tbuckley/cabot-search huggingface dataset:
Systematic difference between Estimated IQ (EIQ) and Full Scale IQ (FSIQ) in survivors irradiated for pediatric brain tumors.
Authors: Laura Burgess, Margaret B. Pulsifer, Beow Y. Yeap, Julie A. Grieco, Elliott R. Weinstein, Shannon M. MacDonald, Nancy Tarbell, Torunn I. Yock
Journal: Journal of Clinical Oncology (2016)

10557 Background: Radiotherapy (RT) for pediatric brain tumors is often essential to attain a cure, but is associated with adverse neurocognitive sequelae (NS) manifested as declines in FSIQ. Processing speed (PS) is the component most affected. EIQ is frequently used to estimate FSIQ and is typically calculated from Vocabulary, Information and Block Design subtests, none of which assess PS. Although EIQ and FSIQ are correlated, we hypothesize that EIQ may systematically underestimate NS of RT in pediatric brain tumor survivors. Methods: 66 pediatric patients treated with proton RT for brain tumors at MGH from 2003-2013 had a baseline (BL) and 1 – 3 follow up (FU) neuropsychological evaluations (n = 156) with data to calculate both FSIQ and EIQ (from subtests). Wechsler Intelligence scales (WISC, age 6 - < 16 and WAIS, age 16+) were used. The differences between EIQ and FSIQ were analyzed using mixed linear models to assess disparities at BL and change over time. Results: Median FU was 25.8 months. At BL, EIQ was 1.3 points (95% CI: -0.3 – 2.9) higher on average than FSIQ (P < 0.016). A difference persists over time (p = 0.0245), with FSIQ losing 0.5 points/year (95% CI: 0.07 – 1.0) relative to EIQ. The difference between EIQ and FSIQ was more pronounced in younger children ( < 8 years vs. 8+; p = 0.146), diverging by 1 point/year. That is, at 5 years after RT in children < 8 years, on average, EIQ overestimates FSIQ by 5 points. RT Field (35 patients with craniospinal irradiation, CSI, and 31 patients without CSI) and gender did not have an effect on the EIQ/FSIQ differences. Conclusions: EIQ systematically overestimates the FSIQ of all children treated with cranial RT, but the effect is magnified in children < 8 years. Although more time consuming, FSIQ is more likely to identify deficits and lead to appropriate recommendations for academic accommodations. Because EIQ tends to underestimate NS compared to FSIQ, it should have a limited role in clinical and research settings. Patients (%) Sex Male 38 (58%) Female 28 (42%) Age Median 11.9 years < 8 years 12 (18%) > 8 years 54 (82%) Histology Medulloblastoma 29 (44%) Other 37 (56%)
Pazopanib plus sirolimus following escape from pazopanib alone: An intriguing observation—A series of 8 metastatic STS patients.
