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Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas

Galbraith, Kristyn; Garcia, Mekka; Wei, Siyu; Chen, Anna; Schroff, Chanel; Serrano, Jonathan; Pacione, Donato; Placantonakis, Dimitris G; William, Christopher M; Faustin, Arline; Zagzag, David; Barbaro, Marissa; Eibl, Maria Del Pilar Guillermo Prieto; Shirahata, Mitsuaki; Reuss, David; Tran, Quynh T; Alom, Zahangir; von Deimling, Andreas; Orr, Brent A; Sulman, Erik P; Golfinos, John G; Orringer, Daniel A; Jain, Rajan; Lieberman, Evan; Feng, Yang; Snuderl, Matija
BACKGROUND:Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS:We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS:There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS:The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.
PMCID:11145445
PMID: 38243818
ISSN: 1523-5866
CID: 5664582

Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review

Cooper, Benjamin T; Mayo, Charles S; Milano, Michael T; Olch, Arthur J; Oh, Cheongeun; Keating, Gesina F; Hallstrom, Anneka; Constine, Louis S; Laack, Nadia N
PURPOSE/OBJECTIVE:Radiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex. METHODS AND MATERIALS/METHODS:We conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity. RESULTS:Of 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P = .04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P = .03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events. CONCLUSIONS:This report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal.
PMID: 38323945
ISSN: 1879-355x
CID: 5632672

Radiation Therapy for Lung Cancer: Imaging Appearances and Pitfalls

Toussie, Danielle; Ginocchio, Luke A; Cooper, Benjamin T; Azour, Lea; Moore, William H; Villasana-Gomez, Geraldine; Ko, Jane P
Radiation therapy is part of a multimodality treatment approach to lung cancer. The radiologist must be aware of both the expected and the unexpected imaging findings of the post-radiation therapy patient, including the time course for development of post- radiation therapy pneumonitis and fibrosis. In this review, a brief discussion of radiation therapy techniques and indications is presented, followed by an image-heavy differential diagnostic approach. The review focuses on computed tomography imaging examples to help distinguish normal postradiation pneumonitis and fibrosis from alternative complications, such as infection, local recurrence, or radiation-induced malignancy.
PMID: 38816092
ISSN: 1557-8216
CID: 5663852

Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Guinn, Samantha; Kinny-Köster, Benedict; Tandurella, Joseph A; Mitchell, Jacob T; Sidiropoulos, Dimitrios N; Loth, Melanie; Lyman, Melissa R; Pucsek, Alexandra B; Zabransky, Daniel J; Lee, Jae W; Kartalia, Emma; Ramani, Mili; Seppälä, Toni T; Cherry, Christopher; Suri, Reecha; Zlomke, Haley; Patel, Jignasha; He, Jin; Wolfgang, Christopher L; Yu, Jun; Zheng, Lei; Ryan, David P; Ting, David T; Kimmelman, Alec; Gupta, Anuj; Danilova, Ludmila; Elisseeff, Jennifer H; Wood, Laura D; Stein-O'Brien, Genevieve; Kagohara, Luciane T; Jaffee, Elizabeth M; Burkhart, Richard A; Fertig, Elana J; Zimmerman, Jacquelyn W
UNLABELLED:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE/UNASSIGNED:Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
PMCID:11065624
PMID: 38587552
ISSN: 1538-7445
CID: 5657242

The Role of Stroma in Cancer Metabolism

Kimmelman, Alec C; Sherman, Mara H
The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
PMID: 37696660
ISSN: 2157-1422
CID: 5593872

Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches

Mashiach, Elad; Alzate, Juan Diego; De Nigris Vasconcellos, Fernando; Adams, Sylvia; Santhumayor, Brandon; Meng, Ying; Schnurman, Zane; Donahue, Bernadine R; Bernstein, Kenneth; Orillac, Cordelia; Bollam, Rishitha; Kwa, Maryann J; Meyers, Marleen; Oratz, Ruth; Novik, Yelena; Silverman, Joshua S; Harter, David H; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS:We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS:Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS:TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.
PMID: 38630386
ISSN: 1573-7373
CID: 5655852

