Citations

29 Background: International Medical Graduates (IMGs) comprise over one-third of internal medicine (IM) trainees and practicing oncologists in the United States. We aimed to examine challenges faced by IM IMG residents in pursuing hematology-oncology (HO) fellowship positions. Methods: We conducted a pilot survey using SurveyPluto to assess demographics and evaluate visa related challenges amongst ACGME residents interested in HO. The survey was disseminated through the ASCO IMG Community of Practice (CoP), the Heme-Onc Fellows Mentorship Empowerment (H.O.M.E) group and the IMG Oncologists social media homepage (@IMG_Oncologists). Results: A total of 59 IMG residents completed the survey (20% PGY-1, 36% PGY-2 and 44% PGY-3). The majority of trainees (88%) were from community or university-affiliated community programs. J-1 visa was the most common visa type (67.8%). The visa process was rated as difficult or very difficult by 36% of trainees. Annual visa renewal was required by 51% trainees and 55.9% reported visa related impact on plans for research grant applications (Table). The greatest challenges associated with visa status were disruption of travel plans and inability to unite with family (35.6%); obtaining documentation from home country (33.9%); visa renewal (28.8%) and lack of clarity in visa instructions (27.1%). Among resources that respondents wanted better access to, IMG networking groups (81.4%), legal/financial aids (47.5%), institutional visa seminars (45.8%) and flexibility from their program to visit family overseas (45.8%) were identified as priorities. Conclusions: Visa related barriers pose significant challenges to IMGs interested in HO. Policy changes, advocacy work and additional resources could be beneficial for future IMG oncologists. Challenges associated with visa status for hematology/oncology aspirants. Greatest visa related barriers during training % of respondents (n=59) Documentation from home country 33.9% Disruption in travel plans/ inability to unite with family 35.6% Lack of clarity in renewal instructions/ renewal process post document procurement 55.9% Ability to secure grant affected by visa 22% Non-monetary grant aspects affected by visa 13.6% Did not pursue grants due to visa 20.3% Desired resources during residency Institutional visa seminars 45.8% IMG network groups 81.4% Program flexibility to visit family overseas/ legal and financial aids 45.8%/47.5%

Autosomal dominant polycystic kidney disease (ADPKD) is a predominant genetic disease, which is caused by mutations in PKD genes and is associated with DNA damage in cystic cells. The intrinsic stimulator of interferon genes (STING) pathway is crucial for recognizing damaged DNA in the cytosol, triggering the expression of inflammatory cytokines to activate defense mechanisms. However, the precise roles and mechanisms of STING in ADPKD remain elusive. In this study, we show that Pkd1 mutant mouse kidneys show upregulation of STING, which is stimulated by the DNAs of nuclear and mitochondrial origin. The activation of STING promotes cyst growth through increasing (1) the activation of NF-κB in Pkd1 mutant cells and (2) the recruitment of macrophages in the interstitial and peri-cystic regions in Pkd1 mutant mouse kidneys via NF-κB mediating the upregulation of TNF-α and MCP-1. Targeting STING with its specific inhibitor C-176 delays cyst growth in an early-stage aggressive Pkd1 conditional knockout mouse model and a milder long-lasting Pkd1 mutant mouse model. Targeting STING normalizes mitochondrial structure and function, decreases the formation of micronuclei, induces Pkd1 mutant renal epithelial cell death via p53 signaling, and decreases renal fibrosis in Pkd1 mutant mouse kidneys. These results support that STING is a novel therapeutic target for ADPKD treatment.

Point of care ultrasound (POCUS) has been a constantly evolving and growing tool utilized by emergency medicine and intensive care practitioners. Ultrasound use for the assessment and management of critically ill patients has been available for several decades with the focused assessment with sonography in trauma (FAST) exam being one of the first widely adopted POCUS protocols. This along with other established protocols has made an impact on the care delivered to critically ill patients. This narrative review will cover some of the history of POCUS in the emergency department, brief considerations for machines and infrastructure, and current uses including in trauma, shock/hypotension, cardiac arrest, dyspnea, abdomen, vascular, and procedural guidance. Furthermore, it will provide a review of the evidence supporting its efficacy in managing critically ill patients and future directions.

Acute kidney injury (AKI) is a frequent complication in patients admitted to the intensive care unit (ICU), and it is known as an independent factor for adverse outcomes like increased length of hospital stay, the development of chronic kidney disease (CKD), and increased mortality with the associated high cost to healthcare systems. The use of AKI biomarkers and new tools such as point-of-care ultrasonography (POCUS) to perform a hemodynamic and volume status assessment has made it more feasible to detect or predict kidney damage in a very accurate way, thereby avoiding the progression of AKI. The design and implementation of a nephrology rapid response team (NRRT) should be considered to improve patient outcomes and healthcare costs. In this paper, we provide an overview of the implementation of an NRRT.

Background and Aims: Disruption of the epigenome is a hallmark of human disease, including liver cirrhosis and HCC. While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target frequently mutated genes in HCC, there is an unmet need for novel therapeutics to prevent or reverse liver damage leading to hepatic tumorigenesis, which the epigenome may provide. Approach and Results: We performed genome-wide profiling of DNA methylation, copy number, and gene expression from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contributions of these processes to liver disease progression. We identified epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity is associated with increased gene expression heterogeneity. Cirrhotic regions comprise 2 distinct cohorts—one exclusively epigenetic, and the other where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (eg, HNF1A) and known tumor suppressors (eg, RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in functional screens, supporting their relevance to hepatocarcinogenesis. Moreover, epigenetic heterogeneity hotspots are linked to clinical measures of outcome. Conclusions: Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.