Authors: Daniela Katz, Tamar Peretz, Feras Eleyan, Yusef Azraq, Ofer Merimsky
Journal: Journal of Clinical Oncology (2016)

e22538 Background: Pazopanib, (P) a multikinase inhibitor targeting the VEGF and PDGF has been the first targeted therapy to supplement the arsenal of chemotherapies in soft tissue sarcoma (STS). With a manageable toxicity profile comprised mainly of fatigue, diarrhea, HTN P is capable of controlling STS for several months before resistance develops and chemotherapy is resumed. Preclinical data showed that mTOR inhibition indirectly affects angiogenesis. It affects endothelial cell proliferation and tumor cell production of VEGF via its downstream effect on the hypoxia inducible factor 1. Sirolimus (S) is an oral mTOR inhibitor. We report on a series of 8 metastatic STS patients for whom P treatment was supplemented by S, after escape from P alone. Methods: Second line and beyond metastatic STS patients, who progressed on P after a response duration of at least 4 months were re-challenged with combination of P 600mg and S 3-4mg, in two medical centers; Hadassah Medical Center and Tel Aviv Medical Center. Patients were evaluated for response after 6 w of treatment; patients with response or SD continued treatment until DP. Results: Eight patients (5 females) (1 ULMS, 2 SFT, 2 UPS, 1 LMS, 1 DSRCT, 1 undifferentiated uterine sarcoma (UUS)) between the ages of 36-74 received the combination (P+S) in 2nd lines and beyond, following 4-28m of P alone. Four patients, 3 and 1 had PD (2 SFT+1 UPS+UUS), SD and PR (UPS) as best response, respectively. Treatment duration on the combination ranges between 5m to not-reached yet. One patient ULMS with SD underwent lung metastasectomy after 8m on the combination her treatment is on-going after 17 m. Except of one case of small bowel perforation, probably related to the efficacy of the combination, surgically treated with complete recovery and one case of hyperglycemia managed with metformin, treatment was very well tolerated without added side effects. Conclusions: Supplementing P with S, has reversed resistance to P in 4 of 8 patients. The combination delays reintroduction of chemotherapy extending the chemo-free window with good quality of life. A study designed to prove this concept is underway.
Effect of Oncology Analytics (OA) cancer care quality initiative on inappropriate use of erythropoiesis stimulating agents (ESA) among cancer patients receiving chemotherapy with curative intent.
Authors: William J. Hrushesky, Charles L. Bennett, Dinah Faith Q Huff, Carol Anthony, Laura Rose Bobolts, Jurgen Kogler, Melissa Armitage, Marc L. Fishman, William S. Shimp, Anmol Baranwal, Val Fishman, Sharon Davis, Robert Walton
Journal: Journal of Clinical Oncology (2014)

e17552 Background: ESA use in cancer patients to counter anemia associated with chemotherapy is extremely common despite the fact that experimental and level 1 clinical data suggest that ESAs have the potential to stimulate cancer growth and spread. FDA/NCI consensus conferences, all major guidelines, and ASCO policy recommend against ESA use in cancer patients being treated with curative intent. OA is a cancer decision-support company which screens all therapeutic requests for patients of one major payor and their network of 2,800 southeastern US oncology providers. In 2011, OA initiated a four-tiered quality enhancement program to manage such ESA requests: (1.) Auto-processing interactions discouraging ESA use in adjuvant/curative settings (2.) Educational fax bringing relevant data to the requesting oncologists (3.) Oncologist-to-oncologist peer review of all relevant data (4.) Recommendation to payer not to approve request and not to pay for ESA. We hypothesize that this OA quality enhancement initiative will diminish the use of ESAs in adjuvant/curative settings over time. Methods: We tabulated all requests for potentially curative cancer chemotherapy over 12 consecutive quarters (2011-2013). We then analyzed the proportions of all concurrent ESA requests for patients being treated in the adjuvant/curative setting over this period by chi squared analysis. Results: 1,989 potentially curative chemotherapy requests were made during these 36 months. Concurrently, 88 (4.4%) ESA requests were made for patients being treated with curative intent. There was a persistence of inappropriate requests throughout these 12 quarters which diminished steadily across time. The proportion of ESA requests declined relative to the number of adjuvant chemotherapy requests, from 9% in early 2011 to 3% by the end of 2013 (chi-sq 76.9; p<0.001). Conclusions: Active monitoring of inappropriate ESA use by board certified OA medical oncologists materially diminishes ESA prescribing in the curative setting resulting in safer, less costly cancer care. Continued monitoring is essential for maintaining this quality advantage.
Circulating biomarkers in a phase II study of hypofractionated proton beam therapy (H-PBT) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).
