tbuckley/cabot-search huggingface dataset:
Poly-ligand profiling (PLP) to differentiate pancreatic cancer patients who benefit from gemcitabine+evofosfamide versus gemcitabine+placebo treatment.
Authors: Valeriy Domenyuk, Daniel Magee, Zoran Gatalica, Adam Stark, Patrick Kennedy, Anna Barker, Donald A. Berry, George H. Poste, David D Halbert, Charles P Hart, Michael Famulok, Gunter Mayer, Michael Korn, Mark Robert Miglarese, David Spetzler
Journal: Journal of Clinical Oncology (2018)

12067 Background: The MAESTRO trial randomized 693 locally advanced or metastatic pancreatic cancer patients to gemcitabine (G) + placebo vs G + evofosfamide (GE). OS hazard ratio (HR) was 0.84; p = 0.059. We developed a PLP assay that identifies patients most likely to benefit from GE vs G alone. By capitalizing on ssDNA aptamer binding properties, PLP measures network changes in tumors, including those that predict drug response. Methods: FFPE tissues of pancreatic cancer patients from the MAESTRO trial with good (OS > 13 mos) or poor (OS < 7 mos) outcome from GE were used for PLP assay development. Assay cut-points were determined using a training set (n = 12) and performance metrics were then determined using an independent blinded test set (n = 172). The study population enrolled in MAESTRO was divided into four cohorts based on treatment and benefit (cut-point = 240 days). The assay performance from the blinded test set was used to generate 1000 different possible patient subsets. Each simulation represents one possible trial outcome if the PLP assay had been used to enroll patients. We used the average value of the simulated median increase in OS from the 1000 random selections to estimate the impact the PLP assay would have had on MAESTRO. Results: 97% of the simulations yielded log-rank p < 0.05. Compared to MAESTRO, the average median OS increase for GE improved by 116±38% (simulation s.d.) with an average HR of 0.72±0.04. Moreover, the sample size in the simulations was 49% smaller compared to the original study, reflecting the percentage of test positive patients in the blinded test set. When only data from primary tumors were used, 100% of the permutations yielded log-rank p < 0.05 with an average median OS increase of 216±36% compared to MAESTRO and an average HR of 0.63±0.03. Conclusions: This retrospective study demonstrates that PLP, if prospectively applied, likely would have resulted in a successful study comparing GE to G pancreatic cancer patients. PLP is a powerful, flexible and facile platform warrants further study of additional therapies and in prospective trials.
Satellite alpha transcripts as a biomarker to predict the development of breast cancer with bilateral or multiple primary malignancies.
Authors: Nao Kakizawa, Koichi Suzuki, Ayuha Yoshizawa, Kosuke Ichida, Masaaki Saito, Kazushige Futsuhara, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2017)

e23202 Background: The impaired stability of chromosomal structure promotes the abnormal segregation of chromosomes, increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation in the centromeric region of chromosomes. Satellite alpha transcripts (SatA) is a non-coding RNA transcribed from the centromere, which could be involved in this machinery. We reported that overexpression of SatA led to chromosomal instability, which was observed in not only cancer regions (CR) but also noncancerous regions (NCR). It was enhanced in NCR of patients with multiple primary malignancies (MPM), suggesting the involvement of SatA in genomic damage in regions where multiple cancers may arise. In this study, we determined whether SatA is involved in breast cancer development with bilateral or MPM. Methods: We constructed lentiviral vectors expressing SatA and control viruses, which were used to infect human mammary epithelial cells. SatA levels were determined by real-time quantitative PCR (qRT-PCR) and copy number alterations were evaluated by array comparative genomic hybridization (CGH). Then, we investigated the levels of SatA in clinical specimens in 135 breast cancer (BC) patients including 128 tumors and 83 matched normal tissues. Results: qRT-PCR showed higher expression levels of SatA in cells infected with SatA virus than in the control. Array CGH analysis indicated frequent copy number alterations at several specific chromosomes in infected cells, despite no alterations in the control. Among the 135 patients, 24 had bilateral breast cancer (BBC) and 18 had MPM. SatA was much higher in CR in BBC and in MPM than in SBC. SatA was also higher in NCR in MPM than without MPM. Considering human epidermal growth factor receptor type2 (HER2), hormone receptor (HR), family history and other factors, the levels of SatA in CR were a significant independent factor predicting the development of BBC patients. Conclusions: Chromosomal instability induced by SatA is involved in the development of BBC and BC with MPM.
Media distorts findings of study on alcohol consumption and dementia risk
Authors: Gabriel L Van Duinen
Journal: BMJ (2018)

