Citations

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10 9/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality. Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC >1.5 x 10 9/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or >5% but <20% in the marrow). Patients with acute myeloid leukemia were excluded. Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range <1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p<0.001, Fisher's exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1:: PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in >50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in <15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2). Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

AbstractThough survival outcomes among adolescents and young adults (AYAs) with lymphoma have improved over the last three decades, socially vulnerable populations including non‐White, low‐income, and publicly insured groups continue to trail behind on survival curves. These disparities, while likely the result of both biological and non‐biological factors, can be largely attributed to inequities in care over the full cancer continuum. Nationally representative studies have demonstrated that from diagnosis through therapy and into long‐term survivorship, socially vulnerable AYAs with lymphoma face barriers to care that impact their short and long‐term survival. Thus, improving outcomes for all AYAs with lymphoma requires dedicated study to understand, and then address the unique challenges faced by non‐White and low‐income lymphoma populations within this age group.

AbstractThe goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event‐free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high‐risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early‐stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.

Abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.