United States

Precise genome engineering of primary human T cells is critical for the development of adoptive immunotherapies. However, conventional Cas9 homology-directed repair (HDR) strategies are inefficient in naïve T cells and carry risks associated with double-strand break toxicity, limiting their therapeutic utility. To address this challenge, we explored Cas9D10A, a double-nickase variant, as an HDR-independent knock-in platform, successfully creating a construct. Guide RNAs were designed, cloned, and electroporated into both naïve and activated human T cells. Knock-in efficiency was quantified using flow cytometry to detect GFP and tNGFR expression. Editing was achieved with 1 of 6 gRNAs tested, and IS2(9) supported dual reporter expression in both activated and naïve subsets. These results provide proof-of-concept that Cas9D10A nickase can effectively edit naïve T cells, a population notoriously resistant to efficient modification. By bypassing HDR dependence, this platform offers a safer and more versatile approach for genome engineering, with potential to expand the scope of adoptive T-cell therapies.

AMA Research Challenge 2025 

Creating an HDR Independent Cas9D10A Nickase to Induce Knock-In
Mutations in T-Cells

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Advances in neuro-oncology have transformed the diagnosis and management of brain tumors, which are among the most challenging malignancies due to their high mortality rates and complex neurological effects. Despite advancements in surgery and chemoradiotherapy, the prognosis for glioblastoma multiforme (GBM) and brain metastases remains poor, underscoring the need for innovative diagnostic strategies. This review highlights recent advancements in imaging techniques, liquid biopsies, and artificial intelligence (AI) applications addressing current diagnostic challenges. Advanced imaging techniques improve the differentiation of tumor progression from treatment-related changes. Additionally, novel positron emission tomography (PET) radiotracers, such as 18F-fluoropivalate, 18F-fluoroethyltyrosine, and 18F-fluluciclovine, facilitate metabolic profiling of high-grade gliomas. Liquid biopsy, a minimally invasive technique, enables real-time monitoring of biomarkers enhancing diagnostic precision. AI-driven algorithms improve accuracy, reduce interobserver variability, and accelerate clinical decision-making.

Modernizing Neuro-Oncology: Impact of Imaging, Liquid Biopsies, and AI on Diagnosis and Treatment

Background
The tibia is known to be the main weight-bearing bone of the leg, with the fibula supporting this function and providing an attachment point for various muscles. However, the precise biomechanical consequences of this functional specialization are poorly understood. We conducted a three-dimensional analysis to quantify the cross-sectional geometry of the central diaphyses in paired tibiae and fibulae to determine if proximodistal variation in mechanical stiffness is correlated between these bones. We hypothesize that the fibula compensates for resistance to bending in areas where the tibia is particularly weak and/or thin. This information can help to explain certain fracture patterns that are commonly seen by orthopedic physicians.

Methods
The CT data from 10 deceased individuals were obtained with permission from the New Mexico Descendent Image Database. CT data from the left leg of each donor were cropped, and the cortical bone was segmented to generate digitized periosteal and endosteal surfaces of both the tibia and fibula. We used these to quantify cross-sectional parameters across 30 equidistant slices taken from the central diaphysis of each bone. This data was then analyzed using the Morphomap cross-sectional geometry package in R. Non-parametric correlations were measured between resistances to mediolateral and anteroposterior bending, longitudinal twisting, and mean diaphyseal thickness and cortical area. 

Results
We found that tibial cortical area was weakly positively correlated with body mass and height, and strongly negatively correlated with age. Comparing the cross-sectional properties of coplanar sections of the tibia and fibula, we found that all second moment of area measurements in the tibia were negatively correlated with cortical area and mean thickness of the fibula. Resistances to mediolateral bending and axial torsion were also found to be inversely proportional between both bones. Generally, the diaphyseal cortical bone of the tibia becomes thinner distally, while the diaphysis of the fibula is thickest in the middle and is at its thinnest proximally and distally. 

Conclusion
These results support the hypothesis that the fibula partially compensates for the reduced bending resistance of the tibia in regions where the tibial cortical bone is particularly thin and/or weak. These data inform functional hypotheses of the fibula and can help explain the mechanism of certain breakage patterns in fractures involving the distal lower limb.

Analysis and Clinical Interpretation of Correlated Cross-sectional Properties of the Tibia and Fibula

BACKGROUND: Approximately 7-25% of grade 1 meningiomas recur, indicating a need for additional criteria for appropriate risk stratification. The growth and development of meningioma are closely linked to its molecular profile. Notably, homozygous CDKN2A/B deletions are associated with shorter time to progression and increased recurrence. Additionally, the rising incidence of meningioma in pregnant patients has suggested an important role of hormone receptors commonly expressed in meningiomas; however, the prognostic value of hormone receptor status remains unclear. This study investigates patient stratification by molecular and hormonal markers to guide clinical management.

