DRESS, notable for frequent and severe organ involvement, to describe its specific histopathology and the correlations between histopathologic and clinical findings.MethodsA retrospective review was conducted to identify patients between 2006 and 2022 who received vancomycin, had archived skin biopsy specimens, and were scored as having probable or definite DiHS/DRESS. Clinical features were retrospectively collected, and biopsy specimens were reviewed by a board‐certified dermatopathologist. A subset of histopathologic and clinical features was analyzed for statistical correlation.ResultsTwenty‐three patients met the inclusion criteria. Most biopsy specimens (87%) showed an eczematous reaction pattern; 17 (74%) showed a secondary reaction pattern. Spongiosis (87%) and neutrophilic infiltration (91%) were common epidermal characteristics. The dermal inflammatory infiltrate was frequently superficial (87%) and consistently included plasma cells (96%). Eosinophils were present in the dermis in 70% of cases. Parakeratosis negatively correlated with liver involvement and positively correlated with desquamative rash. Epidermal lymphocytes were negatively correlated with the RegiSCAR score.ConclusionsVancomycin‐associated DiHS/DRESS histopathology was characterized by a frequent eczematous reaction pattern, multiple coexisting reaction patterns, and epidermal neutrophilic infiltration.

Abstract Background The treatment of locally advanced rectal cancer now includes “watch-and-wait” (WW) management for patients who exhibit a clinical complete response (cCR) to total neoadjuvant therapy (TNT). We assessed patients’ knowledge and preferences regarding WW with the goal of incorporating patient input into clinical trial design. Methods Rectal cancer patients in advocacy groups (COLONTOWN/Rectalburgh and Fight CRC) were surveyed regarding perceptions about treatment strategies, tolerable risks of treatment failure, and preferences on clinical trial design. Surveys were initially distributed in 2019, with the shift toward WW prompting re-survey of select questions in 2023. Results All respondents preferred enrollment in trials that incorporated patient input. Most respondents (76%) preferred treatment that incorporated chemotherapy escalation over radiation escalation. Furthermore, when presented with a hypothetical patient who developed a cCR after chemoradiation (without the option for WW), 58% of patients chose surgical treatment (with 100% risk of permanent ostomy and 80% chance of cure) over omission of surgery (with <80% chance of cure). In contrast, when the hypothetical patient developed a cCR after TNT (with an option for WW), 82% of patients opted for selective WW over surgery. Conclusions This work successfully integrated patient advocacy groups as a resource for obtaining patient input. Surveys revealed patients had a strong preference for chemotherapy escalation, for selective WW when offered, and for incorporation of input into future clinical trial design. These findings describe how well-informed patients approach complex medical decision-making and serve as a starting point for future studies seeking to incorporate patient voices.