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Abstract Background Talquetamab (talq) is a GPRC5D-directed bispecific antibody (BsAb) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). The pivotal monumenTAL-1 clinical trial did not include patients with renal impairment (RI, creatinine clearance<40 mL/min) and therefore, data for the use of this agent in RI is lacking. Methods We examined the outcomes of patients with RRMM treated with standard of care (SOC) talq in a multicenter, retrospective cohort study. RI was defined as creatinine clearance (CrCl) <40 mL/min. For each patient we recorded demographics, disease characteristics, prior therapies, incidence and severity of adverse events of special interest, namely cytokine release syndrome (CRS) and immune-cell associated neurotoxicity syndrome (ICANS), along with response, progression-free (PFS) and overall survival (OS). We compared binary variables between different groups using Chi-squared test and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards models. Patients who received talq as a bridge therapy prior to chimeric antigen receptor T-cells (CART cells) were censored for PFS analysis at the time of subsequent therapy. Results We included 417 patients who received SOC Talq and had complete datasets. 91 (22%) had RI, including 20 (5%) on dialysis. The median age was 68 and 65 years for patients with and without RI. Patients with RI were more likely to be female (64% vs. 51%), less likely to have prior CART cells (35% vs. 48%). There were no differences in performance status, race, presence of high-risk cytogenetic abnormalities [del17p, t(4;14), t(14;16), gain/amplification 1q], lines of prior therapy (median 6 vs. 6), prior ASCT (68% vs. 72%), presence of CNS disease (4% vs. 4%), prior plasma cell leukemia (8% vs 9%), prior BCMA therapy (54% vs. 61%) and triple class refractory disease (90% vs. 94%) among patients with and without RI. Rates of CRS (63% vs. 56%, P=0.21) were similar in the two groups, while severe CRS (grade ≥3: 6% vs 2%, P=0.02) was more common in patients with RI. Any grade (20% vs 14%, P=0.21) and high grade ICANS (grade ≥3: 4% vs 4%, P=0.97) were similar in patients with and without RI. There was no difference between groups on risk of infection (P=0.65) with cumulative risk at 6 months of 39% vs. 40%. With 11.1 months of median follow up, the overall response rate (60% vs 67%; P = 0.12), and progression-free survival (median 7.3 vs. 6.5 mo.; P = 0.9) were comparable between the two groups. There was no difference in outcomes according to RI in both patients previously treated with BCMA-directed therapy and BCMA-naïve. Conversely, among patients with RI, median PFS was 4.6 and 8.5 mo. for patients with and without prior BCMA therapy. Similarly, among patients without RI, median PFS was 6.5 and 6.2 mo, respectively. Among BCMA-naïve patients, there was no difference in OS between patients with and without RI (median not reached, 12 mo. OS rate 71% vs. 73%, P=0.53), while among patients with prior BCMA-directed therapy there was a trend towards better OS for patients without RI (median 8.9 vs. 13.8 mo; 12 mo. OS rate 43% vs 59%, P=0.06). Five patients (25%) became dialysis independent following talq therapy. On multivariable analysis, ECOG >1 (HR 1.62, 95% C.I. 1.25-2.10, P<0.001) and deletion of 17p (HR 1.55, 95% C.I. 1.17-2.06, P=0.003) but not RI or prior BCMA-directed therapy affected PFS. OS was affected by ECOG >1 (HR 2.37, 95% C.I 1.71-3.30, P<0.001), triple-class refractoriness (HR 3.03, 95% C.I. 1.12-8.21, P=0.03) and prior BCMA-directed therapy (HR 1.79, 95% C.I. 1.24-2.59, P=0.002) but not by RI. Conclusion Our findings support the feasibility of talq in patients with RI, including those on dialysis, with similar safety and efficacy profile to patients without RI. While neither prior BCMA-directed therapy nor RI affect PFS, refractoriness to conventional agents and prior exposure to BCMA-directed therapy adversely affects OS. This observation likely reflects better post progression survival following talq due to the availability of efficacious therapeutic options, including those directed at BCMA.

Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Abstract Cardiac involvement in AL amyloidosis significantly impacts both short and long-term survival. Achieving cardiac complete response (CarCR) is linked to excellent survival, comparable to that of the general population. We undertook this study to characterize patients with AL amyloidosis who achieved CarCR. Methods: A single-center retrospective study of patients diagnosed with cardiac AL amyloidosis between 2004 and 2023 and achieved a documented CarCR for at least 12 months. Patients were included if they had evidence of cardiac involvement confirmed by cardiac imaging (transthoracic echocardiogram or cardiac magnetic resonance) and Congo red–positive tissue (non-cardiac or heart biopsy), and were evaluable for cardiac response based on baseline NT-proBNP > 650 pg/mL or BNP > 150 pg/mL. CarCR was defined as a reduction in NT-proBNP to less than 350 pg/mL (or BNP less than 80 pg/mL). Heart transplant patients were excluded. Results: Sixty-three patients were included, representing 4.6% of the cardiac evaluable population in the study period. This proportion increased in the second period compared to the first period (7.5% vs 3.2%, P<0.001). The median age at diagnosis of 57 years (ranging from 29 to 79); 63% were male. Lambda light chain disease was evident in 63% of patients. The median difference between the involved and uninvolved light chain (dFLC) at baseline was 429 mg/L (interquartile range [IQR] 143-708). While all patients had cardiac involvement, 63% also presented with extra-cardiac involvement [kidneys (52%), liver (16%), autonomic nerves (14%), luminal gastrointestinal tract (11%), and peripheral nerves (10%)]. The median baseline NT-proBNP for the entire cohort was 1977 pg/mL (IQR 1393-3026). The median troponin T (n=43) was 0.02 ng/mL (IQR <0.01-0.05) and the median high-sensitivity troponin T (n=19) was 49 ng/L (IQR 38-79 ng/L). Cardiac stage distribution, according to the European modification of the Mayo 2004 staging model, was as follows: 59% stage II, 39% stage IIIa, and 2% stage IIIb. At baseline, echocardiogram features included a median left ventricular (LV) ejection fraction of 63%, a median intraventricular septum thickness of 14 mm, and a median average LV longitudinal strain of -12%. The most common first-line therapies were autologous stem cell transplantation (ASCT; with or without induction, 54%), bortezomib-containing therapy (22%), and daratumumab-containing therapy (13%). Hematological complete response rates at 3-month, 6-month, and best response prior to CarCR were 32%, 49% and 76%, respectively. At CarCR, the median NT-proBNP was 265 pg/mL (IQR 220-307) with a median time from treatment onset to CarCR achievement of 20.6 months. At CarCR, 33% of patients were on loop diuretics. The CarCR rate at 6, 12, 24, 36, 48 and 60 months from treatment onset was 10%, 39%, 81%, 90%, 95% and 96%, respectively. Temporary increase of NT-proBNP above 350 pg/mL with return to CarCR was documented in 46% of patients. Echocardiogram parameters also improved significantly at the time of CarCR, with average left ventricular longitudinal strain showing the greatest median improvement in relation to baseline (from -12% to -17%, p<0.001). However, echocardiographic parameters did not fully normalize in all patients. Cardiac progression was seen in 14% of patients, at a median of 7.6 years from the initial time of CarCR. In addition, subsequent clone-directed therapy was given in 44% of patients at a median of 4.6 years from the initial treatment. With a median follow-up of 9.5 years, eight patients (13%) died, 4 due to causes unrelated to AL. We compared the survival of patients who achieved CarCR to the general U.S. population, matching for age, sex, and the year treatment. The observed survival of CarCR patients was similar to that of the general population (p=0.35). Conclusion: Patients with persistent CarCR >12 months in AL amyloidosis are uncommon and demonstrate excellent outcomes. The achievement of hematological CR was required in 3 out of 4 patients reaching a CarCR. Echocardiographic changes of amyloid infiltration may still persist in this highly favorable cohort, indicating that “complete” response refers primarily to functional and prognostic improvement, not necessarily a full restoration to pre-disease cardiac morphology and function. Achieving CarCR is associated with a low risk of cardiac progression, but the need for subsequent clone-directed therapy remains elevated.