Faculty Bibliography

BACKGROUND AND PURPOSE/UNASSIGNED:To evaluate the dosimetric and toxicity profiles of stereotactic body radiotherapy (SBRT) for prostate cancer, comparing cohorts with and without intraprostatic boost (IPB) to assess feasibility and safety of IPB, with particular attention to urethral and bladder dose and toxicity. MATERIALS AND METHODS/UNASSIGNED:This retrospective cohort study analyzed 349 patients with localized prostate cancer treated between 2018 and 2023. Of these, 266 received SBRT with IPB, and 83 received SBRT without IPB. Patients were treated using a robotic SBRT platform with fiducial tracking. Dosimetric parameters for the urethra, including D0.03cc, D0.3cc, and V40Gy, and for the bladder, including D0.03cc, D5cc, D10cc, and V37Gy, were evaluated. Acute and late toxicities were assessed using CTCAE criteria. RESULTS/UNASSIGNED:For the urethra, median values for D0.03cc, D0.3cc, and V40Gy, and for the bladder, median values D0.03cc, D5cc, D10cc, and V37Gy were compared and no statistically significant differences were observed between the two cohorts. Late urinary toxicity of grade 3 or higher occurred in 2.25 % of patients in the IPB group and 2.47 % in the no IPB group, with no grade 3 acute toxicities reported. DISCUSSION/UNASSIGNED:These findings support the use of SBRT using an IPB as a feasible and safe approach to achieve focal dose escalation to dominant intra-prostatic lesions (DILs) without significantly increasing urethra or bladder dose or toxicity. Future research should focus on standardizing DIL contouring, exploring adaptive planning techniques to increase accuracy, and prospectively studying toxicity and quality of life in patients treated with IPB with SBRT.

We present a case highlighting innominate vein reconstruction for resection of Hurthle cell carcinoma with complex vascular invasion. A 69-year-old man presented with a rapidly enlarging neck mass, dysphagia and dysphonia. Workup demonstrated a 11.2 × 7.0 × 6.5 cm Hurthle cell carcinoma invading the oropharynx and superior mediastinum. We proceeded with left thyroid lobectomy and modified left radical neck dissection. Median sternotomy, resection of the left clavicular head, and partial resection of the left manubrium were performed to circumferentially expose the innominate vein. Tumor thrombus was extruded from the innominate vein followed by patch angioplasty, which remains patent 14 months postoperatively.

MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma.

OBJECTIVE:To obtain perspectives about existing compensation structures in gynecologic oncology, including common challenges and successful strategies within diverse systems. METHODS:Electronic mail was used to recruit OB/GYN department chairs and directors of cancer centers who were gynecologic oncologists and responsible for administering compensation structures at their institution. Using a semi-structured guide, three interviewers conducted 30-min qualitative interviews, which were recorded and transcribed. Two coders used the constant comparative method to summarize key themes. RESULTS:Response rate was 65 %, resulting in 17 interviewees. Participants were a third women and in their current position for a median of 7 years. The most prominent theme was the tension of balancing reimbursement for revenue-generating clinical activities with non-clinical work in research and education. Chair discretionary funds were useful to offset unfunded responsibilities. Broad clinical productivity measures were used: from more traditional work Relative Value Units (wRVUs) to measures that captured downstream impact, such as number of new patients or surgeries. Even in institutions with centralized funds flow systems, disparities were frequently noted for the monetary value assigned per wRVU. Academic scorecards were described as a method to ascribe value for academic work, often for bonus incentives. Another common stressor unique to gynecologic oncology was low reimbursement for chemotherapy-related services compared to surgery. Provision of regular productivity reports was common, but full transparency was controversial. CONCLUSIONS:Our inquiry demonstrates that our academic leaders are unable to use compensation to fully support areas they deem important.

BACKGROUND:The prolonged turnaround time for next-generation sequencing (NGS) results may be a barrier to the timely selection of therapeutics in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with mutated TP53. Biomarker validation for early detection of TP53 mutation may have a significant impact on clinical decision-making. METHODS:In this study, p53 immunohistochemistry (IHC) (index test) and TP53 NGS (referent test) were performed on 145 bone marrow specimens from 82 unique patients with TP53-mutant MDS or AML to validate IHC as an early surrogate for NGS, and to assess the prognostic relevance of IHC. RESULTS:p53 IHC testing was able to correctly identify 95.5% of patients with TP53-mutant MDS and 100% of patients with TP53-mutant AML in this cohort. The mean p53 stain positivity was higher for AML compared to MDS (28% ± 3.67% vs. 8.8% ± 1.61%; p < .001), as well as for multihit TP53 compared to monoallelic TP53. Bootstrap analysis with 2000 iterations showed that a p53 IHC of 7% was the threshold best associated with multihit TP53. False-negative results were obtained with IHC in all TP53 sole nonsense or frameshift mutations. IHC positivity was inversely correlated with overall survival (OS), with the highest quintile of p53 positivity showing a median OS of just 2.53 months. CONCLUSIONS:IHC is a useful biomarker for the early detection of TP53-mutant MDS or AML and for prediction of TP53 allelic state. The results suggest a role for IHC across global markets, especially in geographic areas with inaccessibility to NGS testing.

Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.

