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Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline

Schiff, David; Messersmith, Hans; Brastianos, Priscilla K; Brown, Paul D; Burri, Stuart; Dunn, Ian F; Gaspar, Laurie E; Gondi, Vinai; Jordan, Justin T; Maues, Julia; Mohile, Nimish; Redjal, Navid; Stevens, Glen H J; Sulman, Erik P; van den Bent, Martin; Wallace, H James; Zadeh, Gelareh; Vogelbaum, Michael A
PURPOSE/OBJECTIVE:American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS:was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS:. RECOMMENDATIONS/CONCLUSIONS:is conditionally recommended.Additional information is available at
PMID: 35561283
ISSN: 1527-7755
CID: 5214992

Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer

LaRue, Madeleine M; Parker, Seth; Puccini, Joseph; Cammer, Michael; Kimmelman, Alec C; Bar-Sagi, Dafna
SignificanceThe highly desmoplastic and immunosuppressive microenvironment of pancreatic tumors is a major determinant of the aggressive nature and therapeutic resistance of pancreatic cancer. Therefore, improving our understanding of the mechanisms that regulate the composition and function of the pancreatic tumor microenvironment is critical for the design of intervention strategies for this devastating malignancy. This study identifies a modality for the reprogramming of tumor-associated macrophages involving collagen scavenging followed by a metabolic switch toward a profibrotic paracrine phenotype. These findings establish a molecular framework for the elucidation of regulatory processes that could be harnessed to mitigate the stroma-dependent protumorigenic effects in pancreatic cancer.
PMID: 35412885
ISSN: 1091-6490
CID: 5201902

Precision medicine in pancreatic cancer: Patient derived organoid pharmacotyping is a predictive biomarker of clinical treatment response

Seppälä, Toni T; Zimmerman, Jacquelyn W; Suri, Reecha; Zlomke, Haley; Ivey, Gabriel D; Szabolcs, Annamaria; Shubert, Christopher R; Cameron, John L; Burns, William R; Lafaro, Kelly J; He, Jin; Wolfgang, Christopher L; Zou, Ying S; Zheng, Lei; Tuveson, David A; Eshlemann, James R; Ryan, David P; Kimmelman, Alec C; Hong, Theodore S; Ting, David T; Jaffee, Elizabeth M; Burkhart, Richard A
RATIONALE/BACKGROUND:Patient-derived organoids (PDOs) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping). METHODS:PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized-controlled clinical trial. RESULTS:Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathological response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, CA-19-9 and favorable RECIST imaging response. CONCLUSION/CONCLUSIONS:PDOs establishment from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically-certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in-vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.
PMID: 35363262
ISSN: 1557-3265
CID: 5206092

Nodal Metastases in Pediatric and Adult Acinic Cell Carcinoma of the Major Salivary Glands

Dublin, Jared C; Oliver, Jamie R; Tam, Moses M; Persky, Michael J; Jacobson, Adam S; Liu, Cheng; Hu, Kenneth S; Vaezi, Alec E; Morris, Luc G T; Givi, Babak
OBJECTIVE:Acinic cell carcinoma (AciCC) is a rare, usually low-grade salivary malignancy. Evidence on rates of lymph node metastases (LNMs) is limited in pediatric patients and varies significantly (4%-45%) in adults. We set out to determine and compare rates of LNMs in pediatric and adult AciCC and to analyze their impact on survival, using the National Cancer Database. STUDY DESIGN/METHODS:Historical cohort study. SETTING/METHODS:National Cancer Database. METHODS:All AciCCs of the major salivary glands with complete clinical and pathologic nodal staging were selected between 2010 and 2016. Patient demographics, tumor characteristics, treatment, and survival were analyzed. Univariable and multivariable regression were performed to determine factors associated with LNMs and survival. RESULTS:< .001) were associated with LNM in adult patients. CONCLUSION/CONCLUSIONS:LNMs in AciCC of the major salivary glands are rare in children and adults. However, high-grade and T3-T4 tumors are associated with an increased risk of LNM. LNM is associated with worse survival.
PMID: 35259039
ISSN: 1097-6817
CID: 5183472

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline

Vogelbaum, Michael A.; Brown, Paul D.; Messersmith, Hans; Brastianos, Priscilla K.; Burri, Stuart; Cahill, Dan; Dunn, Ian F.; Gaspar, Laurie E.; Gatson, Na Tosha N.; Gondi, Vinai; Jordan, Justin T.; Lassman, Andrew B.; Maues, Julia; Mohile, Nimish; Redjal, Navid; Stevens, Glen; Sulman, Erik; Van Den Bent, Martin; Wallace, H. James; Weinberg, Jeffrey S.; Zadeh, Gelareh; Schiff, David
Purpose: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature. Results: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.
ISSN: 1522-8517
CID: 5198312

Five-Fraction Prone Accelerated Partial Breast Irradiation: Long-Term Oncologic, Dosimetric, and Cosmetic Outcome

