Citations

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P < .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.

AbstractBackgroundThe aggregation of α‐synuclein protein, encoded by the SNCA gene, forms Lewy bodies (LBs) in neurons and is a key pathological feature of Lewy body dementia (LBD). Interestingly, the apolipoprotein E gene (APOE), primarily expressed in glial cells, is the strongest genetic modifier for LBD. The ε4 allele of this gene (APOE4) notably increases the risk of LBD. However, the specific mechanisms through which APOE‐regulated glial cells affect α‐synuclein aggregation in neurons are not yet fully understood.MethodTo explore this, we conducted spatial transcriptomics using the 10X Genomics Visium CytAssist platform on Formalin‐Fixed Paraffin‐Embedded tissue slides from the temporal cortex of human LBD brains (N = 4 brains in controls and N = 6 brains in LBD group, with an equal ratio of APOE3/3 and APOE3/4 genotypes). We defined the neuronal layers of the gray matter (Layers 1 to 6, L1‐6) and white matter in each brain based on the gene signature of each spot. We also identified LBs from hematoxylin and eosin (H&E) staining on the same slides, and annotated LB‐positive (LB+), LB‐surrounding and LB‐negative (LB‐) spots in each brain using Loupe Browser. We evaluated SNCA and APOE gene expression in each layer and analyzed cell‐cell communication using the CellChat tool across the layers.ResultWe observed that the SNCA gene was highly expressed in L5, which corresponded to the areas where most LBs were found. Notably, within LB+ spots across all layers, both SNCA and APOE gene expression levels were elevated in APOE3/4 cases compared to APOE3/3 cases. Furthermore, we identified cell‐cell communication networks between LB+ and LB‐surrounding spots, particularly in L4 and L5. These networks were enriched by microglia‐related signaling pathways, including APOE signaling, migration inhibitory factor (MIF) signaling, and colony stimulating factor 1 (CSF1) signaling. Interestingly, APOE3/4 brains exhibited significantly reduced interactions and lower interaction strength in these networks compared to APOE3/3 samples.ConclusionOur findings indicate that impaired cell‐cell communication, such as microglia‐mediated immune responses around LB regions, may be associated with the increased risk presented by the APOE4 allele in LBD brains.

Abstract Extant literature reveals how patients of marginalized social identities, socioeconomic status (SES), and medical experiences – especially patients of color and older adults – are underrepresented in cancer clinical trials (CCTs). Emerging evidence increasingly indicates CCT underrepresentation among patients of lower SES or rural origin, sexual and gender minorities, and patients with comorbid disability. This review applies an intersectional perspective to characterizing CCT representativeness across race and ethnicity, age, sexual and gender identity, SES, and disability. Four databases were systematically queried for articles addressing CCT participation inequities across these marginalizing indicators, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. One hundred one articles were included in a qualitative evaluation of CCT representativeness within each target population in the context of their intersectional impacts on participation. Findings corroborate strong evidence of CCT underrepresentation among patients of color, older age, lower SES, rural origin, and comorbid disabling conditions while highlighting systemic limitations in data available to characterize representativeness. Results emphasize how observed inequities interactively manifest through the compounding effects of minoritized social identity, inequitable economic conditions, and marginalizing medical experiences. Recommendations are discussed to more accurately quantify CCT participation inequities across underserved cancer populations and understand their underpinning mechanisms.

We describe a method that lowers the limit of quantification of a glucagon immunoassay thereby enhancing the ability to differentiate between normal and abnormal α-cell responsiveness to glucagon.