Sabia and colleagues report their interesting, albeit controversial, findings, which indicate that, starting from midlife, moderate drinkers have a reduced risk of developing dementia.1

The public will always be interested in research on health matters that affect a broad segment of society, and this article is no exception. Coverage of its findings in the media has been extensive. Unfortunately, …
A deep-learning radiomics model for predicting survival in early-stage non-small cell lung cancer.
Authors: Tafadzwa Lawrence Chaunzwa, David C. Christiani, Michael Lanuti, Andrea Shafer, Nancy Diao, Raymond H. Mak, Hugo Aerts
Journal: Journal of Clinical Oncology (2018)

8528 Background: There is a growing body of evidence suggesting radiomic phenotypes can augment prognostic power, when used in combination with clinical features and tumor genomic profiles in lung cancer. In this study we present a deep-learning model that can act as a non-invasive prognostic biomarker in patients with Stage-I Non-Small Cell Lung Cancer (NSCLC). Our model would be able to assign patients to short term or long term survival groups, based on CT characteristics. Methods: Pretreatment CT studies were retrieved for 299 patients who underwent surgery for Stage-I NSCLC at MGH between 2004-2010. Image pre-processing included manual tumor identification, and isotropic rescaling of CT data. Further data curation resulted in a final cohort of 186 patients. Median follow-up from time of diagnosis was 2.9 years and 9.7% of patients were deceased at 2 years. To mitigate bias against a low probability event (mortality), data augmentation was performed yielding 242 50x50 pixel patches to feed into our model. A pre-trained 16 layer deep neural network (VGG-16) was used to perform visual recognition and data analysis. Fine-tuning of the last two convolutional blocks and a fully-connected classifier was performed with a training set of 144 labeled CT scans, matched to one of two groups based on 2 year survival. 34 samples were used for initial cross-validation. Data containing variations of imaging scanners and protocols were used in training to create a model that is robust for the variations. Results: Our model learned to classify patients with long term vs short term survival in an independent validation set of 64 samples with 75% accuracy and AUC = 0.798. In comparison, a multivariate linear regression model of conventional clinical prognostic factors (age, gender, tumor stage, histology, and smoking status) had a lower predictive performance (AUC = 0.665). Event rates were balanced between training and independent-validation groups. Conclusions: These findings suggest that Artificial Intelligence-enhanced radiomic feature extraction and predictive modeling can aid the clinician in assessing the benefits of treatment for patients with early-stage NSCLC.
Impact of hearing and visual impairment in older adults with cancer.
Authors: Enrique Soto Perez De Celis, Can-Lan Sun, William P. Tew, Supriya Gupta Mohile, Ajeet Gajra, Heidi D. Klepin, Cynthia Owusu, Cary Philip Gross, Hyman B. Muss, Stuart M. Lichtman, Andrew E. Chapman, Harvey Jay Cohen, William Dale, Heeyoung Kim, Vani Katheria, Arti Hurria
Journal: Journal of Clinical Oncology (2017)

10036 Background: Hearing and visual impairment increase the risk of psychological, functional, and cognitive deficits in older adults. However, little is known about their impact in older patients (pts) with cancer. Methods: This is a cross-sectional analysis of 2 prospective studies of pts ≥65 with cancer (Hurria et al. JCO 2011 &amp; 2016) which identified risk factors for chemotherapy (CT) toxicity. Relationships between self-reported hearing/visual impairment (fair, poor or deaf/blind) and the need for assistance in instrumental activities of daily living (IADL, i.e. shopping), or activities of daily living (ADL, i.e. bathing); anxiety; depression and cognitive deficit (&gt;11 on Blessed OMC test) were assessed (adjusted for age, sex, race, education, cancer type/stage, comorbidity, falls &amp; medication). Results: Among 750 pts (median age 72, range 65-94) with solid tumors (28% lung, 27% GI, 30% breast/GYN; 58% stage IV), 28% (n = 213) reported 1 impairment (61% hearing, 39% visual) and 7% (n = 55) both. On multivariate analysis, impaired hearing was associated with IADL dependency, anxiety and depression. Visual impairment was associated with IADL dependency, ADL limitation and depression. Impairment in both was associated with IADL dependency, anxiety, depression and cognitive deficit. Conclusions: Older pts with cancer and hearing/visual impairment are at higher risk of functional, psychological and cognitive deficits. Interventions aimed at improving vision and hearing of older adults with cancer should be studied. [Table: see text]
Utility of PET/CT in primary identification and management of cancers of unknown primary.
Authors: Hannah Marie Cherniawsky, Michael B. Sawyer, Sunita Ghosh, Winson Y. Cheung, Maria Yi Ho
Journal: Journal of Clinical Oncology (2017)