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains among the most aggressive cancers, due to its limited therapeutic options and poor prognosis. Even with the adoption of total neoadjuvant therapy (TNT) and potentially curative surgical resection, PDAC relapse rates remain unacceptably high. Current systems for evaluating tumor response are valuable but limited, as they fail to capture the ecological complexity and broader architecture of the tumor microenvironment (TME). This results in uncertainty regarding the prognosis and recurrence risk of patients. To address this and to capture the complexity of the PDAC TME, we developed the Tumor Landscape Analysis (TLA). Using digitized H&E slides from 203 PDAC patients who received TNT and surgical resection at our institution, we applied a machine-learning pipeline to segment tumor and stromal compartments. We then quantified the TME architecture using ecological frameworks to assess the disease in multiple scales: individual patches, whole-slide landscapes, and aggregated patient-level summaries. Our analysis revealed that higher-order spatial features are independently prognostic of disease-free survival (DFS). Two statistical models showed different but complementary spatial characteristics that predict disease risk. In the first model, patients with more irregular cancer patch shapes and lower variability in stromal shape had significantly better DFS, with high-risk patients relapsing in a median of 7.2 months compared to 11.6 months in the low-risk group (HR=1.82, p=0.0003). In the second model, smaller stromal patch areas combined with greater tumor-stroma edge density identified patients at elevated risk, with high-risk individuals showing a median DFS of 8.0 months versus 15.7 months in low-risk patients (HR=1.73, p=0.0007). Importantly, these associations persisted even after adjustment for the T and N stage, showing that spatial features provide unique information beyond traditional pathology measures. These models help visualize PDAC as a comprehensive ecosystem that carries clinical significance. By quantifying tumor conformation and configuration, our models reveal prognostic information not available through CAP grading, percent tumor burden, or routine cell counts. This study suggests that tumor-stroma interactions and their spatial organizations are potentially biologically important for recurrence. We present a new, ecologically inspired approach to digital pathology for PDAC that not only improves our ability to predict recurrence and survival in PDAC but also sheds light on cancer as a complex, evolving ecosystem. Citation Format: Merih D. Toruner, Luis H. Cisneros, Miranda Lin, Andrea Maraone, Carlo Maley, Paul Dizona, Qian Shi, Martin E. Fernandez-Zapico, Ryan M. Carr. Ecological landscape analysis of the tumor microenvironment predicts recurrence risk in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B027.

Abstract Computational analysis of speech enables precise, objective measurements of a behavioral signal closely linked to manic episodes. In a prospective cohort study conducted in Rochester, MN ( ClinicalTrials.gov Identifier: NCT05956340 ) , eighteen English-speaking adults voluntarily hospitalized for a manic episode of Bipolar I Disorder between August 2023 and September 2024 were enrolled. Participants completed semi-structured research interviews during both acute episodes and remission, with manic symptom severity assessed at each session using the Young Mania Rating Scale (YMRS). Across 57 recorded interviews, temporal prosodic features were extracted using automated computational algorithms. After adjusting for individual differences and moderating effects, participant articulation rate (β = 0.24, p = 0.0038), speech rate variability (β = 0.23, p = 0.0041), floor transfer offset (β = -0.31, p = 0.007), and speaking duration (β = 0.54, p < 0.001) were significantly associated with manic symptom severity. These temporal elements classified manic (CV AUC = 0.85) and remission (CV AUC = 0.83) status, highlighting their potential as monitoring and prognostic biomarkers for manic episodes.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.