tbuckley/cabot-search huggingface dataset:
Effect of colon cancer sidedness compared to tumor biology on stage-specific survival.
Authors: Ahmed Dehal, Brooke Vuong, Amanda N Graff-Baker, Jihey Lee, Anton Bilchik, Melanie R Goldfarb
Journal: Journal of Clinical Oncology (2017)

543 Background: Recent studies have reported a survival difference between right colon cancer (RCC) and left colon cancer (LCC) but were limited by lack of data on surgical therapy and underlying tumor biology including microsatellite instability (MSI) status. Our objective was to examine the influence of tumor sidedness on stage-specific survival after adjustment for those factors using a large national database. Methods: Adult patients with primary invasive colon cancer were identified from the National Cancer Data Base (NCDB) between 2009 and 2012. Cecum, ascending colon, hepatic flexure, and transverse colon were classified as “RCC” and sigmoid, descending colon, and splenic flexure were classified as “LCC”. Differences in 3-year overall survival (OS) between RCC versus LCC, stratified by stage, were obtained. Results: Of 24,092 patients, 9,095 (37.75%) presented with a LCC and 14,997 (62.25%) with a RCC. After adjustment for confounding factors, including demographics, MSI, KRAS, nodal retrieval and treatment, patients with RCC stage I, III, or IV had a 31-35% decreased OS compared to those with a LCC. However, in patients with stage II disease, RCC had a 15% improvement in OS compared to LCC (Table 1). MSI positivity was not significantly different in RCC versus LCC stage for stage nor did it contribute to decreased OS for either side. Conclusions: Colon cancer sidedness is an independent risk factor for decreased survival after adjusting for potential confounders including tumor biology and treatment characteristics. For patients with stage I, II, and IV disease, RCC portends a decreased survival compared to LCC, whereas the opposite is true for patients with stage II disease. Further research is needed to elucidate the exact the role of sidedness in risk-profiling and staging for colon cancer patients. [Table: see text]
Natural variation at the soybean J locus improves adaptation to the tropics and enhances yield
Authors: Sijia Lu, Xiaohui Zhao, Yilong Hu, Shulin Liu, Haiyang Nan, Xiaoming Li, Chao Fang, Dong Cao, Xinyi Shi, Lingping Kong, Tong Su, Fengge Zhang, Shichen Li, Zheng Wang, Xiaohui Yuan, Elroy R Cober, James L Weller, Baohui Liu, Xingliang Hou, Zhixi Tian, Fanjiang Kong
Journal: Nature Genetics (2017)
Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD
Authors: Ajay E. Kuriyan, Thomas A. Albini, Justin H. Townsend, Marianeli Rodriguez, Hemang K. Pandya, Robert E. Leonard, M. Brandon Parrott, Philip J. Rosenfeld, Harry W. Flynn, Jeffrey L. Goldberg
Journal: New England Journal of Medicine (2017)

Adipose tissue-derived "stem cells" have been increasingly used by "stem-cell clinics" in the United States and elsewhere to treat a variety of disorders. We evaluated three patients in whom severe bilateral visual loss developed after they received intravitreal injections of autologous adipose tissue-derived "stem cells" at one such clinic in the United States. In these three patients, the last documented visual acuity on the Snellen eye chart before the injection ranged from 20/30 to 20/200. The patients' severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation. After 1 year, the patients' visual acuity ranged from 20/200 to no light perception.
Germline variants in cancer risk genes detected by NGS-based comprehensive tumor genomic profiling (CGP).