e18219 Background: The role of PET/CT in staging and management of cancers of unknown primary (CUP) is poorly defined. Our study sought to evaluate PET/CT versus standard CT in determining the primary site, lymph node status and solid organ metastases, and assess whether results of PET scans altered management of patients with CUP. Methods: We conducted a retrospective chart review of CUP patients to measure concordance of PET/CT and CT scans in patients diagnosed with CUP at two Western Canadian academic centres; the Cross Cancer Institute and BC Cancer Agencies from 2008 to 2015. Results: We identified 244 patients who had standard CT and PET/CT during their work-up. Of the 70 patients whose primary identification status was recorded, standard CT imaging detected 16.1% of primaries compared to 12.1% on PET/CT. 63.3% of primaries were concordantly identified on both modalities. PET/CT identified 2 primaries not seen on CT whereas standard CT identified 9 primaries not seen on PET/CT. Concordance rates between PET/CTs and standard CTs were 77.9% and 93.9% regarding lymph node status and extent of metastases, respectively. PET/CT identified a greater extent lymph node involvement in patients; 93.8% versus 79.0%. (CCOR = 2.92, 95% CI = 0.87-9.72) and identified a greater extent of solid organ involvement; 96.5% versus 92.4%. (CCOR = 45.25, 95% CI = 7.79-262.78). Data from the CCI of patients who had discordant imaging in either domain or identification of primary showed no cases in which PET/CT alone provided information that changed patient management. Conclusions: Our results suggest PET/CT scans do not provide additional diagnostic information with respect to identifying the primary site but may be superior in clarifying extent of metastases and nodal status though this did not alter therapy. Future studies investigating the impact of PET/CT scans on management and cost effectiveness in CUP are critical.
Efficacy of pegvorhyaluronidase alfa (PEGPH20) plus FOLFIRINOX in a preclinical model of human pancreatic ductal adenocarcinoma.
Authors: Jesse Bahn, Feng Gao, Xiaoming Li, Susan Zimmerman, Kelly Chen, Chunmei Zhao, Daniel C. Maneval, Curtis Thompson
Journal: Journal of Clinical Oncology (2018)

e16244 Background: Hyaluronan (HA) accumulates in the solid tumor microenvironment, and is associated with poor drug penetration and negative clinical outcomes. Pegvorhyaluronidase alfa (P) is a novel biologic that enzymatically degrades HA. In preclinical models, P decreases tumor interstitial fluid pressure and increases tumor perfusion, as well as access and efficacy of chemo- and immunotherapies. To date, P has been evaluated clinically with other therapeutics (docetaxel, FOLFIRINOX [FFX], nab-paclitaxel + gemcitabine, eribulin, pembrolizumab) in HA-accumulating solid tumor cancers, including PDA, NSCLC, gastric, and breast. Methods: Here, we evaluated whether P alters the cytotoxity of the components of FFX, a common therapeutic regimen for advanced PDA, on human and murine PDA cells. In 2D cell culture and 3D tumor spheroids, P did not alter FFX cytotoxicity. We also evaluated P + FFX in vivo anti-tumor activity in BxPC3/HAS3, a HA over-expressing human PDA model. Mice were inoculated with BxPC3/HAS3 cells adjacent to the right tibial periosteum and tumor growth was monitored via ultrasonography. When tumors reached ~230 mm3, mice (n = 8/gp) were staged into treatment groups: 1) vehicle; 2) 0.0375 mg/kg P BIW; 3) low FFX – 30 mg/kg leucovorin, 15 mg/kg fluorouracil, 30 mg/kg irinotecan, and 1.2 mg/kg oxaliplatin QW; 4) high FFX – 65 mg/kg leucovorin, 32.5 mg/kg fluorouracil, 65 mg/kg irinotecan, and 2.6 mg/kg oxaliplatin QW; 5) P + low FFX; and 6) P + high FFX. FFX was administered 24h after P. Results: Combination of P + low or high FFX resulted in greater anti-tumor activity than either low or high FFX alone (table), and P + low FFX was superior to high FFX alone. A maximum 5% BW loss followed the initial FFX doses. Conclusions: In vitro results showed no inhibition of the cytotoxic effects of FFX components on PDA cells when combined with P, and P-mediated HA degradation increased the anti-tumor efficacy of FFX in a preclinical PDA model. Group Tumor Growth Inhibition (SD18) P value (relative to control) Median Time to Survival Endpoint (days) Vehicle Control 22 PEGPH20 (P) 24.9% 0.0443 27 Low FFX 11.3% n.s. 23.5 High FFX 39.8% 0.0018 32 P + Low FFX 56.3% 0.0001 32 P + High FFX 64.3% 0.0001 36
Association of intratumoral PD-L1 expression with survival of patients with Epstein-Barr virus-associated gastric cancer.
Authors: Jong Gwang Kim, Byung Woog Kang, Yee Soo Chae, Soo Jung Lee, In Hee Lee, Dong Won Baek, An Na Seo
Journal: Journal of Clinical Oncology (2017)