Authors: Theodore S. Hong, Erin I McDonnell, Beow Y. Yeap, Jennifer Yon-Li Wo, Lawrence Scott Blaszkowsky, Eunice Lee Kwak, Jeffrey W. Clark, Lipika Goyal, David P. Ryan, Thomas F. DeLaney, Andrew X. Zhu, Dan G. Duda
Journal: Journal of Clinical Oncology (2016)

4083 Background: To explore the association of circulating biomarkers with outcome of patients treated with H-PBT for HCC and ICC. Methods: Pts enrolled at MGH in a phase II study (NCT00976898) of H-PBT for localized HCC (n = 21) or ICC (n = 20) (Hong, JCO 2016) had plasma biomarkers measured at baseline and weekly during PBT, and included growth factors, inflammatory cytokines, soluble receptors, and markers of hypoxia and fibrosis. Associations of PFS and OS were analyzed by dichotomizing at the observed median of baseline levels and reported as a hazard ratio (HR) estimated by proportional hazards regression, with exact p-values based on a 2-sided logrank test. Results: 2 yr OS and PFS was 49% and 30% for HCC pts and 32% and 17% for ICC pts. Baseline levels and changes of biomarkers of tumor microenvironment (hypoxia, fibrosis, inflammation) were significantly correlated with PFS and OS for HCC (Table, select OS sig values), but not ICC. However, baseline levels of plasma HGF were significantly correlated with OS of both ICC and HCC pts. Conclusions: The outcome of PBT inboth HCC and ICC was associated with baseline values and on-treatment changes in circulating biomarkers. While HGF data suggest a common mechanism of resistance for HCC/ICC, markers of microenvironment suggest differential mechanism, consistent with the different biology and outcomes. Clinical trial information: NCT00976898. HCC: OS HCC: PFS ICC: OS ICC: PFS Baseline Post-PBT Baseline Post-PBT Baseline Post-PBT Baseline Post-PBT HR P HR P HR P HR P HR P HR P HR P HR P Growth Factors HGF 8.7 0.001 0.2 0.236 2.4 0.115 0.05 0.044 3.3 0.043 0.5 0.351 1.5 0.419 0.7 0.476 PlGF 6.0 0.011 0.7 0.619 3.0 0.048 0.9 0.832 1.7 0.303 0.5 0.231 2.1 0.159 0.5 0.173 Ang-2 4.3 0.027 1.6 0.745 2.5 0.087 1.1 0.859 1.0 0.968 3.4 0.068 0.9 0.899 0.8 0.667 Soluble Receptors sMet 5.8 0.009 1.6 0.503 3.0 0.036 1.2 0.800 1.7 0.329 0.8 0.781 0.8 0.750 1.3 0.693 Inflammatory Cytokines IL-8 17.4 .0002 0.7 0.536 4.4 0.007 0.5 0.274 1.7 0.321 0.5 0.285 0.7 0.511 1.2 0.751 SDF1a 9.3 .0008 1.2 0.785 2.7 0.062 1.2 0.823 2.2 0.136 0.6 0.525 1.1 0.922 0.2 0.074 Hypoxia CAIX 7.0 0.009 NA 0.061 4.9 0.006 6.2 0.042 1.5 0.507 0.8 0.735 1.5 0.444 0.7 0.639 Fibrosis TIMP1 22.4 .0002 0.9 0.857 6.0 0.003 1.3 0.681
P04.10 Chains of magnetosomes induce full destruction of intracranial U87-Luc and subcutaneous GL-261 glioma in mice under the application of an alternating magnetic field
Authors: E Alphandery, A Idbaih, C Adam, J Delattre, C Schmitt, F Guyot, I Chebbi
Journal: Neuro-Oncology (2018)

Among the new approaches to treat glioma, lies the idea to heat locally the tumor cells using nanoparticles exposed to an alternating magnetic field (AMF). Until now, chemically synthesized nanoparticles were tested, leading to partial antitumor activity due to their sub-optimal magnetic properties. We had the idea to use a new type of nanoparticles synthesized by magnetotactic bacteria called magnetosomes with a series of advantageous properties: i), a chain arrangement that leads to uniform nanoparticle and heat distribution in the tumor, ii), ferrimagnetic properties that enhance nanoparticle heating power and iii), a controllable release of endotoxins that can attract immune cells possibly involved in tumor destruction. We administered a suspension of magnetosomes in intracranial U87-MG and subcutaneous GL-261 glioma tumors followed by several AMF applications and we monitored the evolution of the tumor size after treatment using either an IVIS spectrum for the