Faculty Bibliography

PURPOSE/OBJECTIVE:Immune checkpoint inhibition (ICI) has revolutionized the treatment of melanoma care. Stereotactic radiosurgery combined with ICI has shown promise to improve clinical outcomes in prior studies in patients who have metastatic melanoma with brain metastases. However, others have suggested that concurrent ICI with stereotactic radiosurgery can increase the risk of complications. METHODS:We present a retrospective, single-institution analysis of 98 patients with a median follow up of 17.1 months managed with immune checkpoint inhibition and stereotactic radiosurgery concurrently and non-concurrently. A total of 55 patients were included in the concurrent group and 43 patients in the non-concurrent treatment group. Cox proportional hazards models were used to assess the relation between concurrent or non-concurrent treatment and overall survival or local progression-free survival. The Wald test was used to assess significance. Significant differences between patients in both groups experiencing adverse events including adverse radiation effects, perilesional edema, and neurological deficits were tested for using the Chi-square or Fisher's exact test. RESULTS:Patients receiving concurrent versus non-concurrent ICI showed a significant increase in overall survival (median 37.1 months, 95% CI: 18.9 months - NA versus median 11.4 months, 95% CI: 6.4-33.2 months, p = 0.0056) but not local progression-free survival. There were no significant differences between groups with regards to adverse radiation effects (2% versus 3%), perilesional edema (20% versus 9%), neurological deficits (3% versus 20%). CONCLUSION/CONCLUSIONS:These results suggest that the timing of ICI does not increase risk of neurological complications when delivered within 4 weeks of SRS.

BACKGROUND:Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment. METHODS:591 Non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N=367) by occurrence of thrombosis or hypertension (grade ≥2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the clinical model as a single nucleotide polymorphism (SNP) -dose effect variable to produce the final genetic models. RESULTS:Thrombosis and hypertension were experienced by 62 (11%) and 59 (10%) patients, respectively. Patients who experienced hypertension displayed improved survival over those without hypertension (median overall survival: 25.72 vs 15.47 months, p=0.002). The genetic model of thrombosis included corticosteroid use (OR: 7.13, p=0.02), absolute neutrophil count (OR: 1.008, p=0.19), body surface area (OR: 18.87, p=0.0008), and the SNP-dose effect (3 variants; OR: 3.79, p<.0001). The genetic model of hypertension included bevacizumab use (OR: 0.97, p=0.95) and the SNP-dose effect (6 variants; OR: 4.44, p<.0001). CONCLUSION/CONCLUSIONS:In this study, germline variants were superior in predicting hypertension than clinical variables alone. Additionally, corticosteroid use was a considerable risk factor for thrombosis. Future investigations should confirm the hazard of corticosteroid use on thrombosis and the impact of bevacizumab in other malignancies after accounting for the genetic risk of hypertension.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Hydrocephalus after Gamma Knife® stereotactic radiosurgery (SRS) for vestibular schwannomas is a rare but manageable occurrence. Most series report post-SRS communicating hydrocephalus in about 1% of patients, thought to be related to a release of proteinaceous substances into the cerebrospinal fluid. While larger tumor size and older patient age have been associated with post-SRS hydrocephalus, the influence of baseline ventricular anatomy on hydrocephalus risk remains poorly defined. METHODS:A single-institution retrospective cohort study examining patients who developed symptomatic communicating hydrocephalus after undergoing Gamma Knife® SRS for unilateral vestibular schwannomas from 2011 to 2021 was performed. Patients with prior hydrocephalus and cerebrospinal fluid diversion or prior surgical resection were excluded. Baseline tumor volume, third ventricle width, and Evans Index (EI)-maximum width of the frontal horns of the lateral ventricles/maximum internal diameter of the skull-were measured on axial postcontrast T1-weighted magnetic resonance imaging. RESULTS:A total of 378 patients met the inclusion criteria; 14 patients (3.7%) developed symptomatic communicating hydrocephalus and 10 patients (2.6%) underwent shunt placement and 4 patients (1.1%) were observed with milder symptoms. The median age of patients who developed hydrocephalus was 69 years (IQR, 67-72) and for patients younger than age 65 years, the risk was 1%. For tumor volumes <1 cm3, the risk of requiring shunting was 1.2%. The odds of developing symptomatic hydrocephalus were 5.0 and 7.7 times higher in association with a baseline EI > 0.28 (P = .024) and tumor volume >3 cm3 (P = .007), respectively, in multivariate analysis. Fourth ventricle distortion on pre-SRS imaging was significantly associated with hydrocephalus incidence (P < .001). CONCLUSION/CONCLUSIONS:Patients with vestibular schwannoma with higher baseline EI, larger tumor volumes, and fourth ventricle deformation are at increased odds of developing post-SRS hydrocephalus. These patients should be counseled regarding risk of hydrocephalus and carefully monitored after SRS.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Stereotactic radiosurgery (SRS) is effective for patients with medically refractory trigeminal neuralgia with a 75%-90% response rate. Consideration of the integral dose (ID) to the target nerve within the 50% isodose line was reported to help select prescription doses to maximize effectiveness and minimize bothersome numbness. The objective of this study was to externally validate the ID as a predictor of outcomes after SRS. METHODS:We reviewed the outcomes and parameters of 94 consecutive patients of type 1 trigeminal neuralgia who had SRS for the first time where nerve ID was calculated. 70% of the prescription doses were 80 Gy, with 28% at 85 Gy, and 2% at 70 Gy. RESULTS:The median follow-up time was 14.4 months. A total of 85 (90%) patients reported significant pain relief (Barrow Neurological Institute I-III) after initial SRS. The median pain recurrence-free survival was 82 months (95% CI 41.1-NA), and estimates at 1, 3, and 5 years were 80.5%, 65.5%, and 55.9%, respectively. The ID was not significantly associated with initial pain relief, or affect the risk of pain recurrence or sensory dysfunction after SRS using the Cox proportional hazards model. A nerve mean dose ≥65 Gy was associated with a reduced risk of pain recurrence on multivariate analysis (hazard ratio 0.408, P = .039). Twenty (21%) patients experienced sensory dysfunction after SRS with 3 (3%) requiring further medications, which was not correlated with the prescription dose or brainstem maximum dose. CONCLUSION/CONCLUSIONS:The ID did not predict recurrence-free survival or sensory dysfunction. Our observations suggest improved nerve coverage by the most powerful area of the isocenter, for instance, by targeting a narrower segment if feasible, could result in more durable pain relief. Further studies to validate these findings are needed.