Impact of Multiple Sclerosis Subtypes on Pain Management in Patients With Trigeminal Neuralgia After Stereotactic Radiosurgery: An International Multicenter Analysis

De Nigris Vasconcellos, Fernando; Mashiach, Elad; Alzate, Juan Diego; Bernstein, Kenneth; Rotman, Lauren; Levy, Sarah; Qu, Tanxia; Wegner, Rodney E; Shepard, Matthew J; Patel, Samir; Warnick, Ronald E; Moreno, Nuria Martínez; Martínez Álvarez, Roberto; Picozzi, Piero; Franzini, Andrea; Peker, Selçuk; Samanci, Yavuz; Elguindy, Ahmed N; Palmer, Joshua D; Lunsford, L Dade; Jose, Shalini G; Wei, Zhishuo; Niranjan, Ajay; Blagui, Sarra; Iorio-Morin, Christian; Mathieu, David; Briggs, Robert G; Yu, Cheng; Zada, Gabriel; Dayawansa, Samantha; Sheehan, Jason; Schulder, Michael; Goenka, Anuj; Begley, Sabrina; Khilji, Hamza; Urgošík, Dušan; Liščák, Roman; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:Trigeminal neuralgia affects approximately 2% of patients with multiple sclerosis (MS) and often shows higher rates of pain recurrence after treatment. Previous studies on the effectiveness of stereotactic radiosurgery (SRS) for trigeminal neuralgia did not consider the different MS subtypes, including remitting relapsing (RRMS), primary progressive (PPMS), and secondary progressive (SPMS). Our objective was to investigate how MS subtypes are related to pain control (PC) rates after SRS. METHODS:We conducted a retrospective multicenter analysis of prospectively collected databases. Pain status was assessed using the Barrow National Institute Pain Intensity Scales. Time to recurrence was estimated through the Kaplan-Meier method and compared groups using log-rank tests. Logistic regression was used to calculate the odds ratio (OR). RESULTS:Two hundred and fifty-eight patients, 135 (52.4%) RRMS, 30 (11.6%) PPMS, and 93 (36%) SPMS, were included from 14 institutions. In total, 84.6% of patients achieved initial pain relief, with a median time of 1 month; 78.7% had some degree of pain recurrence with a median time of 10.2 months for RRMS, 8 months for PPMS, 8.1 months for SPMS (P = .424). Achieving Barrow National Institute-I after SRS was a predictor for longer periods without recurrence (P = .028). Analyzing PC at the last available follow-up and comparing with RRMS, PPMS was less likely to have PC (OR = 0.389; 95% CI 0.153-0.986; P = .047) and SPMS was more likely (OR = 2.0; 95% CI 0.967-4.136; P = .062). A subgroup of 149 patients did not have other procedures apart from SRS. The median times to recurrence in this group were 11.1, 9.8, and 19.6 months for RRMS, PPMS, and SPMS, respectively (log-rank, P = .045). CONCLUSION/CONCLUSIONS:This study is the first to investigate the relationship between MS subtypes and PC after SRS, and our results provide preliminary evidence that subtypes may influence pain outcomes, with PPMS posing the greatest challenge to pain management.
PMID: 38051068
ISSN: 1524-4040
CID: 5595452

Effectiveness and toxicity of five-fraction prone accelerated partial breast irradiation