intracranial luminescent tumors or a caliper for the subcutaneous ones. Mice were kept during 6 months after treatment to verify that GBM tumor does not regrow and a few mice were euthanized 6 months after treatment to examine if the brain had been damaged by the treatment. we show that we can induce the disappearance of GBM tumors using the magnetosomes, a behavior that was not observed using chemically synthesized nanoparticles administered at equivalent quantity. Mice treated with the magnetosomes and AMF applications are alive 6 months following treatment and histological analysis of their brain tissue does not show any sign of brain damage. Interestingly, it also appears that full glioma destruction is achieved when magnetosomes occupy only 10% of the whole tumor volume suggesting involvement of an indirect anti-tumor mechanism which is valuable in treatment of infiltrating tumor, such as glioma, that can hardly be fully covered by nanoparticles. In this study, we present a method that yields the full disappearance of GBM tumors in two different GBM mouse models using biological nanoparticles heated by an AMF. The treatment appears to be efficient in mice without resulting in significant observable side effects.
In vivo synergism between PARP-inhibitor olaparib and HSP90-inhibitor AT13387 in high grade serous ovarian cancer patient derived xenografts.
Authors: Panagiotis Konstantinopoulos, Sangeetha Palakurthi, Qing Zeng, Shan Zhou, Joyce F. Liu, Elena Ivanova, Cloud Paweletz, Naveen Kommajosyula, Alan D. D'Andrea, Geoffrey Shapiro, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2016)

e17045 Background: Our previous in vitro work has demonstrated that HSP90-inhibition suppresses homologous recombination (HR) DNA repair and sensitizes HR-proficient ovarian cancer lines to platinum and PARP-inhibitors(PARPis). In this study, we evaluated the combination of PARPi olaparib and the HSP90-inhibitor AT13387 in vivo, in a panel of molecularly characterized high grade serous ovarian cancer patient derived xenograft (PDX) mouse models. Methods: PDX models were established from fresh human ascites samples from patients with either newly diagnosed or recurrent ovarian cancer through an IRB approved protocol. High grade serous ovarian cancer (HGSOC) cells were implanted intraperitoneally into immunocompromised mice and these models were luciferized thereby providing the ability to follow tumor growth and response to therapy by non-invasive bioluminescent imaging technology. Response to therapy was also evaluated by CA125 levels. Olaparib and AT13387 combination tolerability studies were performed prior to the initiation of combination efficacy studies. Results: Tolerability studies demonstrated that doses of olaparib up to 100mg/kg po daily x 3 weeks and AT13387 up to 45mg/kg po for 2 days on / 5 days off x 3 weeks (Days 1, 2, 8, 9, 15, 16) were well tolerated without weight loss in the mice or gross changes in normal tissue histology. Preclinical evaluation of efficacy of treatments (vehicle vs AT13387 vs olaparib vs olaparib plus AT13387) was subsequently performed in one mouse per treatment arm in each PDX model. The combination of AT13387 and olaparib inhibited tumor growth in 8 of 14 PDX models including one BRCA1-mutated/PARPi-resistant model, 2 models with CDKN2A loss and 1 model with CCNE1 amplification. Of these 8 models, 4 were clinically platinum resistant, 2 platinum sensitive, and 2 unknown. Of 11 models with measurable CA125, CA125 responses were seen in 7 models. Pharmacodynamic studies are ongoing. Conclusions: PARPi olaparib and HSP90i AT13387 exhibit synergistic activity in vivo, in a number of high grade serous ovarian cancer PDX models, including HR proficient models. A phase I clinical trial of this combination in HGSOC is planned.