Authors: Michael J. Hall, Mary Beryl Daly, Eric A. Ross, Jeff Boyd, Eric M. Sanford, James Sun, Phil Stephens, Daniel Liss, Saisai Chen, Vincent A. Miller, Roman Yelensky, Veda N. Giri
Journal: Journal of Clinical Oncology (2015)

11084 Background: NGS-based CGP is increasingly used in oncology to assess patient eligibility for targeted therapies. Previous work has demonstrated that variant germline/somatic status may be accurately predicted for research use from data generated by CGP (AACR 2014 #1893). The prevalence of germline variants in hereditary cancer risks genes and their potential clinical implications have not been previously reported in patients referred for CGP. Methods: Germline variants were predicted in data from 15060 tumor samples analyzed by Foundation Medicine. Variant analyses focused on 20 penetrant hereditary cancer risk genes identified by the ACMG as high priority for disclosure to patients if discovered during genomic testing. Pathogenicity of each variant and association with tumor histology (known vs unexpected) was assessed through expert review of clinical evidence from public variant annotation databases (dbSNP/ClinVar, BIC, HGMD), and other resources (PubMed, Internet). Results: Of tumors tested, 30.8% (4633/15060) had > 1 germline variant in a cancer risk gene, with 521 unique variants identified overall. A likely pathogenic variant (PV) was found in 3.1% tumors (n = 466/15060), and an additional 3.9% (587/15060) had a suspicious variant but conflicting pathogenicity data. PV prevalence appeared higher than in the general population (CGP PV prevalence; estimated population prevalence): MUTYH (1.3%; 0.02%), RET (0.7%; 0.02%), BRCA1 (0.6%; 0.001%), BRCA2 (0.5%; 0.001%); MLH1 (0.02%; 0.002%), PMS2 (0.02%; 0.001%) and TP53 (0.02%; 0.0002%). Early-onset cancer was most strongly associated with PV in BRCA1(p < 0.001). Bladder cancer (4.1%, 10/243 tumors tested), squamous cell lung cancer (4.4%, 13/293) and kidney cancer (3.4%, 5/148) had the most unexpected PV. Data were insufficient to determine clinical pathogenicity for the majority of the missense variants identified. Conclusions: Germline PV in cancer risk genes are found in 3-7% of patients tested by CGP. There is a pressing need for further research to determine the association of these variants to disease risk. Additional clinical resources are needed to guide oncologists in the interpretation and management of potential PV uncovered by CGP.
Phase I study of preoperative chemoradiation with temozolomide and capecitabine in patients with locally advanced rectal cancer.
Authors: Yong Sang Hong, Seong Joon Park, Jeong Eun Kim, Kyu-Pyo Kim, Jae-Lyun Lee, Jin-hong Park, Jong Hoon Kim, Chang Sik Yu, Jin Cheon Kim, Tae Won Kim
Journal: Journal of Clinical Oncology (2015)

3569 Background: Preoperative chemoradiation (CRT) with capecitabine is one of the standard treatment strategies in patients with locally advanced rectal cancer (LARC). Temozolomide improved survival of patients with glioblastoma when administered with radiotherapy (RT), especially in those with hypermethylated MGMT (O6-methylguanine DNA methyltransferase). MGMT hypermethylation has been suggested as one of the colorectal carcinogenesis pathways. Methods: RT was delivered with 45 Gy/25 daily fractions with coned-down boost of 5.4 Gy/3 fractions. Concurrent chemotherapy consisted of fixed dose of capecitabine (825 mg/m2 twice daily) and escalated dose of temozolomide (45 [level 1], 60 [level 2], and 75 mg/m2/day [level 3]). MGMT hypermethylation was examined by methyl-specific PCR in the pre-treatment tumor samples. Results: Between May 2013 and Apr 2014, a total of 22 patients with LARC of cT3-4N0 or cTanyN1-2 were accrued. Dose-limiting toxicity did not occur among 10 patients up to dose level 3, and the dose level 3 was chosen as the recommended dose (RD). Additional 12 patients were accrued in the RD. There was no grade 4 adverse event (AE), and grade 3 AEs included leucopenia (9.1%), nausea (4.5%), and vomiting (4.5%). Pathologic complete responses (pCR) were observed in 7 patients (7/22, 31.8%). MGMT hypermethylation was found in 16 patients (16/22, 72.7%). The pCR rate was 37.5% (6/16) in the hypermethylated MGMT group and 16.7% (1/6) in the unmethylated MGMT group (p= 0.62). Conclusions: The RD of temozolomide was determined to 75 mg/m2/day when added in the preoperative CRT with capecitabine. Preoperative CRT with temozolomide plus capecitabine was tolerable. There was a tendency of higher pCR rates in those with hypermethylated MGMT, therefore, further randomized study will be warranted. Clinical trial information: NCT01781403.