Hardy-Abeloos, Camille; Xiao, Julie; Oh, Cheongeun; Barbee, David; Shah, Bhartesh; Maisonet, Olivier; Perez, Carmen; Adams, Sylvia; Schnabel, Freya; Axelrod, Deborah; Guth, Amber; Karp, Nolan; Cahlon, Oren; Gerber, Naamit
PURPOSE/OBJECTIVE:Our institution was an early adopter of 5-fraction accelerated partial breast irradiation (ABPI) to treat women with early-stage breast cancer. This study reports long-term oncologic and cosmetic outcomes. METHODS:We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Logistic regression models were used to identify factors associated with development of late toxicities, clinician, and patient-rated cosmesis. Kaplan-Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free survival (LR-RFS). RESULTS:442 patients received APBI either daily (56%) or every other day (44%) in the prone position (92%). At a median follow-up of 48 months (range: 5.96-155 months), 12 (2.7%) patients developed a local recurrence (LR). Out of 258 patients with > 3-month toxicity data available, the most common late grade ≥ 2 adverse event was breast fibrosis (6.2%). On multivariate analysis, daily APBI treatment (vs every other day) did not correlate with an increased risk of any late grade ≥ 2 toxicity though it did correlate with a lower risk of any late grade ≥ 2 fibrosis. Overall, at a median follow-up of 80 months, the rates of good-excellent physician and patient-rated cosmesis were 95% and 85%, respectively, with no difference between patients treated on consecutive vs. every other day. On multivariate analysis, patients who did not receive any adjuvant therapy were at increased risk of developing a LR. Five-year OS, LRFS, and DFS were 97.2%, 97.7%, and 89.5%, respectively. CONCLUSIONS:Five-fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity, and excellent cosmesis at long-term follow-up.
PMID: 38183516
ISSN: 1573-7217
CID: 5644242

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy

Lischalk, Jonathan W; Sanchez, Astrid; Santos, Vianca F; Mendez, Christopher; Akerman, Meredith; Carpenter, Todd; Tam, Moses; Byun, David; Wise, David R; Mahadevan, Anand; Evans, Andrew; Huang, William; Katz, Aaron; Lepor, Herbert; Haas, Jonathan A
PURPOSE/OBJECTIVE:Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor. METHODS:A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement. RESULTS:From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234). CONCLUSIONS:With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.
PMCID:10913228
PMID: 38439040
ISSN: 1748-717x
CID: 5664372

Outcomes of Gamma Knife Radiosurgery for Brain Metastases in the Motor Cortex

Prasad, Shefalika; Alzate, Juan Diego; Mullen, Reed; Bernstein, Kenneth; Qu, Tanxia; Silverman, Joshua; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:To study the clinical, imaging, and survival outcomes in patients with motor cortex brain metastases treated with stereotactic radiosurgery (SRS). METHODS:Imaging and clinical data were obtained from our prospective patient registry. Tumor volumes were obtained from serial imaging data. RESULTS:The outcomes of 208 patients with metastases involving the motor cortex who underwent SRS between 2012 and 2021 were analyzed. A total of 279 metastases (0.01 cm3-12.18 cm3, mean 0.74 cm3) were irradiated. The SRS margin dose varied from 10 to 20 Gy (mean 16.9 Gy). The overall tumor control rate was 97.8%. Perilesional edema was noted in 69 (25%) tumors at presentation. Adverse radiation effects (ARE) were noted in 6% of all tumors but were symptomatic in only 1.4%. Median time to appearance of symptomatic ARE was 8 months. Edema without ARE was observed in 13%. New focal seizures were noted in 5 patients (2%) and new generalized seizures in 1 patient (0.3%). Thirty-six patients (17%) presented with motor deficits. At final follow-up, 32 (85%) were improved or unchanged, 13 (41%) had a normal examination, 10 (31%) had mild deficits, and 9 (28%) still had moderate deficits. New remote brain metastases were found in 31% of patients at a median of 8 months. After treatment, the Karnofsky performance score distribution of the population showed an overall right shift and a median survival of 10 months. Patients with incidentally found brain metastases had significantly better survival than those presenting with deficits (median 13 vs 9 months) (P = .048). Absence of a neurological deficit, recursive partitioning analysis Class I and II, and dose >18 Gy were each associated with a significant survival advantage. CONCLUSION/CONCLUSIONS:SRS for motor cortex metastases is safe in most patients and effective in providing tumor control. Patients treated before neurological deficits develop show better outcomes.
PMID: 37823677
ISSN: 1524-4040
CID: 5604472