Shah, Bhartesh A; Xiao, Julie; Oh, Cheongeun; Taneja, Sameer; Barbee, David; Maisonet, Olivier; Huppert, Nelly; Perez, Carmen; Gerber, Naamit K
PURPOSE/OBJECTIVE:Randomized data support accelerated partial breast irradiation (APBI) for early-stage breast cancer with variable techniques and cosmesis outcomes. We have treated patients with 5-fraction prone external beam APBI for over a decade and herein report acute and late outcomes. METHODS AND MATERIALS/METHODS:Patients receiving APBI 600 cGy × 5 between 2010 and 2019 were included. APBI was primarily delivered prone, with opposed tangents targeting the tumor bed expanded by 1.5 cm (cropped 6 mm from skin). Ipsilateral breast was constrained to V50% < 60% and V100% < 35%. Survival was estimated with Kaplan-Meier. Late toxicities and clinician- and patient-rated cosmesis were evaluated for patients with >6 months follow-up (FU). RESULTS:Of 345 patients meeting criteria, 14 were excluded due to APBI given for ipsilateral breast tumor recurrence (IBTR; n = 3), palliation (n = 9), and incomplete radiation therapy course (n = 2). Of the 331 remaining, median age was 70, 7.2% had ductal carcinoma in situ, and 94.3% were treated prone, with 32% treated every other day and 68% on consecutive days. Mean heart dose was 23.8 cGy for left-sided and 12.7 cGy for right-sided cancers. Ipsilateral lung V30% was 0.4%. At 5-year median FU, there were 7 (2.1%) IBTR, 9 (2.7%) contralateral recurrences, and 1 (0.3%) distant metastasis. Five-year local recurrence-free, disease-free, and overall survival was 99.5%, 96.7%, and 98.1%, respectively. When comparing patients with IBTR versus without, a higher proportion did not receive hormone therapy (71.4% vs. 26.2%, P = .018). Rates of acute grade 1 to 2 dermatitis, fatigue, and pain were 35.4%, 21.8%, and 9.4%, respectively, with no grade 3 toxicity. The rate of good-excellent physician- and patient-rated cosmesis (n = 199, median FU 2.8 years) was 92.5% and 89.4%, respectively. Patients experienced low rates of telangiectasia, fibrosis, and retraction/atrophy. CONCLUSIONS:We report excellent dosimetric, oncologic, cosmetic, and late toxicity outcomes for patients treated with 5-fraction APBI. To our knowledge this is the largest series of women treated with prone APBI.
PMID: 34474168
ISSN: 1879-8519
CID: 5026612

Osteoradionecrosis following radiation to reconstructed mandible with titanium plate and osseointegrated dental implants

Byun, David J; Daar, David A; Spuhler, Karl; Anzai, Lavinia; Witek, Lukasz; Barbee, David; Jacobson, Adam S; Levine, Jamie P; Hu, Kenneth S
PMID: 34706296
ISSN: 1879-8519
CID: 5042562

Toxicity and cosmetic outcome of breast irradiation in women with breast cancer and autoimmune connective tissue disease: the role of fraction and field size

Purswani, Juhi M; Jaros, Brian; Oh, Cheongeun; Sandigursky, Sabina; Xiao, Julie; Gerber, Naamit K
BACKGROUND:Hypofractionation has historically been underutilized among breast cancer patients with connective tissue diseases given a theoretical risk for increased toxicity and their overall underrepresentation in clinical trials that established hypofractionation as standard of care. We aim to compare the rates of toxicity in patients with autoimmune connective tissue diseases treated with conventionally fractioned radiation therapy (CF-RT) and hypofractionated RT (HF-RT) including accelerated partial breast irradiation. MATERIALS AND METHODS/METHODS:1,983 patients treated with breast conservation between 2012 and 2016 were reviewed for diagnosis of autoimmune disease. Univariate analysis using binary logistic regression was performed to evaluate the effect of disease and treatment variables on acute and late toxicity. Multivariate analyses using Cox regression models were used to evaluate the independent associations between covariates and the primary endpoints. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated for reach risk group. RESULTS:92 patients with autoimmune disease were identified. Median follow-up was 59 months. 35% of patients received CF-RT and 65% of patients received hypofractionated RT (HF-RT), of which 70% received whole breast radiation (WBI) without regional nodal irradiation (RNI), 12% received WBI with RNI, and 18% received accelerated partial breast radiation. Patients who received CF-RT were significantly more likely to have AD symptoms (78% vs 37%, p<0.001), to be managed on DMARDs (41% vs 15%, p=0.013) and to have active autoimmune disease (84% vs 43%, p<0.001). On multivariate analysis, HF-RT was associated with a significantly decreased odds of acute and late grade 2/3 toxicity compared to CF-RT fractionation (acute: OR 0.200 95% CI 0.064-0.622, p=0.005; late: OR 0.127 95% CI 0.031 - 0.546, p=0.005). CONCLUSION/CONCLUSIONS:Hypofractionation including APBI is associated with less acute or late grade 2/3 toxicity in this population.
PMID: 34774868
ISSN: 1879-8519
CID: 5048852

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement

Bagley, Stephen J; Kothari, Shawn; Rahman, Rifaquat; Lee, Eudocia Q; Dunn, Gavin P; Galanis, Evanthia; Chang, Susan M; Nabors, Louis Burt; Ahluwalia, Manmeet S; Stupp, Roger; Mehta, Minesh P; Reardon, David A; Grossman, Stuart A; Sulman, Erik P; Sampson, John H; Khagi, Simon; Weller, Michael; Cloughesy, Timothy F; Wen, Patrick Y; Khasraw, Mustafa
Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on as "recruiting" or "not yet recruiting" as of February 2021.
PMID: 34561269
ISSN: 1557-3265
CID: 5178432

Update on Radiation Therapy for Central Nervous System Tumors

Rahman, Rifaquat; Sulman, Erik; Haas-Kogan, Daphne; Cagney, Daniel N
Radiation therapy has long been a critical modality of treatment of patients with central nervous system tumors, including primary brain tumors, brain metastases, and meningiomas. Advances in radiation technology and delivery have allowed for more precise treatment to optimize patient outcomes and minimize toxicities. Improved understanding of the molecular underpinnings of brain tumors and normal brain tissue response to radiation will allow for continued refinement of radiation treatment approaches to improve clinical outcomes for brain tumor patients. With continued advances in precision and delivery, radiation therapy will continue to be an important modality to achieve optimal outcomes of brain tumor patients.
PMID: 34711456
ISSN: 1558-1977
CID: 5042732