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4⁺ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

PURPOSE/OBJECTIVE:In patients with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose. Though prone positioning is routinely used for whole breast RT, its use when treating the regional lymph nodes is not widespread. METHODS AND MATERIALS/METHODS:In this phase 1/2 trial for stage IB-IIA breast cancer treated with lumpectomy or mastectomy, patients received 40.5 Gy in 15 fractions to the breast or chest wall and regional lymph nodes with an integrated tumor bed boost for lumpectomy patients. Primary endpoints were grade >2 acute toxicity and dosimetric feasibility. Secondary endpoints were the incidence of resimulation to improve dosimetry and late toxicity. Exploratory endpoints were local recurrence, disease-free survival, distant recurrence-free survival, and overall survival. RESULTS:From 2009 to 2016, 97 patients were enrolled (68% lumpectomy and 32% mastectomy), among which 92 were treated in the prone position. Five patients were resimulated and treated supine. Among the prone-treated patients, there were no acute toxicities greater than grade 2. A total of 92%, 98%, and 89% met a planning target volume tumor V48 Gy ≥98%, breast V40.5 Gy ≥95%, and nodal V38.5 Gy ≥95%, respectively. All met the heart V5 Gy <5%, contralateral lung V5 Gy <15%, spinal cord dose maximum (Dmax) ≤37.5 Gy, esophagus V30 Gy <50%, and Dmax ≤40.5 Gy. Ninety-eight percent met the ipsilateral lung V10 Gy. Brachial plexus Dmax <42 Gy was met in 74% with a mean increase of 1.61 Gy (SD, 1.96 Gy) over the target. At a median follow-up of 8 years, grade 2 to 3 late toxicity was 23% for prone patients. There were 2 local recurrences (2%) and no chest wall or nodal recurrences. The 8-year distant recurrence-free survival, disease-free survival, and overall survival were 88% (95% CI, 81%-95%), 86% (95% CI, 78%-95%), and 91% (95% CI, 84%-98%), respectively. CONCLUSIONS:Toxicity was low, and outcomes were excellent in this prospective trial of prone hypofractionated nodal RT.

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.

PURPOSE/OBJECTIVE:The purpose of this study was to investigate an extended self-adapting nnU-Net framework for detecting and segmenting brain metastases (BM) on magnetic resonance imaging (MRI). METHODS AND MATERIALS/METHODS:Six different nnU-Net systems with adaptive data sampling, adaptive Dice loss, or different patch/batch sizes were trained and tested for detecting and segmenting intraparenchymal BM with a size ≥2 mm on 3 Dimensional (3D) post-Gd T1-weighted MRI volumes using 2092 patients from 7 institutions (1712, 195, and 185 patients for training, validation, and testing, respectively). Gross tumor volumes of BM delineated by physicians for stereotactic radiosurgery were collected retrospectively and curated at each institute. Additional centralized data curation was carried out to create gross tumor volumes of uncontoured BM by 2 radiologists to improve the accuracy of ground truth. The training data set was augmented with synthetic BMs of 1025 MRI volumes using a 3D generative pipeline. BM detection was evaluated by lesion-level sensitivity and false-positive (FP) rate. BM segmentation was assessed by lesion-level Dice similarity coefficient, 95-percentile Hausdorff distance, and average Hausdorff distance (HD). The performances were assessed across different BM sizes. Additional testing was performed using a second data set of 206 patients. RESULTS:. Mean values of Dice similarity coefficient, 95-percentile Hausdorff distance, and average HD of all detected BMs were 0.758, 1.45, and 0.23 mm, respectively. Performances on the second testing data set achieved a sensitivity of 0.907 at an FP rate of 0.57 ± 0.85 for all BM sizes, and an average HD of 0.33 mm for all detected BM. CONCLUSIONS:Our proposed extension of the self-configuring nnU-Net framework substantially improved small BM detection sensitivity while maintaining a controlled FP rate. Clinical utility of the extended nnU-Net model for assisting early BM detection and stereotactic radiosurgery planning will be investigated.