METHODS: We identified patients aged 18 and older with histologically confirmed meningioma, stratified by WHO grade, hormone receptor status, and molecular alterations. Primary outcomes were overall survival and progression-free survival.

RESULTS: Of 99 patients, 70 were grade 1 (70.7%), 25 were grade 2 (25.3%), and 4 were grade 3 (4.04%). PR-positivity was seen in 72 patients (72.7%), AR-positivity in 39 (39.4%), and ER-positivity in 1 (1.01%). Among PR-positive patients, 57 were grade 1 (79.2%) and 15 were grade 2 (20.8%). In AR-positive patients, 31 were grade 1 (79.5%), 7 were grade 2 (17.9%), and 1 was grade 3 (2.56%). The ER-positive patient was grade 2. In the PR-positive group, 16 (22.2%) progressed and 56 (77.8%) did not. In the AR-positive group, 5 (12.8%) progressed and 34 (87.2%) did not. The ER-positive patient showed no progression. Molecularly, 27 patients were NF2 mutant (27.3%), 2 had CDKN2A/B deletions (2.02%), 2 had AKT mutations (2.02%), and 2 had SMO mutations (2.02%).

CONCLUSION: Preliminary findings suggest PR-positivity may be a favorable prognostic marker, whereas AR-positivity may be unfavorable. Due to the rarity of ER-positivity, prognostic conclusions could not be made. Hormone receptor status may aid in risk stratification and guide treatment planning and surveillance intervals in meningioma patients.


Risk Stratification of Meningioma Based on Molecular & Hormone Receptor Status

Introduction 
Fibrostenotic complications of Crohn’s disease (CD) affect up to 50% of patients and often require surgery due to a lack of antifibrotic therapies. The renin-angiotensin-aldosterone system (RAAS) has been implicated in intestinal fibrosis, and RAAS inhibitors, such as angiotensin receptor blockers (ARBs), improve outcomes in animal models, but clinical validation is limited.

Methods
We performed a retrospective study using the multi-institutional database TriNetX to compare rates of endoscopic balloon dilation or surgery—proxies for fibrotic complications—in CD patients taking ARBs versus those not taking ARBs through July 8, 2025. One-to-one propensity score matching (PSM) balanced cohorts by age, sex, race, and smoking status. Outcome risk was expressed with hazard ratios (HRs) and Kaplan-Meier curves.

Results
After PSM, 7,708 CD patients taking ARBs (mean age 60.5 ± 13 years; 54% female; 75% White) were compared to an equal number not taking ARBs. Any ARB use was associated with a 27% lower risk of intervention (HR: 0.73, 95% CI: 0.66–0.80, P<0.01). Losartan (N=5,480) and olmesartan (N=586) reduced risk by 32% and 44%, respectively (HR: 0.68, 95% CI: 0.61–0.77; HR: 0.56, 95% CI: 0.39–0.80; P=0.01). Valsartan (N=1,698) showed no significant effect (HR: 0.88, 95% CI: 0.72–1.09, P=0.24). Higher ARB doses conferred greater benefit (losartan ≥50 mg: HR 0.59; olmesartan ≥20 mg: HR 0.44; valsartan ≥160 mg: HR 0.42; all P≤0.02).

Discussion
ARB use is associated with reduced endoscopic or surgical interventions for CD-related fibrosis, with evidence of dose dependence, supporting a potential antifibrotic mechanism and the need for prospective clinical evaluation.

Angiotensin Receptor Blockers are Associated with Reduced Risk of Fibrostenotic Complications in Crohn’s Disease

Background

Idiopathic sudden sensorineural hearing loss (ISSNHL) is a rapid decrease in hearing ability, typically occurring in one ear. Treatments for ISSNHL are difficult to study as patients can recover hearing spontaneously, making it difficult to separate treatment effects from the natural course of the disease. Current first-line therapies are oral and intratympanic corticosteroids, yet the mechanisms underlying their benefit remain poorly understood. Hyperbaric oxygen therapy (HBOT) has also emerged as a potential ISSNHL treatment, yet it is not clear if it offers benefits beyond steroids. This study assessed the effect of HBOT, in combination with corticosteroids, on hearing improvement following ISSNHL.

Methods

We analyzed data from the HBOT Registry, a global, multicenter collaboration that tracks outcomes of ISSNHL patients treated with HBOT across 33 institutions. In addition, we conducted a retrospective case series of selected ISSNHL patients at Dartmouth-Hitchcock Medical Center, who received HBOT following corticosteroid therapy, to determine if there were cases that showed a benefit beyond steroids.