Introduction: Richter transformation is the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma, in patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Transformation into Hodgkin lymphoma (HT) is a rare event and outcomes in pts with this complication in the current CLL/SLL therapeutic era of small molecule inhibitors (SMI; e.g., Bruton tyrosine kinase inhibitors [BTKi] and BCL2 inhibitors [BCL2i]) are unknown. Methods: We conducted a retrospective study of pts from 12 academic centers. Pts with HT who had not previously received chemotherapy for CLL/SLL-directed treatment (tx) were included. Pt, disease, and tx characteristics were collected. HT was categorized into 3 groups: “Concurrent HT,” defined as HT and CLL/SLL diagnosed simultaneously (within 3 months); “HT without prior CLL/SLL tx,” defined as HT and CLL/SLL diagnosed >3 months apart with the CLL/SLL never treated; and “HT with prior non-chemotherapy tx for CLL/SLL” defined as having received non-chemotherapy CLL/SLL-directed tx prior to the diagnosis (dx) of HT. Overall survival (OS) was measured from HT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: Within a total cohort of 402 pts with Richter transformation (all histologies) without prior chemotherapy, 41 pts with HT (10%) were identified: 12 with concurrent HT, 10 with HT without prior CLL/SLL tx, and 19 with HT with prior non-chemotherapy tx for CLL/SLL. The median age at CLL/SLL dx was 62 years (range 31-96 years) and 73% were male. At CLL/SLL dx, 67% (14/21 evaluated) had unmutated IGHV, and 24% (8/34 evaluated) had TP53 disruption (del(17p) and/or TP53 mutation). The median age at HT dx was 65 years (range 31-96 years) among all pts. At HT dx, there was no significant difference in highest SUV on PET (median 12.3, range 3-31.1), lactate dehydrogenase (LDH) level (median 242 U/L, range 112-859 U/L), or lymph node longest diameter (median 4.6 cm, range 1.6-25 cm) among the 3 subgroups. The median time from CLL/SLL dx to HT dx was 5.4 years (range 0.3-16.5 years) in pts with HT without prior CLL/SLL tx and 4.2 years (range 0.5-17.3 years) in pts with HT with prior non-chemotherapy tx for CLL/SLL. The median number of prior non-chemotherapy CLL/SLL-directed tx was 1 (range 1-6) and included BTKi only (n=17) and BTKi and BCL2i sequentially (n=2); no patient had received only prior BCL2i. Among the 19 pts with HT with prior non-chemotherapy tx for CLL/SLL, 18 pts were on active tx at time of dx (17 BTKi, 1 BCL2i). Initial HT management included: doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; n=16), brentuximab vedotin (BV)-AVD (n=10), radiation only (n=2), other systemic tx (n=11), and supportive cares / hospice (n=2). All but 1 of the 11 other systemic tx were various HL tx regimens. Across all pts with available data (n=32), the overall response rate to 1st line HT tx was 78% (69% complete response rate); 13% had progressive disease and 9% (n=3; all with concurrent HT) died within 6 months without formal response assessment. A total of 11 pts received at least 1 additional line of therapy for HT, which included BV (n=4), an immune checkpoint inhibitor (n=1), or both (n=6) at any point beyond 1st line HT tx. Median follow-up from HT dx was 32.8 months (range 2.4-253.8 months). The 36-month OS for the entire cohort was 75% (95% CI: 55-87%). The 36-month OS estimates by subgroups were: 62% (95% CI: 26-84%) in pts with concurrent HT, 100% in pts with HT without prior CLL/SLL tx (no events by 36 months), and 67% (95% CI: 33-87%) in pts with HT with prior non-chemotherapy tx for CLL/SLL. Exploratory univariable analysis identified TP53 disruption at CLL dx (HR 12.36; 95% CI: 2.55-59.84) and lymph node longest diameter (HR 1.32 per 1 cm increase; 95% CI: 1.12-1.55) and LDH 2-fold increase (HR 3.97; 95% CI 1.24-12.68) at HT dx as prognostic for worse OS. HT subgroup was not prognostic. Conclusions: This is the largest report of outcomes in pts with CLL/SLL who develop HT following SMI tx without any prior chemotherapy, representing a contemporary cohort. Prior CLL/SLL tx status was not associated with OS; however, cautious interpretation is required given the sample size. Our findings support the use of appropriate HL-directed treatment in the setting of HT; however, OS estimates remain worse than would be expected in an older adult de novo HL cohort (Cheng Blood Adv 2022).