BACKGROUND AND AIMS/OBJECTIVE:Liver biopsy is the gold standard for assessing fibrosis in cirrhotic livers, yet cirrhosis is spatially heterogeneous and continuously remodels. This study evaluates a novel phenotypic digital pathology platform for continuous fibrosis severity quantification and sensitivity to sampling variability. APPROACH AND RESULTS/RESULTS:Five needle biopsies were collected from 20 HCV-cirrhotic livers during transplantation. Histological staging used the Laennec (4A-4C) and Beijing (progressive, regressive, indeterminate) systems. Collagen proportionate area (CPA) was measured via computerised morphometry. The FibroNest platform analysed high-resolution, single-fibre images to extract 336 parameters, generating a continuous fibrosis severity score (Ph-FCS) and tailored scores for Laennec (Ph-FCS(L)) and Beijing (Ph-FCS(B)) systems. A comparative MASLD cohort (n = 73, NASH-CRN stages) was also included. The range of the Ph-FCS was broader to cover the cirrhosis spectrum (6.44 units) than from F0 to F3 (5.39 units). Ph-FCS was less affected by biopsy variability (16.7% ± 1.3%) compared to CPA (47.3% ± 4.5%). Ph-FCS(L) and Ph-FCS(B) demonstrated moderate concordance with the Laennec and Beijing stages. Their ability to classify patients into Laennec and Beijing stages was limited (0.610 < AUROCS < 0.789). At best, Ph-FCS(L) and Ph-FCS(B) distinguished stages 4A from 4C and P from R with AUROCs of 0.747(95% CI: 0.611-0.879) and 0.798 (95% CI: 0.645-0.929). CONCLUSIONS:Phenotypic digital pathology biomarkers provide robust, continuous measures of fibrosis severity and activity. They enhance traditional staging systems by offering improved resolution and reduced sensitivity to biopsy variability, with potential value in cirrhosis sub-staging and clinical decision-making.

BACKGROUND/UNASSIGNED:This study investigates the association between intra-operative balance and 2-year outcomes within subgroups defined by demographics and pre-operative joint balance. Our hypothesis is that patient demographics and the pre-operative state of the joint will impact patient sensitivity to post-operative balance and laxity and subsequent impact on outcome. METHODS/UNASSIGNED:A retrospective analysis of prospectively captured data across 5 sites with 5 surgeons was performed. All cases completed pre-operative demographics surveys, 2-year post-operative Knee Injury and Osteoarthritis Outcome Score (KOOS) and had a robot assisted total knee arthroplasty with an integrated digital joint balancing tool. Differences in associations between intra-operative final joint balance and 2-year KOOS pain outcomes in demographic and pre-operative balance subgroups were characterized. Associations informed clinically relevant thresholds to optimize TKA treatment for subgroups. RESULTS/UNASSIGNED:A total of 276 patients completed 2-year KOOS scores. Subgroups were defined from Sex, Age, BMI and pre-operative extension laxity. Men prefer a tight tolerance medially in extension and mid-flexion while females prefer a tight lateral flexion gap. Patients <70 years show a strong preference for equal rectangular gaps in extension, mid-flexion, and flexion, while older patients do not show a preference. Patients with BMI ≤30 demonstrate a preference for rectangular gaps, while patients with higher BMI do not. Finally, patients with looser pre-operative extension laxity (>3 mm) preferred a TKA with increased extension laxity compared to patients with minimal preoperative laxity. CONCLUSION/UNASSIGNED:Intraoperative differences in knee balance can influence patient outcome scores among different demographic groups at two years postoperatively. This suggests further research is warranted to determine how ligament balance and laxity may be optimized based on individual patient factors.

Chemotherapy-induced alopecia and radiation-induced alopecia, the thinning or loss of hair due to cytotoxic chemotherapy and radiation therapy, respectively, are distressing adverse effects of cancer treatment. Chemotherapy, targeted therapies, and radiation therapy used in pediatric oncology often lead to alopecia by damaging hair follicles, with varying degrees of severity depending on the specific treatment type, mechanism of action, and damage-response pathway involved. Pediatric chemotherapy-induced alopecia, radiation-induced alopecia, and permanent alopecia, defined as hair regrowth that remains incomplete 6 months or more after treatment, have significant negative impacts on mental health, self-esteem, and social interactions, highlighting the need for further research into supportive care strategies. There are currently no standard interventions for chemotherapy-induced alopecia or radiation-induced alopecia in children, with most recommendations limited to gentle hair care and camouflaging techniques during treatment. Scalp cooling has demonstrated safety and efficacy in reducing chemotherapy-induced alopecia in adults and is currently under investigation in children and adolescents. Topical and low-dose oral minoxidil have been studied in children for other hair loss disorders and may improve hair regrowth after chemotherapy or radiation. Increased awareness and continued research into management strategies for pediatric chemotherapy-induced alopecia and radiation-induced alopecia are necessary to help mitigate its significant negative impact on quality of life.

BACKGROUND:Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells. METHODS:A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints. FINDINGS/RESULTS:This triple regimen was safe and achieved a DCR of 54% (3/13 partial response [PR] and 4/13 stable disease [SD]) in mostly heavily pretreated patients. Responding tumors included non-small cell lung cancer (2/2 PR + SD), head-and-neck squamous cell carcinoma (2/3 PR + SD), and Hodgkin's lymphoma (2/2 PR in patients after 12 or 16 prior lines of therapy). PR + SD patients had significantly higher GEF-H1 immune-activation scores in peripheral blood and intratumorally at pretreatment/baseline and DC activation/T cell clonal expansion post-treatment compared with progressive disease patients. CONCLUSIONS:These preliminary results provide a rationale for testing RT/plinabulin/ICI combination in future post-ICI-failure confirmatory trials. FUNDING/BACKGROUND:This study was funded by BeyondSpring Pharmaceuticals, Inc.