Results

HBOT Registry data showed that HBOT was associated with overall improvement in measured hearing thresholds (i.e., pure tone average across frequencies 500Hz, 1000Hz, 2000Hz, and 4000Hz) among ISSNHL patients (n=256). Specifically, 41.02% of patients were found to have achieved clinically significant hearing recovery, defined as a ≥15 dB improvement in pure tone

average. The mean improvement in pure tone average following HBOT was 14.4 dB. Since most patients typically receive steroids prior to HBOT, this suggests an additional benefit from HBOT. In a retrospective case series conducted at Dartmouth-Hitchcock, we highlight 10 patients with complete audiometric data in which HBOT was associated with additional hearing recovery beyond that achieved with steroid treatment alone. This recovery was particularly apparent amongst low frequencies (i.e., 500-1000 Hz). This is a limited case series and additional study on the interaction between corticosteroid therapy and HBOT is warranted.

Conclusion

Our findings suggest HBOT improves hearing beyond what is achieved with corticosteroids in some individuals. Further controlled studies are needed to delineate the effects of spontaneous recovery, corticosteroids, and HBOT in ISSNHL.

Hyperbaric Oxygen Therapy for Sudden Sensorineural Hearing Loss

Background
Hyper IgE Syndrome (HIES) is a rare primary immunodeficiency characterized by elevated IgE levels, recurrent infections, and eczema. Diagnostic delays are common due to phenotypic variability and overlap with other inflammatory conditions. This case report aims to highlight diagnostic challenges in atypical HIES presentations and explore potential connections with hidradenitis suppurativa.

Case Presentation
We report a 30-year-old Caucasian female with Type I HIES who experienced a 12-year diagnostic delay from symptom onset to definitive diagnosis. Her clinical presentation began in infancy with oral thrush, chronic diarrhea, and severe eczema, progressing to recurrent skin abscesses during adolescence. She required multiple hospitalizations for incision and drainage of abscesses predominantly affecting bilateral breasts and right lower extremity. Significant complications included pneumonia with osteomyelitis (2020), ocular candidiasis with choroidal
involvement (2022), and a recent Candida glabrata lower extremity abscess (February 2025). The patient also experienced chronic perioral and periorbital dermatitis and approximately 30 episodes of otitis media throughout childhood. Initially misattributed to recurrent cellulitis (2008- 2018), the patient was later evaluated for hidradenitis suppurativa due to the anatomical distribution of abscesses in apocrine gland-rich areas. Immunological evaluation was finally initiated in 2020 following pneumonia with osteomyelitis. Laboratory investigations revealed
markedly elevated IgE levels (4,200 IU/mL; normal <100 IU/mL), while other immunoglobulin levels remained within normal limits. Genetic testing confirmed a heterozygous pathogenic STAT3 mutation (c.1144C>T, p.Arg382Trp), consistent with autosomal dominant HIES.

Discussion
Recent research suggests that some patients diagnosed with hidradenitis suppurativa may have underlying primary immunodeficiencies. This case provides evidence for this emerging connection through shared characteristics including anatomical predilection for apocrine gland- rich areas, chronic inflammatory processes with bacterial colonization, predominance of Staphylococcus aureus infections, and frequent treatment resistance. However, distinguishing
features include onset timing (HIES typically begins in infancy vs. HS post-puberty), systemic involvement (multisystem in HIES vs. primarily cutaneous in HS), and laboratory findings (markedly elevated IgE in HIES vs. normal in typical HS). The patient's STAT3 mutation affects the DNA-binding domain, resulting in dominant-negative effects on STAT3 function. This leads to impaired T-helper 17 cell differentiation, reduced IL-17 production, defective neutrophil
chemotaxis, and increased susceptibility to bacterial and fungal infections. The immune dysfunction involves multiple pathways including defective Th17 responses, impaired neutrophil function, regulatory T-cell abnormalities, and defective antimicrobial peptide production. This case demonstrates that HIES presentations can be highly variable, and the absence of classical features should not preclude diagnosis.