e15590 Background: The present study analyzed the expression of tumoral (t-) PD-L1/L2 and stromal (str-) PD-L1/L2, and their impacts on the survival of a relatively large group of Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). Methods: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. Immunohistochemistry of PD-L1 and PD-L2 was carried out and the intensity was scored as an intensity score 0 (no staining), 1 (weak intensity), 2 (intermediate intensity), and 3 (high intensity). The expression was also evaluated in tumor tissues and stromal immune cells and divided into two groups (2 and 3 were interpreted as a positive result). Results: Among the 120 patients, 57 patients (47.5%) and 66 patients (55.0%) were determined as t-PD-L1-positive and str-PD-L1 positive, while 23 patients (19.2%) and 41 patients (34.2%) were determined as t-PD-L2-positive and str-PD-L2 positive. In a univariate analysis, t-PD-L1-positive was significantly associated shorter disease-free survival (DFS, P = 0.032), yet not overall survival (P = 0.482). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, gender, WHO classification, and tumor-infiltrating lymphocytes, t-PD-L1 positivity was independently associated with poor DFS (Hazard ratio = 4.183, P = 0.044). Meanwhile, in the univariate analysis, t-PD-L2-positive and str-PD-L2-positive showed a better DFS trend than t-PD-L2-negative and str-PD-L2-negative, respectively (P = 0.071 and P = 0.092). However, t-PD-L2 and str-PD-L2 expressions showed no prognostic significance on DFS in the multivariate analysis. Conclusions: The level of t-PD-L1 expression represents a significant difference for DFS in patients with EBVaGC. The current findings support the concept that PD-L1 may be a prognostic parameter for predicting patient outcome and act as a therapeutic target in EBVaGC.
AIDS-associated Kaposi sarcoma: A subset analysis of the County Hospital AIDS Malignancy Project (CHAMP study) exploring epidemiology, staging, and prognostic factors.
Authors: Camille E. DeMarco, Pei Lu, Xavier Alberto Andrade Gonzalez, Ronald J. Lubelchek, Dennis F. Angelov, Shweta Gupta, Ahmed T Ahmed, Paul G. Rubinstein
Journal: Journal of Clinical Oncology (2018)