A new risk assessment model for VTE derived from a prospective multicenter longitudinal study for the evaluation of VTE risk in ambulatory cancer patients: The COMPASS cancer study.
Authors: Ismail Elalamy, Ali Taher, Hikmat Abdel-Razeq, Essam Abo El Nazar, Grigoris Gerotziafas
Journal: Journal of Clinical Oncology (2016)

e21662 Background: In ambulatory patients with common cancers the risk of VTE increases during chemotherapy. In these patients individual risk factors cannot evaluate the risk whereas the Khorana risk assessment model (RAM) is not applicable. The COMPASS CANCER study was designed to elaborate and prospectively validate a VTE RAM specific to ambulatory cancer patients on anticancer treatment. Methods: . Patients from 6 centers (France, Lebanon, Jordan, KSA, Kuwait and Syria) with breast, lung, colorectal or ovarian cancer were included and followed at 3, 6 and 12 months. Documented symptomatic VTE was the end-point. Multivariate analysis was done and the RAM was developed using the logistic regression. Sensitivity, specificity and predictive value of the RAM were calculated. The ROC Curve was plotted. Results: The study included 1355 patients (age 55±12 years, 77% female) with breast (60%), colorectal (19%), lung (14%) or ovarian cancer (7%); 30% were at a localized stage, 30% were at a locally advanced stage and 40% had metastatic disease. In 60% of patients, the cancer was diagnosed within 6 months prior to inclusion. Patients were on chemotherapy (63%) or radiotherapy (26%) and 32% had indwelling venous devices (IVD). In total, 88 symptomatic VTE were diagnosed (6.5%), 77% of which occurred within the first 3 months after inclusion. The RAM includes the following variables: Anticancer Treatment (hormone-chemotherapy), Hospitalization, Time Since Cancer Diagnosis, Platelet Count, Advanced Stage of Cancer, IVD, Personal or Family History of VTE, Cardiovascular Risk Factors. Rates of VTE were 2.4%, 5.6% and 25.2% in the low, moderate and high risk groups respectively. The AUC of ROC analysis was 0.81. The sensitivity and the specificity were 75% and 78%, respectively. The positive and negative predictive values are 25.2% and 97%, respectively. Conclusions: The new RAM for VTE is specific for ambulatory patients with common cancers currently receiving treatment. It can reliably predict VTE risk using simple clinical variables and can be used by physicians for the identification of ambulatory cancer patients eligible for thromboprophylaxis.
Outcome of cetuximab plus irinotecan in relation to RAS and BRAF mutational status in patients with colorectal cancer prior treated with a fluoropyrimidine, oxaliplatin and irinotecan.
