Faculty Bibliography

INTRODUCTION/UNASSIGNED:negative myeloproliferative neoplasm (MPN) driven by recurrent acquired somatic mutations in hematopoietic stem cells and characterized by progressive bone marrow fibrosis, cytopenias, and extramedullary hematopoiesis. Janus kinase inhibitors (JAKi) improve splenomegaly and MF symptom burden but without achieving molecular remission or clear disease course modification. Novel therapies targeting epigenetic dysregulation through bromodomain and extra-terminal domain (BET) proteins have emerged as a key therapeutic approach, aimed at reducing pro-inflammatory and oncogenic transcription to deepen clinical responses in combination with JAKi therapy. AREAS COVERED/UNASSIGNED:This review summarizes the biology, preclinical data, and emerging clinical data in the development of novel BET inhibitor (BETi). Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. EXPERT OPINION/UNASSIGNED:BET protein inhibition is a promising therapeutic target complementing JAK inhibition by co-targeting inflammatory pathways, fibrosis, and clonal proliferation. Pelabresib is a pan-BETi furthest in development demonstrating clinical benefit with ongoing trials. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies is ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.

Idasanutlin is a small molecule inhibitor that restores p53 activity, triggering apoptosis. Two trials (phase 1/2) of idasanutlin therapy in polycythemia vera patients that were intolerant or refractory to hydroxyurea resulted in substantial clinical and molecular responses. Here the long term outcomes of these patients are reported.

Mitochondria are critical cellular powerhouses that produce adenosine triphosphate to maintain the structure and integrity of the cell. Mitochondria generate 90% of the energy of a cell. Chronic inflammation causes damage to mitochondria. When enough mitochondria are dysfunctional, the involved organ will suffer. Mitochondria become dysfunctional in the setting of chronic inflammation. Under noninflammatory conditions, the body generates new mitochondria (mitochondrial biogenesis) and removes old and damaged mitochondria via mitophagy. When mitochondria are damaged, they "spontaneously" leak out reactive oxygen species, mitochondrial DNA, and damage-associated molecular patterns, generating erroneous innate immune responses. Autophagy is a recycling and housekeeping process that removes dysfunctional components, organelles, and proteins, promoting the recovery and maintenance of cell health. Mitophagy is a specific variant of this process that removes dysfunctional mitochondria from the cell. Mitophagy declines with age, allowing dysfunctional mitochondria to accumulate, and chronic inflammation leads to cardiovascular disease (CVD). In CVD, impairment of both autophagy and mitophagy leads to more chronic inflammation, characterized by hyperactivation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a key component of the immune system. Once activated, it triggers inflammation, leading to excessive cytokine activity, proinflammatory macrophage polarization, pyroptosis, and increased immune cell infiltration into cardiac and vascular tissues. Pyroptosis is a form of inflammatory cell death triggered by programmed cues; however, in autoimmunity and cancer, when overactivated, this process can become detrimental. Adequate regulation of these events reduces oxidative stress, inflammatory cascades, fibrosis, and maladaptive remodeling, thereby improving overall cardiovascular health. Targeted therapeutic enhancement of autophagy and mitophagy represents a promising strategy to modulate immune-driven pathology and improve outcomes in cardiovascular conditions. We will review the mechanisms of how this inflammation causes CVD.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

BACKGROUND:Parents in the United Kingdom seeking an assessment for attention-deficit/hyperactivity disorder (ADHD) for their child experience a significant wait before receiving an appointment with Child and Adolescent Mental Health Services (CAMHS), yet little has been written on how parents experience this period. Through qualitative interviews, we sought to understand how the period of waiting from being accepted onto a service waitlist and receiving a diagnostic assessment impacts parents and their children. METHOD:The study was nested within a large randomised controlled trial. We conducted semi-structured interviews with 41 parents of children aged 5-11 years. 30% of parents had waited between 18 and 24 months on a CAMHS waitlist, with 10% waiting more than 2 years. Reflexive thematic analysis was used to analyse data. RESULTS:At the point of the interview, around 50% of children were still waiting for an initial assessment. Six themes reflecting parents' uncertainty around the assessment process, lack of communication from services, the importance of receiving a diagnosis, difficulty accessing support and the negative impact of waiting on mental health and education, as well as recommendations to improve communication between services and families, emerged. CONCLUSION:Parents recognised the pressures on services to offer timely support; however, their well-being could be substantially improved by more clarity around wait times, as well as more effective signposting and support from services concerning the assessment process. This may help alleviate some of the stressors associated with their child's assessment journey, such as feeling responsible for their child's difficulties and the burden of supporting their educational needs. PATIENT AND PUBLIC CONTRIBUTION:This study was nested within the OPTIMA trial, where PPI panel members provided ongoing support in various aspects of the study, including advising on participant communication, study design and data analysis. All PPI members have lived experience of having a neurodivergent child. For this study, the PPI co-produced the interview schedule and took part in transcript analysis using a thematic framework approach. To acknowledge their contributions, members of the PPI panel are included as co-authors.