Background: Patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase (ASP) based induction therapy have a high risk of venous thromboembolism (VTE). Studies investigating universal thromboprophylaxis strategies have yielded sub-optimal results. Risk prediction models are needed to identify high-risk patients who would be candidates for intensification of thromboprophylaxis, and lower risk patients who are unlikely to benefit. Aims: Derive and externally validate a risk prediction model for VTE in patients with ALL receiving ASP therapy. Methods: We conducted a multicenter, international, cohort study of patients with newly-diagnosed ALL receiving ASP-based induction therapy (≥18yrs). The derivation and external validation cohorts included 306 and 97 patients without VTE prior to ASP therapy, respectively. Patients on therapeutic anticoagulation at index were excluded. Patients were followed from date of first ASP dose for 100 days post ALL diagnosis or until VTE, therapeutic anticoagulation or death. Candidate predictors were documented at ALL diagnosis and included demographics, disease and treatment characteristics, VTE history, comorbidities, thromboprophylaxis, complete blood count, fibrinogen and d-dimer. D-dimer was only analyzed within the 7 derivation cohort centers who routinely tested this at ALL diagnosis with <20% missing values. Primary outcome was VTE at any site (centrally confirmed). Secondary outcomes included major bleeding by ISTH criteria. Cause-specific Cox proportional hazard regression was performed to identify VTE risk factors in the derivation cohort while treating death as a competing event. Variables with p-value <0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value <0.05. Lastly, the derived VTE risk prediction model was tested in the external validation cohort for association with time to VTE using cause-specific Cox proportional hazard model. All analyses were stratified by center and use of low molecular weight heparin prophylaxis (at any dose on the date of first ASP dose). Results: The cumulative incidence of VTE in the derivation cohort was 17% at 30 days (95% confidence interval [CI] 13% - 21%) and 22% at 90 days (95% CI 17% - 27%). The multivariable model included hyperlipidemia (hazard ratio [HR] 1.35; 95% CI 0.56 - 3.27), body mass index ≥ 25 kg/m² (HR 1.49; 95% CI 0.75 - 2.95), platelet count ≥ 25 x 10⁹/L (HR 1.42; 95% CI 0.67 - 3.00), increasing hemoglobin per 1 g/dL (HR 1.17; 95% CI 1.03 - 1.32) and d-dimer ≥ 1 µg FEU/mL (HR 2.68; 95% CI 1.08 - 6.66). Hemoglobin as a continuous variable and d-dimer ≥ 1 µg FEU/mL were included in the final model and used to create a risk score which was weighted by estimated log-HR sum of these risk factors. The lowest risk quartile (risk score below 2.1) successfully differentiated between a lower 30-day cumulative VTE incidence (4%, 95% CI 0.72% - 12%) compared with the other quartiles (20%, 95% CI 14% - 27%; HR 4.40, 95% CI 1.54 - 12.5) which were defined as high risk (score ≥2.1). The risk score's negative predictive value (NPV) for VTE at 30 days was 96% and positive predictive value (PPV) was 20%. The validation cohort (n=97 from 3 external cohorts with routine d-dimer measurement) included 16 (16.5%) patients in the low-risk group and 81 (83.5%) in the high-risk group, with a 30-day VTE incidence of 6.3% (95% CI 0% - 17%) and 21% (95% CI 12% - 30%), respectively (HR 6.22; 95% CI 0.85 - 45.8; p = 0.073)). The NPV (93.7%) and PPV (21%) were comparable to the derivation cohort. The 30-day incidence of major bleeding was 0% (95% CI NR - NR) in low-risk patients (HR 1.36; 95% CI 0.27 - 6.77) and 2.0% (95% CI 0.55% - 5.4%) in the high-risk group. Conclusion: Patients with ALL receiving ASP induction therapy have a 17% VTE risk at 30 days. We derived and externally validated a VTE risk prediction model based upon d-dimer and hemoglobin. This model successfully identifies at least 16.5% of patients with ALL who have a low VTE risk after ASP treatment. Using this model, novel prevention strategies which may be associated with cost and risk could now be tailored to patients with higher risk. Prospective studies are needed to validate the model's performance and role in VTE risk management.