e13587 Background: Kaposi Sarcoma (KS) is a malignancy of endothelial cells. The epidemic form, AIDS-associated, has decreased from about 8 cases in the early 1990s to 0.9-2 cases/100,000 patient years (yrs) in the United States (US) between 2000-2013. Most epidemiological studies examine large geographic areas, and insights into cancer/HIV in the underserved populations have been underrepresented in the literature. Stroger Hospital (CCH) and the Ruth M. Rothstein CORE Center (CC) are the largest health providers for HIV+ patients (pts) in Chicago. CCH/CC treat about 5,000 HIV+ individuals per year and 40 newly diagnosed HIV-associated cancers yearly. The CHAMP Study is a prospective data base of pts diagnosed with HIV/AIDS-associated malignancies. Here we present an analysis of the KS cohort. Methods: Patient, HIV/cancer characteristics, and survival data were compiled from the KS cohort. Survival data was analyzed using Kaplan-Meier analysis and Cox Proportional Hazards model and statistical comparisons between groups was done via the Fisher exact test. Results: 162 pts with KS were assessed from 1995-2017. Per data by Royse, CCH/CC diagnosed 2.6% of the new cases of KS in the US. 98% of pts were men. 64% were African American (AA), 15% Hispanic, and 19% Caucasian. The median CD4+ T-cell count at dx was 112 cells/ul (Range 4-963). The median HIV-viral load was 247,682 copies/ml (range <40-1.77x107). Staging was done per the ACTG staging system (T,I,S). The overall survival (OS) of S1 vs. S0 showed a 60% vs. 85% OS respectively at 5 yr, P<0.003. I, defined at a CD+ T-cell count of 100 cells/ul, I1 vs. I0 showed an OS decrease at 5 yrs from 95 to 75%, p< 0.036. Pts with Stage T1S1 or T1I1S1 vs other stages imparted at 5 yr OS of just 50% vs. 80% (p<0.001). While 64% of the KS pts are AA, 90.5% of deaths were AA vs other races (p<0.006). The OS of AA vs. other races at 60 months of 77 vs. 95% (p<0.039). Conclusions: CCH/CC sees 2.6% of the newly diagnosed KS pts in the US. Stages T1S1/T1I1S1 imparted a survival of 50% of pts at 5 yrs. The racial breakdown of KS cohort was 64% AA, however, 90.5% of all deaths were AA, demonstrating a clear disparity.
Duration of complete response (DurCR) impacts overall survival (OS) in multiple myeloma (MM).
Authors: Surbhi Sidana, Nidhi Tandon, Angela Dispenzieri, Morie A. Gertz, Francis Buadi, Martha Lacy, David Dingli, Amie L. Fonder, Suzanne R. Hayman, Miriam A. Hobbs, Wilson I. Gonsalves, Rahma M. Warsame, Taxiarchis Kourelis, Yi Lisa Hwa, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, S. Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2018)

8045 Background: DurCR has a direct impact on progression free survival in MM, but its impact on OS is not well described. Methods: We retrospectively analyzed 351 patients with MM from 2004-16 who achieved CR (IMWG criteria) with first line therapy to assess impact of DurCR (time from achievement to loss of CR) on OS. Results: The table lists baseline characteristics. Loss of CR was experienced by 68% (239) patients, with (1) symptomatic progression in 25% (59); (2) biochemical progression in 24% (58); (3) two consecutive positive immunofixation or rise in monoclonal protein not meeting progression criteria in 37% (88); (4) two abnormal FLC ratios in light chain MM in 14% (34). In group 3, progression was seen in 73/88 (85%) patients (13 symptomatic, 60 biochemical) with median time from loss of CR to progression of 7 months and in 21/34 (62%) patients in group 4 (3 symptomatic, 18 biochemical) with median time of 4 months. After median follow-up of 72 months, median OS from start of therapy with DurCR ≥ 24 (n = 179, 51%) vs. < 24 months (n = 172, 49%) was 150 vs. 80 months, p < 0.001. Estimated 5 and 10 year OS in DurCR ≥ 24 was 95% and 70% and in DurCR < 24 was 66% and 25%, respectively. Landmark analysis for patients alive at 24 months from start of treatment showed similar results (DurCR ≥ 24 vs. < 24, median OS: 150 vs. 83 months, p < 0.001). Among patients who experience loss of CR, OS from loss of CR was higher in patients with DurCR ≥ 24; 82 vs 56 months, p = 0.005. On multivariate Cox Proportional hazards model, DurCR remained a significant predictor of OS from start of treatment (CR < 24 months vs. ≥ 24 months, HR: 4.0 (2.4-7.0), p < 0.001), after adjusting for revised ISS, age ≥ 65 years, ASCT and maintenance therapy. Conclusions: DurCR is an important independent predictor of OS in MM, with estimated 5 and 10 year OS with DurCR ≥ 24 months being 95% and 70%, respectively. Importantly, majority of patients who experience loss of CR meet criteria of progression within median of 4-7 months. Median (IQR) or n (%) Age 61 years (54-66) Males 198 (56) High risk FISH: del17p, t(4;14),t(14;16) & t(14;20) 58/283 (21) ISS N = 295 115/96/84 (39/33/28) R-ISS N = 230 61/141/28 (27/61/12) BMPCs 50% (30-70) ASCT 269 (77) Maintenance 133 (39) Time to CR 8 months (5-9) Duration of CR 24 months (13-42)