Authors: Jesper Andreas Palshof, Troels Dreier Christensen, Tim Svendstrup Poulsen, Benny Vittrup Jensen, Dorte Linnemann, Jakob Vasehus Schou, Per Pfeiffer, Mette K. N. Yilmaz, Ib Jarle Christensen, Estrid V. Høgdall, Dorte Nielsen
Journal: Journal of Clinical Oncology (2016)

e15115 Background: Recently, analyses of tumor samples from large phase III studies have demonstrated that epidermal growth factor (EGFR)-targeted monoclonal antibodies (mAbs) treatment in first-line should be limited to patients with KRAS and NRAS exons 2, 3 and 4 wild-type (wt) tumors. Since only limited data exist on patients receiving later-line treatment with EGFR-targeted therapy and outcome in relation to RAS status, we analyzed the mutational status of RAS and BRAF in 480 patients receiving cetuximab and irinotecan. All patients were prior treated with a fluoropyrimidine, oxaliplatin and irinotecan. Methods: A Danish national cohort of 480 consecutive patients with mCRC prior treated with a fluoropyrimidine, oxaliplatin and irinotecan who received at least one treatment of cetuximab plus irinotecan from 2005 to 2009 without knowledge of KRAS/RAS status were retrospectively included. DNA was extracted from primary tumor specimens. Sequencing analyses of KRAS (exons 2, 3, 4), NRAS (exons 2, 3, 4), BRAF(V600E) were performed on Ion Torrent PGM. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations with 100X coverage. Results: RAS and BRAF mutational status was assessed in 448 (93 %) patients. Totally, 278 patients (62%) were KRAS (exon 2) wt,237 (53%) RAS wt, 418 (93 %) BRAF wtand 207 (46%) were RAS/BRAF wt. Fifty-seven patients were not assessable for response evaluation. The overall response rate for the 480 patients was 18%. Patients with RAS wt tumors had a significant better progression-free survival (PFS) with a hazard ratio (HR) of 0.60 (CI 0.49–0.73; p < 0.0001), overall survival (OS) HR 0.75 (CI 0.62–0.90; p = 0.002) and odds ratio (OR) for response OR 4.8 (CI 2.67–8.66; p < 0.0001) compared with patients with RAS mutated tumors. For patients with RAS/BRAFwt tumors we found a HR of 0.55 (CI 0.45–0.66; p < 0.0001) for PFS, a HR 0.68 (CI 0.56–0.82; p < 0.0001) for OS and an OR for a response were OR 4.6 (CI 2.69–8.12; p < 0.0001). Conclusions: Our data suggest that in later-line treatment of mCRC, patients with RAS and BRAF wt tumors are significantly associated with outcome.
Hepatocellular carcinoma outcomes at an academic transplant center: A single-institution retrospective study.
Authors: Charles Vincent Kurkul, Elizabeth Ryer, Abiramy Maheswaran, Erik Holzwanger, Bradley Alan Switzer
Journal: Journal of Clinical Oncology (2017)

e15624 Background: Although there have been recent advances in locoregional therapies, liver transplant remains the only curative treatment for hepatocellular carcinoma. Previous single-institution studies suggest that despite aggressive management, OS for non-transplantable patients remains poor. It has been proposed that multidisciplinary evaluation at a high volume academic center will improve outcomes, though this has not been well reported. Methods: 249 patients with diagnosed HCC evaluated in the UMass multidisciplinary HCC clinic between 2006 and 2016 were identified. Patient demographics, interventions, and outcomes were documented through chart review. Kaplan-Meier survival curves were calculated to compare outcomes. Results: Of the 249 patients, 77% were male and the median age was 64 (22-83). Child-Pugh score at diagnosis was 53% A/32% B/13% C. Comorbidities included hepatitis C (54%), hepatitis B (9%), and NASH (1.2%). Alcoholic liver disease was present in 45% of patients (25% HCV+EtOH). The stage at diagnosis was I/II/III/IV in 43/37/16/4% respectively. 101 patients were eligible for transplant. 54 received a liver. 38 remain on the waiting list. In the 169 non-transplant patients, multiple modalities were utilized including resection (3%), Y90 (6%), TACE (40%), RFA (30%), EtOH ablation (1%), and SBRT (19%). 38% of patients received sorafenib, and 3.5% cytotoxic chemotherapy. 40% of patients had one intervention, 21% had two, 16% had three, and 7% had four or more. 16% of patients received only active surveillance. The median OS for all patients was 4.4 years. Transplanted patients had a 5 year OS of 80%. The median OS for non-transplant patients was 36 months. Median OS by C-P in non-transplant patients was 52/24/11 months (A/B/C). Median OS by stage in the same population was NR/32/11/6 months. Conclusions: While patients with very advanced and severe disease still did poorly, this aggressively treated group demonstrated favorable outcomes when compared to the historically poor survival without transplant.This would imply that multidisciplinary treatment in a high volume center improves outcomes. Further prospective and comparative work is pending.