Uncoupling of BCR Internalization and Signaling in Treatment Naive and Btki-Treated Patients with Chronic Lymphocytic Leukemia
Authors: Eve M Coulter, Andrea Buggins, Silvia Mele, Najeem Folarin, William Townsend, Kirsty Cuthill, Elizabeth Phillips, Piers Patten, Stephen Devereux
Journal: Blood (2016)
Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML).
Authors: Joshua F. Zeidner, Matthew C. Foster, Amanda Blackford, Mark Robert Litzow, Lawrence Morris, Stephen Anthony Strickland, Jeffrey E. Lancet, Prithviraj Bose, M. Yair Levy, Raoul Tibes, Ivana Gojo, Christopher D Gocke, Gary L. Rosner, Jacqueline Greer, Joan M Cain, Richard F. Little, John Joseph Wright, L. Austin Doyle, B Douglas Smith, Judith E. Karp
Journal: Journal of Clinical Oncology (2014)

7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (667 mg/m2/days 6-8) and mitoxantrone (40 mg/m2 day 9) yields complete remission (CR) rates of nearly 70% in pts with newly diagnosed, poor-risk AML. This trial compares "FLAM" with 7+3 in newly diagnosed AML pts. Methods: Between May 2011-July 2013, 165 (FLAM, n=109; 7+3, n=56) newly diagnosed AML pts (18-70 years) with non-favorable cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day, daunorubicin 90 mg/m2) across 10 institutions. Randomization was stratified by age, secondary AML and leukocyte count. Pts with residual leukemia on day 14 received 5+2 on the 7+3 arm, whereas pts treated with FLAM were not retreated on day 14. The primary endpoint was to compare CR rates between 1 cycle of FLAM and 1 cycle of 7+3. Secondary endpoints were safety, CR rates after 1 cycle of FLAM vs 7+3 + 5+2, overall survival (OS), and disease-free survival (DFS). Results: The majority of pts on both arms had at least 1 poor-risk feature, excluding age (FLAM=77%, 7+3=68%). FLAM resulted in higher CR rates compared to 7+3 (70% vs 46%, p=0.003), though this difference was less when compared to 7+3 + 5+2 (70% vs 57%, p=0.08). FLAM also produced higher CR rates in pts with secondary AML (60% vs 35%, p=0.05), pts with >1 poor-risk feature (61% vs 34%, p=0.01), pts without poor-risk features (100% vs 72%, p=0.009), and pts <60 years (79% vs 52%, p=0.02). Relapse rates as of this analysis were similar (FLAM: 36% vs 7+3: 38%). Toxicities were similar between both arms, including grade >3 toxicities, early treatment-related mortality, and time to count recovery. Conclusions: FLAM induction results in significantly higher CR rates compared with 7+3 without increased toxicity. FLAM appears to be more active than 7+3 in pts <60 years of age and those with poor-risk features. Although follow-up is too early to assess OS and DFS, these results are promising and a phase 3 comparison of FLAM vs 7+3 is being explored. Clinical trial information: NCT01349972.
Visual functioning in adult survivors of retinoblastoma.