Hyper IgE Syndrome with Atypical Presentation: Diagnostic Challenges and
Potential Links to Hidradenitis Suppurativa

Background: Takotsubo Cardiomyopathy (TTC) mimics acute coronary syndrome but typically occurs without obstructive coronary disease. Rare complications, such as acute ventricular septal defect (VSD), carry a poor prognosis.
Case Summary: An 83-year-old woman with multiple comorbidities presented with chest pain and dyspnea. Suspected ST-elevation myocardial infarction (STEMI) led to coronary angiography, which confirmed TTC with acute VSD. Echocardiography revealed VSD and reduced ejection fraction (30–35%). An Impella CP device was placed within 2 hours, and urgent surgical VSD repair was performed within 32 hours. Postoperatively, Bi-Pella support optimized biventricular unloading.
Discussion: Acute VSD in TTC is rare and often fatal. Early mechanical circulatory support can stabilize patients and improve surgical outcomes. This case highlights the importance of prompt intervention in TTC-related VSD.
Take-Home Message: Early mechanical support and timely surgical intervention in TTC with VSD can be life-saving and improve outcomes.

Rescue of Acute VSD in Takotsubo Cardiomyopathy: Bi-Pella Support's Role in High-Risk Recovery

Pseudoangiomatous stromal hyperplasia (PASH) is a rare, benign hormonally-sensitive breast condition caused by an overgrowth of stromal myofibroblasts. These cells form slit-like spaces that mimic blood vessels but lack a true endothelial lining. While PASH is frequently an incidental histologic finding in breast biopsies, tumor-forming PASH is far less common, and involvement of the axilla is exceedingly rare. Fewer than a dozen cases of axillary PASH have been documented in the literature thus far.

We report the case of a woman in her 20’s who presented to our clinic with a progressively enlarging, slightly tender mass in the lower right axilla that had been present for over a year. She denied a history of hormonal therapy, oral contraceptive use, or family history of breast cancer. Physical examination revealed a firm, mobile, protuberant mass without overlying skin changes or palpable lymphadenopathy. Breast ultrasound demonstrated a well-circumscribed, hypoechoic mass without internal vascularity. Core needle biopsy revealed a benign stromal proliferation composed of bland spindle cells forming slit-like spaces, and the patient subsequently underwent surgical excision due to continued tumor growth and discomfort.

Histopathologic analysis confirmed the diagnosis of PASH, showing dense collagenous stroma and characteristic pseudoangiomatous channels without cytologic atypia. Immunohistochemical staining for CD4, vimentin, and smooth muscle actin supported the diagnosis. At six-month follow-up, the patient has shown no evidence of recurrence.

This case highlights a rare presentation of PASH in the axillary tail of the breast, where it clinically mimicked a protuberant lipoma. Although rare, PASH should be considered in the differential diagnosis of axillary soft tissue masses in hormonally active women. Accurate diagnosis relies on correlating imaging findings with histologic and immunohistochemical features, to help distinguish PASH from low-grade angiosarcoma. Given its benign behavior, surgical excision is typically reserved for symptomatic or enlarging lesions. Awareness of this entity is essential for clinicians and pathologists to prevent misdiagnosis and unnecessary aggressive treatment.

Pseudoangiomatous Stromal Hyperplasia Presenting as a Protuberant Axillary Tumor

Abstract Title

Paraneoplastic Hypercalcemia as the Initial Presentation of Hepatocellular Carcinoma in a Patient with Alcoholic Cirrhosis
Authors :
Isha Gupta , MD Muhammad Usman , MD
Mayur Ravjibhai Kaklotar , MBBS Suriya Shan , MD

Background

Hypercalcemia is a serious metabolic disturbance that can serve as a paraneoplastic manifestation of malignancy. While commonly associated with squamous cell, renal, and breast cancers, hypercalcemia in hepatocellular carcinoma (HCC) is rare but clinically important. One key mechanism is PTH-related peptide (PTHrP)-mediated hypercalcemia, where tumor cells secrete PTHrP, mimicking parathyroid hormone and causing increased bone resorption and renal calcium retention.

In patients with cirrhosis or other chronic liver diseases, symptoms such as fatigue or weakness are often nonspecific and attributed to hepatic dysfunction. However, the presence of unexplained hypercalcemia, especially without bone metastases or supplement use, should prompt evaluation for an underlying malignancy. Though uncommon, PTHrP-producing HCC can be the initial presentation of liver cancer.
Recognizing this paraneoplastic syndrome is essential for timely diagnosis and management, particularly in patients with known risk factors such as alcohol-related cirrhosis.