Point-of-care ultrasonography (POCUS) is emerging as a valuable tool in nephrology, providing real-time insights into the etiology of acute kidney injury (AKI). This narrative review explores POCUS applications in AKI, emphasizing its role in diagnostic kidney ultrasound and comprehensive hemodynamic assessments. AKI, prevalent in hospitalized patients, poses significant morbidity and mortality risks. POCUS aids in unraveling AKI’s multifaceted origins, categorizing it into hemodynamic, obstructive, and intrinsic renal causes. We discuss the utility of POCUS in urinary obstruction by identifying hydronephrosis and detecting stones and providing prompt diagnostic assistance. In intrinsic AKI, POCUS has limited utility but can potentially differentiate between acute and chronic kidney disease and identify infectious complications. POCUS-assisted hemodynamic AKI assessment involves thorough evaluation of the cardiac, lung, and end organ venous congestion. As technology advances, the role of POCUS in the diagnosis and management of AKI is likely to increase, offering a portable, cost-effective, and radiation-free bedside diagnostic modality. This also has the potential to improve patient outcomes. However, proper training in techniques of POCUS and an understanding of the limitations of POCUS are essential elements in ensuring its optimal and appropriate use in the right clinical context.

PURPOSE Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536 ) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC. METHODS Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

e23310 Background: Chimeric antigen receptor T-cell therapy (CAR T) is FDA-approved in pts with triple-class exposed (TCE) relapsed/refractory (RR) MM after four or more prior lines of therapy (LOTs). Real-world access to CAR T remains challenging due to manufacturing capacity, financial barriers, and pt fitness. Pts with certain pre-existing comorbidities (e.g., central nervous system disease, heart disease, secondary malignancies) are commonly excluded from clinical trials, including those investigating CAR T. The objective of this study was to identify the factors associated with the use of CAR T in pts with TCE RRMM to better understand the unmet need in this population. Methods: We conducted an observational cohort study using Medicare fee-for-service data; each pt in the CAR T intention-to-treat (ITT) population between 2021 and 2023 was matched to three non-CAR T pts, without replacement. Pts were eligible if they had an initial MM diagnosis, were continuously enrolled, were TCE, and did not receive treatment in a clinical trial. The index date was the ITT date. Baseline characteristics included age, sex, race/ethnicity, census region, three comorbidity indexes (Charlson, Elixhauser, CMS hierarchical condition categories [HCCs]), a claims-based frailty index (CFI), and dual enrollment in Medicare and Medicaid (as a proxy to social economic status [SES]). Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) comparing the characteristics of CAR T vs non-CAR T pts. Results: Seventy-three ITT CAR T pts (nine underwent apheresis but did not receive CAR T) were matched to 219 non-CAR T pts by LOT and index year. Matched pts were treated with varied standard regimens (daratumumab-containing: 63%). Median prior LOTs were similar in the two cohorts (8; range 2–13). Median time from MM diagnosis to index date was 44.6 and 51.9 months for CAR T and non-CAR T pts, respectively. Compared with non-CAR T pts, pts in the CAR T population were younger (aged < 75 years: 59% CAR T vs 36% non-CAR T), less frail (mean CFI: 0.18 vs 0.20) and had higher SES (without dual enrollment in Medicare and Medicaid: 96% vs 81%), but were similar in terms of sex, region, and race/ethnicity. Variation in individual comorbidity prevalence was observed between CAR T and non-CAR T pts. In a multivariable regression analysis, factors strongly associated with lower odds of CAR T use included age ≥75 years (OR 0.29; 95% CI 0.16–0.53), comorbidities (lung/other severe cancers [OR 0.39; 95% CI 0.20–0.74] and chronic obstructive pulmonary disease [OR 0.32; 95% CI 0.10–0.99] defined by HCCs), and SES (OR 0.09; 95% CI 0.02–0.37). Conclusions: Older age, certain comorbidities, and lower SES are associated with lower odds of receiving CAR T in real-world pts with TCE RRMM, demonstrating an unmet need for more accessible and effective treatment options with acceptable safety profiles for these pts.

The primary cilium is a microtubule-based sensory organelle that plays a critical role in signaling pathways and cell cycle progression. Defects in the structure and/or function of the primary cilium result in developmental diseases collectively known as ciliopathies. However, the constituents and regulatory mechanisms of the primary cilium are not fully understood. In recent years, the activity of the epigenetic modifier SMYD3 has been shown to play a key role in the regulation of cell cycle progression. However, whether SMYD3, a histone/lysine methyltransferase, contributes to the regulation of ciliogenesis remains unknown. Here, we report that SMYD3 drives ciliogenesis via the direct and indirect regulation of cilia-associated components. We show that SMYD3 is a novel component of the distal appendage and is required for centriolar appendage assembly. The loss of SMYD3 decreased the percentage of ciliated cells and resulted in the formation of stumpy cilia. We demonstrated that SMYD3 modulated the recruitment of centrosome proteins (Cep164, Fbf1, Ninein, Ttbk2 and Cp110) and the trafficking of intraflagellar transport proteins (Ift54 and Ift140) important for cilia formation and maintenance, respectively. In addition, we showed that SMYD3 regulated the transcription of cilia genes and bound to the promoter regions of C2cd3, Cep164, Ttbk2, Dync2h1 and Cp110. This study provides insights into the role of SMYD3 in cilia biology and suggests that SMYD3-mediated cilia formation/function may be relevant for cilia-dependent signaling in ciliopathies.