Authors: Danielle Novetsky Friedman, Joanne F. Chou, Jennifer Ford, Jasmine Francis, Charles A. Sklar, Yuelin Li, Mary S. McCabe, Leslie L. Robison, Ruth Kleinerman, Brian Marr, David H. Abramson, Kevin C. Oeffinger, Ira J. Dunkel
Journal: Journal of Clinical Oncology (2017)

122 Background: Retinoblastoma (Rb) survivors are at risk for adverse oculo-visual outcomes. Limited data are available regarding long-term visual functioning among adult Rb survivors. Methods: Rb survivors, diagnosed from 1932–1994 and treated in New York, completed a comprehensive questionnaire that included the National Eye Institute Visual Function Questionnaire (VFQ-25), which measures self-reported vision-targeted health in individuals with chronic eye diseases. Items are scored from 0–100 with 100 representing the best possible score. Results: 470 adult Rb survivors participated (53.6% with bilateral disease; mean age at study 43.3 yrs, standard deviation [SD] 11); 86% had at least one eye removed (one eye: 74.5%; both eyes: 11.5%) and 53.4% were treated with radiotherapy. 61.3% rated their eyesight as excellent/good while 16.5% reported complete blindness. Among Rb survivors with some vision, 4% described staying home “most of the time” due to their eyesight and 12% reported often feeling frustrated due to their visual status. The overall VFQ composite score for all Rb survivors was 89.2 (SD 10.1) [unilateral Rb survivors: 92.2 (SD 6.3); bilateral Rb survivors: 84.1 (SD 13.0); p &lt; 0.001).Survivors with bilateral disease were significantly more likely to report inferior visual functioning in all domains when compared to those with unilateral disease (Table 1). Conclusions: Rb-related ocular problems continue to impact survivors’ functional status into adulthood, particularly among those with bilateral disease. [Table: see text]
Phase I trial of a nucleoside analog CP-4055 given daily for 5 days every 3 weeks in patients (pts) with advanced solid tumors - preliminary results
Authors: S. Aamdal, S. Dueland, M. J. Lind, H. Thomas, C. R. Franks, M. L. Sandvold, W. Rasch
Journal: Journal of Clinical Oncology (2004)

2049 Background: CP-4055 is a novel optimized nucleoside analog with a wide spectrum of pre-clinical activity in solid tumors due to improved uptake, reduced efflux and resistance to deamination. We report on the first phase I trial in pts with advanced non-small-cell lung cancer (NSCLC), malignant melanoma (MM) and ovarian cancer (OC). Methods: CP-4055 is administered for 5 consecutive days (d) every 3 weeks in a 30-min infusion at 30, 60, 100, 150 and 175 mg/m2/d, 3 pts/dose level (DL) in the absence of dose limiting toxicity (DLT). Standard hematological, biological and clinical DLT definitions are used. Activity is assessed every 2 cycles (cy). PK is determined in all pts at d 1 and 4 of cy 1 Results: : From Dec 02 to Dec 03, 17 pretreated pts (NCSCL: 2 pts, MM: 10 pts, OC: 5 pts) received in total 45 cy of CP-4055 (median 2, range 1–8), M/F: 6 / 11. Three pts were treated at each DL, apart from 5 pts at DL5 (175 mg/m2) due to an apparent DLT. Accrual is ongoing. Safety: The main treatment-related adverse events (AEs) are nausea and vomiting, neutropenia, anemia and moderate fatigue. No significant unexpected AEs occurred, while non-DLT hematological grade 3 and 4 toxicities were seen at the 2 last DLs explored. Efficacy: Stable disease was noted in 6 out of 17 pts, all of whom had progressive disease at inclusion. One NSCLC pt (60 mg/m2) had stabilization of lung lesions for 10+ months in addition to complete resolution of pleural effusion. One OC pt (60 mg/m2) had a reduction of CA125 (189 to 83) in addition to stable disease (2.5 months). Four MM pts (30, 60 [2 pts] and 175 mg/m2) had disease stabilization between 7 and 17 weeks. PK data, linear between DL1 and 4, suggest an intracellular CP-4055 reservoir with sustained Ara-U release. Conclusions: The MTD is expected to be DL5 (175 mg/m2) or 6 (200 mg/m2). On the basis of the favorable safety profile and evidence of activity, further development including schedule/regimen optimization, combination studies and phase II activity exploration are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Clavis Pharma AS Clavis Pharma AS
Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative magnetic resonance imaging.