Background Obesity is a global epidemic. The prevalence of obesity has significantly increased in recent decades and is expected to impact a large portion of the US population. Hypertension continues to be one of the most common complications associated with obesity, and the overlap between these two conditions has been growing over time. However, mortality trends in patients with obesity and hypertension have not been investigated in the literature. Objectives This study aimed to investigate mortality trends, stratified by sex, race, age groups, and geographic distribution, in the US population between 1999 and 2020. Methods Death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) were examined and analyzed between 1999 and 2020 for patients with obesity and hypertension as the contributing causes of death. The age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) per 100000 people were calculated by sex, race, age group, and geographic region. Results Among individuals aged ≥15, a total of 294854 deaths occurred in individuals with obesity and hypertension between 1999 and 2020. The overall AAMR increased from 1.08 in 1999 to 12.14 in 2020. The AAMR has steadily increased since 1999, with a sudden spike occurring between 2018 and 2020 during the COVID-19 pandemic. This trend has been observed across nearly all variables analyzed in our study. Our results exhibited a 28% increase in mortality related to obesity and hypertension during the early years of the COVID-19 pandemic. During the study period, men had a higher overall AAMR than women (men, 5.92; women, 4.32). Mortality was highest among the 55-74-year-old age group, followed by the 75-plus-year-old, 35-54-year-old, and finally 15-34-year-old age groups, which displayed the lowest AAMR (AAMR: 55-74, 11.76; 75+, 10.83; 35-54, 4.73; and 15-34, 0.54). Among the races, non-Hispanic (NH) Blacks had the highest overall AAMR (9.81), followed by NH American Indians or Alaskan Natives (6.01), NH Whites (4.64), Hispanics (4.08), and NH Asians or Pacific Islanders (1.17). However, NH Whites showed the highest average APC (AAPC) (11.44), indicating a possible future shift in mortality. By geographic region, the Southern United States had the highest AAMR, followed by the Western, Midwestern, and Northeastern regions. Non-metropolitan areas had consistently higher obesity- and hypertension-related AAMRs (5.63 overall) compared to metropolitan areas (4.99 overall). Conclusion In our retrospective analysis of death certificate data from 1999 to 2020, we found that age-adjusted mortality rates among individuals with both obesity and hypertension consistently displayed an increasing trend across all demographic groups. The overall rising AAMRs, compounded by the disproportionately high average annual percent changes among White individuals and those aged 15-34, raise serious concerns for the healthcare system. These findings have significant implications for public health policy. Focused interventions are essential to curb the upward trajectory of mortality in this population, as early intervention can greatly help tackle the dual burden of obesity and hypertension, which are largely preventable.

Myeloproliferative neoplasms (MPNs) are a spectrum of clonal hematologic malignancies, characterized by an acquired somatic mutation in hematopoietic stem cells (HSC). Consequent constitutive activation of the JAK/STAT signaling pathway ultimately leads to HSC clonal expansion, a heightened inflammatory state, and aberrant trafficking of the malignant stem cells to sites of extramedullary hematopoiesis. While polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are distinct disease entities, each with their own diagnostic criteria, risk stratification, and molecular profiles, they share a common pathogenesis and exist on a spectrum, with overlapping clinical features, propensity for thrombohemorrhagic events, and risk for transformation to acute leukemia. Interferon alpha (IFN-α) has both anti-proliferative and immunomodulatory effects on MPN HSCs, and therefore is an effective treatment modality for PV, ET, and MF. In this review, we discuss the rationale for IFN-α use in MPNs, examine the evidence supporting its use, and convey practical considerations.

Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient's quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.

IMPORTANCE/UNASSIGNED:In a phase 2 randomized clinical trial, high-dose vitamin D3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D3 in patients with metastatic colorectal cancer (mCRC). OBJECTIVE/UNASSIGNED:To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). INTERVENTIONS/UNASSIGNED:mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D3 (8000 IU daily × 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. RESULTS/UNASSIGNED:Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D3 (n = 228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D3 (n = 227) (1-sided log-rank P = .25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P = .12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P = .66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n = 67 [32%] vs n = 62 [30%]) and hypertension (n = 42 [20%] vs n = 49 [23%]) or in incidence of vitamin D-associated toxicities. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Among patients with previously untreated mCRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy plus bevacizumab did not improve PFS. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04094688.