Background: The majority of patients respond to steroid treatment for graft-vs-host disease (GVHD), but the typically high doses and prolonged courses can cause substantial morbidity. GVHD can be classified at onset into two groups with significant differences in treatment response and non-relapse mortality (NRM) by clinical criteria (Minnesota risk) but the more favorable standard risk group still experiences high rates of treatment failure and NRM [MacMillan, BBMT 2015]. We previously validated a serum biomarker-based (ST2+REG3α) risk stratification system, MAGIC algorithm probabilities (MAPs), that can stratify patients both at initiation and during treatment into risk groups for treatment response and NRM [Hartwell, JCI Insight 2017, Srinagesh, Blood Adv 2019]. GVHD that is Minnesota standard risk and has a low MAP (i.e., Ann Arbor 1) at start of treatment represents a low risk group with >80% response rate to steroids and ~10% NRM [Etra, Blood 2023]. We hypothesized that serial monitoring of GVHD symptom severity and MAPs twice (days (d) 7 and 14) in patients with clinical and biomarker defined low risk GVHD could further stratify patients into clinically meaningful groups. Methods: We retrospectively determined MAPs at d7 and 14 in 450 patients with low risk GVHD who participated in a prospective, multi-center, observational trial and were treated with systemic steroids between 2015-2023. MAPs <0.291 at days 7 and 14 were defined as low risk based on a previously validated threshold [Major-Monfried Blood 2018]. Clinical responses were scored as complete (CR), partial (PR), or non-response (NR) by standard criteria. Initiation of second line therapy was considered NR. Patients were categorized into three groups (A-C) based on clinical responses and MAPs at days d7 and 14. A: CR/PR by d14 and low MAP at both d7+14; B: stable or worse GVHD (NR) by d14 with low MAP at both d7 and 14; C: any response with a high MAP at d7 or 14. The endpoints were clinical response at day 28 (overall response rate, ORR=CR or PR), regardless of earlier response status, and 6-month NRM. Results: The median age of the study population was 54 years (range: 0-79); 19% of patients received PT-Cy for GVHD prophylaxis. Target organ involvement was skin ± upper GI (66%), lower GI (23%), isolated UGI (11%), and skin+liver (1%), and GVHD severity was grade I (35%), II (61%), and III (4%) at start of treatment. Patients in group A (n=310, 69%), clinical responders with low MAPs through day 14, had excellent d28 ORR (93%) and very low NRM (4%). GVHD in this group was considered ultra-low risk (ULR) and subset analyses revealed highly consistent d28 ORR and NRM, regardless of target organ severity, age (<18, 18-59, >60), HCT-CI score, conditioning intensity, and GVHD prophylaxis. Group B patients comprised clinical non-responders with low MAPs through day 14 (n=112, 25%); half of them responded by d28 and their NRM was low (8%), albeit double that of group A (p=0.079). Group C was small (n=28, 6%) and included both clinical responders (n=20, 4%) and clinical non-responders (n=8, 2%) who had at least one high MAP through day 14. Their d28 ORR was 54% but NRM increased four-fold (32%) and was significantly worse than patients who maintained low MAPs regardless of clinical response (p<0.001). Conclusion: Serial monitoring by clinical response and biomarkers during the first two weeks of treatment identifies a small number of high risk patients whose GVHD is initially low risk (group C). This group experiences high NRM regardless of clinical response to steroid treatment and may benefit from treatment escalation. Patients with low risk GVHD who do not have an early clinical response to steroids but maintain low MAPs, (group B) have reasonably good long-term outcomes with standard treatment. Finally, serial monitoring identifies a very large subset of patients with ULR GVHD (group A) who respond exceptionally well to standard treatment and experience very low rates of 6-month NRM regardless of pre-transplant characteristics and GVHD prophylaxis. Such patients may benefit from treatment de-escalation strategies such as shorter courses of lower dose steroids, a strategy we are currently testing in a clinical trial (NCT05090384).

Background Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response. Methods The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV). We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196). Results The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p<0.01; MAGIC: 9% vs 37%, p<0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (>80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (<7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%). In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p<0.01; MAGIC: 13% vs 55%, p<0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease. Conclusion We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.