Authors: Ivan Pedrosa, Yue Zhang, Durga Udayakumar, Ling Cai, Zeping Hu, Payal Kapur, Alberto Diaz de Leon, Qing Yuan, Takeshi Yokoo, Jin Ye, Mathew Mitsche, Hyeonwoo Kim, Jeffrey McDonald, Yin Xi, Ananth J Madhuranthakam, Robert Lenkinski, Jeffrey A Cadeddu, James Brugarolas, Ralph DeBerardinis
Journal: Journal of Clinical Oncology (2017)

460 Background: Dysregulated lipid and glucose metabolism has been implicated in clear cell renal cell carcinoma (ccRCC) progression. Pre-operative tissue-based assessment of tumor metabolic alterations is challenging due to the characteristic heterogeneity of ccRCC. Non-invasive prediction of metabolic alterations in the whole tumor with an imaging method would be appealing for optimal patient management and possibly selection of targeted neoadjuvant therapy. Methods: In this IRB-approved, HIPAA-compliant study, 43 patients (34 M, 9 F) with pathologically confirmed primary ccRCC underwent pre-surgical MRI to quantify whole-tumor intra-tumoral lipid accumulation (% fat fraction, FF) and tumor enhancement (% enhancement) with Dixon-based MRI and dynamic contrast-enhanced MRI, respectively. All patients signed informed consent. Quantitative MRI measures were also obtained from targeted regions of interest within tumors and correlated to lipid accumulation (Oil Red O, ORO) and mass spectrometry-based lipidomics and metabolomics of tissue samples isolated from anatomically co-registered locations in the same tumor using fiducial markers placed at the time of surgery. Linear regression was performed to correlate FF and ORO %. Univariate statistical differences of the metabolites between two groups were analyzed using Student’s t-test. Results: In vivo tumor FF correlated positively with histologic fat content (Spearman correlation coeff. ρ = 0.86, p &lt;0.0001), spectrometric triglycerides (ρ = 0.56, p = 0.0007) and cholesterol (ρ = 0.47, p = 0.006), respectively; and negatively with spectrometric free fatty acids (ρ = -0.44, p = 0.01) and phospholipids (ρ = -0.65, p = 0.001), respectively. ISUP grade 2 and 3 tumors exhibited marked intra-tumoral FF heterogeneity, whereas grade 4 tumors had reduced lipid accumulation compared to grade 3 (p = 0.016). Aqueous metabolites were different in tumors compared to renal parenchyma and 11 metabolites showed significant correlation with tumor vascularity (FDR p &lt;0.05). Conclusions: MRI-derived FF and tumor enhancement correlated with the altered metabolic features of ccRCC and the metabolic heterogeneity within a given tumor.
Haploidentical stem cell transplantation (Haplo-HSCT) with nonmyeloablative conditioning regimen (NMAC) and postinfusion cyclophosphamide in advanced non-Hodgkin lymphoma (NHL) patients.