Case Presentation

A 55-year-old male with hypertension, hyperlipidemia, type 2 diabetes, and a history of heavy alcohol use (abstinent for three years) presented with progressive weakness over two weeks. Initial labs showed marked hypercalcemia (15.6 mg/dL) without supplement use. He was treated with intravenous fluids and calcitonin, reducing calcium to 10.3 mg/dL. Additional labs revealed elevated AST and ALP, hypoalbuminemia (2.5 g/dL), and mild anemia. Viral hepatitis markers were negative. A pan-CT showed no evidence of metastases. MRI abdomen revealed cirrhosis with multiple LIRADS-5 lesions showing arterial enhancement with washout, suggestive of hepatocellular carcinoma (HCC). Bone scan was negative for metastases. PTH-related peptide

was elevated (6.0 pmol/L) with a non-elevated intact PTH, consistent with humoral hypercalcemia of malignancy. The final diagnosis was PTHrP-mediated paraneoplastic hypercalcemia secondary to HCC in the setting of cirrhosis. The patient was discharged after stabilisation and advised to follow up with oncology for further evaluation and management.


Discussion

Hypercalcemia is rare in compensated cirrhosis, but when present without a clear cause, it may indicate an underlying malignancy such as hepatocellular carcinoma (HCC). In fewer than 5% of HCC cases, paraneoplastic hypercalcemia occurs due to PTHrP secretion. Routine calcium monitoring in patients with heavy alcohol use may aid in early detection of serious complications like HCC.

References : 
1. Hu MI, Glezerman IG, Leboulleux S, Insogna K, Gucalp R, Misiorowski W. Advanced therapies for hypercalcemia of malignancy. Front Endocrinol (Lausanne). 2023;14:1039490. doi:10.3389/fendo.2023.1039490
2. Alameri HF, Abdel-Rahman ME, Guturu P. Humoral hypercalcemia of malignancy as a presenting manifestation of hepatocellular carcinoma: a case report and literature review. HPB (Oxford). 2024;26(9):1321-1324. doi:10.1016/j.hpb.2024.06.009
3. Chen S, Li J, Zhang J, et al. Paraneoplastic syndromes in hepatocellular carcinoma: recent advances and clinical implications. World J Clin Cases. 2024;12(5):856-867. doi:10.12998/wjcc.v12.i5.856
4. Rahman M, Alqahtani S, Farghaly M, et al. Paraneoplastic hypercalcemia due to hepatocellular carcinoma: a case report and review of the literature. Cureus. 2022;14(4):e23978. doi:10.7759/cureus.23978
5. Mirrakhimov AE. Hypercalcemia of malignancy: an update on pathogenesis and management. J Clin Endocrinol Metab. 2015;100(5):2024-2034. doi:10.1210/jc.2015-100


Paraneoplastic Hypercalcemia as the Initial Presentation of Hepatocellular Carcinoma ina Patient with Alcoholic Cirrhosis

Background: Efforts to expand patient portal use across the country, while well-intentioned, may inadvertently widen health inequities by failing to address the distinct challenges faced by marginalized populations. Safety-net clinics, which serve those most at risk for health disparities, continue to report low portal adoption, suggesting that drivers of engagement differ fundamentally from national trends. This mixed-methods study wants to moves beyond documenting disparities and instead identify context-specific patient profiles that explain barriers to portal adoption. We aimed to (1) identify distinct patient subgroups influenced by local barriers using clustering analysis, (2) use qualitative data to characterize these profiles, and (3) evaluate whether national models adequately predict portal use in this context. 
Methods: We conducted a cross-sectional, mixed-methods study at a student-run free clinic that primarily serves Spanish-speaking, uninsured Latine patients. A total of 112 patients completed surveys assessing portal use and confidence in managing health information, and 42 providers shared perspectives on implementation. Patient profiles were identified using K-means clustering, and 11 semi-structured interviews added nuance and context from patient voices. To assess generalizability, findings were compared with national data from the Health Information National Trends Survey (HINTS6; n=6,252).
Results: Portal adoption in our clinic was 22.3%, less than half the national rate of 58%. Our primary analysis identified four distinct patient profiles: “Healthcare Engaged” (high confidence, high use), “Digitally Disengaged” (low confidence, low use), “Information Access Challenged” (engaged but struggling with usability), and “System Navigators” (moderately engaged). Qualitative interviews highlighted that engagement patterns were shaped primarily by usability challenges and trust, not by deficits in health literacy. A predictive model based on local behavioral data performed no better than chance (Area Under the Curve [AUC] = 0.47). In contrast, the same model applied to national HINTS6 data was highly predictive (AUC = 0.93), underscoring that drivers of portal use locally are fundamentally different.
Conclusion: Patient portal adoption in safety-net settings is shaped by local barriers, especially those related to usability and trust, that are not captured by national datasets. Our findings illustrate how models built on national predictors, though effective at the population level, may fail to account for the specific challenges faced by underserved communities. By identifying distinct patient subgroups through mixed-methods analysis, we provide a practical framework that healthcare organizations can use to design more equitable and targeted digital health strategies.

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