Authors: Sylvain Garciaz, Luca Castagna, Sabine Furst, Stefania Bramenti, Jean El Cheikh, Roberto Crocchiolo, Diane Coso, Benjamin Esterni, jean Marc Schiano, Barbara Sarina, Boris Calmels, Angela Granata, Raynier Devillier, Samia Harbi, Reda Bouabdallah, Armando Santoro, Didier Blaise
Journal: Journal of Clinical Oncology (2014)

7039 Background: In patients lacking HLA identical (HLA-id) donors, haploidentical (Haplo) donors is increasingly considered as a valid alternative stem cell source.The introduction of post-infusion Cyclophosphamide (Cy) as prophylaxis for immunological complications using T-cell replete graft is one of the most usual strategy. However, efficacy is still a matter of debate. Here we reviewed the outcome of 28 consecutives Haplo-HSCT patients with advanced NHL that we compared to an historical control cohort of patients transplanted from HLA-id donors. Methods: 28 Haplo-HSCT were performed between 04/06/2010 and 27/09/2013. Diagnoses were aggressive NHL in 22 patients and low-grade NHL in 6. Median age was 48 years (19-67). At transplant, 64% were in complete remission, 29% in partial remission and 7% in stable disease. These 28 patients were fully matched to 61 HLA-id patients. Conditioning regimen varied according to donor source. Haplo-HSCT patients received a NMAC associating of Fludarabine (150mg/m² total dose over 5 days), pre-infusion Cy (29 mg/kg total dose over two days), Low dose TBI 2 gray and post infusion Cy (100mg/kg total dose over 2 days). The HLA-id cohort reduced intensity conditionning consisted in Fludarabine (150mg/m² total dose over 5 days), intravenous Busulfan (6.4 mg/kg total dose over 2 days) and antithymocyte globulin (Thymoglobulin; 5 mg/kg total dose over 2 days). Results: With a median follow up of 15 months (2-70), the 2-year PFS and OS were 67% and 62% respectively in the Haplo-HSCT group. Incidence of day-100 acute grade 3-4 GVHD was 7%. The 24-months estimated incidence of chronic GVHD (cGVHD) and extensive cGVHD, was 7% and 4%. The 2-year NRM was 18%. The 2-year cumulative incidence of relapse was 20%. There was no statistical difference found when compared to the HLA-id group of patients for all outcomes. Conclusions: These results suggest that NMAC HSCT from Haploidentical donors achieves promising anti-tumor effect with an acceptable NRM and a low incidence of GVHD. Haplo-HSCT should represent a valuable alternative for patients with advanced NHL without available HLA-id donors.
Response of nonenhancing regions in glioblastoma to VEGF-signaling inhibitor cediranib correlates with tumor infiltration.
Authors: Summer A Fakhro, Dominique Jennings, Marco C Pinho, Nancy U. Lin, A. Gregory Sorensen, Tracy Batchelor, Elizabeth Robins Gerstner
Journal: Journal of Clinical Oncology (2012)

3036 Background: Antiangiogenic therapy has limited direct antitumor effect in glioblastoma (GBM). Mainly its benefits may derive from anti-permeability and anti edema effects. In GBMs treated with cediranib we found that regions on MRI that are suggestive of being vasogenic edema, according to Diffusion Tensor Imaging (DTI) data, experience a greater decrease in volume than non-enhancing regions suggestive of being tumor infiltrated. Methods: Thirty-four newly diagnosed GBM patients were scanned on 3Tesla Siemens at two pre-therapy time points (2 days apart). Patients were treated with cediranib, standard radiation and temozolomide. Due to technical difficulties, 4 patients were left out of the analysis. Diffusion images were acquired with TR=7500ms, TE=84ms and b-values 0 and 700s/mm 2 in 42 directions. A board certified radiologist determined the extent of abnormality on FLAIR and T1-weighted post contrast images. Non-enhancing regions (NER) were determined by subtracting the T1 enhancing area and any necrosis from the FLAIR abnormality. Volume of NERs was observed at baseline and day 47 of treatment. Mean Apparent Diffusion Coefficient (ADC) and mean Fractional Anisotropy (FA) of the NER were used to represent extent of tumor burden. Tumor Infiltration Index (TII), a measure based on comparing DTI metrics in metastatic tumors to GBM, was also derived. Twelve patients with metastatic cancer to the brain who underwent the same imaging and analysis pretreatment were used. High FA and low ADC and TII represent areas with more tumor burden. Results: There was a significant correlation between mean FA in the NERs at baseline and the percent volume reduction of the NER at day 47 (rho=0.45, p&lt;0.02). Similarly, ADC and TII were correlated with percent volume reduction in the NER. Conclusions: DTI metrics have been used in GBMs to measure tumor infiltration. We found volume reduction of NERs to be inversely correlated to tumor burden. Thus, glioma patients with greater vasogenic edema may benefit from a different treatment paradigm than patients with lower vasogenic edema. [Table: see text]