tbuckley/cabot-search huggingface dataset:
Prognostic and functional characterization of AQP1 and AQP4 in patients with glioma.
Authors: Meihua Chen, Jichuan Wang, Ming Fan, Jin Yi Lang, Jialin Yang
Journal: Journal of Clinical Oncology (2018)

e14063 Background: Gliomas are the most common type of primary brain tumors and are the leading cause of cancer-related mortality worldwide. The aquaporins (AQPs) are small hydrophobic integral transmembrane water channel proteins, and there is a positive correlation between histological tumor grade and the AQPs expression, implying their potentials as novel independent biomarkers for cancer diagnosis and prognosis. However, the prognostic and functional significance of AQPs expression profile in glioma is unclear. Methods: In this study, the expression of AQP1 and AQP4 in gliomas was evaluated based on TCGA website GEPIA. Then the detailed histological phenotypes and clinical significance of AQP1 and AQP4 in glioma were evaluated by website LinkedOmics and UALCAN. With the LinkedOmics, the co-expressed genes of AQP1 and AQP4 were analyzed. And the GO and KEGG Pathway enrichment analysis were carried for these co-expressed genes. Results: Based on the GEPIA website, we found AQP1 and AQP4 have higher expression in lower grade gliomas (LGGs) and glioblastomas (GBMs) than adjacent normal tissues, but the higher expression of these two AQPs only shown poor prognosis in LGGs. With the histological phenotypes and clinical analysis of these two AQPs in LGGs, we found AQP1 shows differential expression in patients with different histological type, ethnicity, race and radiation therapy. And AQP4 only showed differential expression in patients with different histological type and race. Higher expression of AQP1 showed poor prognosis in gender, race and tumor grade, but higher expression of AQP4 only showed poor prognosis in gender and tumor grade. Furthermore, KEGG and GO enrichment analysis for co-expressed genes suggested that these two AQPs were involved in Cell adhension moleculars (CAMs) and Poly ADP-ribose Polymerase (PRAP) signaling pathway. Conclusions: These findings suggest that higher levels of aquaporin 1 and aquaporin 4 expression are associated with a poor prognosis in LGG in different histological phenotypes. These two AQPs also have potential role in LGGs progression. Our results warrant further studies on AQPs that will improve our understanding of the mechanisms associated with pathogenesis and progression of glioma.
Photoacoustic detection of circulating melanoma cells as a predictor of metastasis in stage III patients.
Authors: John Andrew Viator, Martin Sanders, Ahmad A. Tarhini, Cindy Sander, Robert Hugh Edgar, Benjamin Goldschmidt
Journal: Journal of Clinical Oncology (2017)

e21053 Background: Circulating tumor cells have been correlated with disease state and distant metastatic spread in cancer patients. We postulated that enumerating circulating melanoma cells (CMCs) may predict the onset of distant metastasis in Stage III patients. We detected CMCs using our photoacoustic flow cytometer, in which we irradiated enriched blood samples with nanosecond pulsed laser light. While there is no effect on non-optically active leukocytes, absorption of laser light by pigmented melanoma cells resulted in robust ultrasonic waves that indicated CMCs in the sample. Methods: We tested 32 archived samples from 9 Stage III melanoma patients using our photoacoustic flow cytometer. Each patient had between 2 and 6 serial blood samples. We used a pulsed Nd:YAG laser to irradiate mononuclear cells in suspension and under flow. The number of CMCs detected after testing was recorded, indicating the time sequence of circulating tumor cell activity. Results: The numbers of CTCs for each sample is shown in the table below. The ultimate disease state, whether the patient became metastatic or not, was blinded to the investigators who performed the photoacoustic tests. One sample for patient 3 indicated 63 CMCs, though this test was known to be contaminated and had an unknown number of false detections. Conclusions: We found that patients who had a series of more than 4 CMCs were more likely to become metastatic than those patients who tested for 4 CMCs for fewer, indicating that a sequence of CMC detections in serial blood draws provides a potentially strong predictor of metastasis in Stage III melanoma patients warranting further investigation at this and lower stages of melanoma. We are developing a more rigorous model based on time series analysis of CMCs for prediction of metastasis. [Table: see text]
Proteomic and mRNA expression analysis identifies PDL-1 expression as a marker of treatment failure in head and neck cancer.
Authors: Heath Devin Skinner, Uma Giri, Michael D. Story, Jing Wang, Li Shen, Suk Y. Yoo, Lauren Averett Byers, Curtis R. Pickering, Jeffrey Myers, Michelle D. Williams, John Heymach
Journal: Journal of Clinical Oncology (2016)

6042 Background: With the exception of human papilloma virus (HPV), there are no effective biomarkers in Head and Neck Cancer (HNSCC). To identify novel biomarkers in HPV-negative HNSCC we utilized a screening approach including reverse phase protein array (RPPA) and mRNA expression array on HNSCC tumor specimens from multiple cohorts of patients. Methods: All cohorts were locally advanced HPV-negative HNSCC treated with surgery and post-operative radiotherapy. RPPA examining 144 proteins and phospho-proteins was performed on tumor samples from 70 patients. Illumina mRNA gene array was performed on a separate cohort of 102 patients. Immunohistochemical validation studies for PDL-1 expression were performed on HNSCC tumors from 115 patients. Results: Cox regression analysis was performed on the RPPA and several proteins were associated with loco-regional recurrence (LLR), including PDL-1 (p = 0.0034). PDL-1 was associated with LRR on multivariate analysis accounting for significant clinical variables (p = 3.2x10-4). On mRNA expression array, both PDL-1 and PDL-2 were in the top ten genes associated with LRR (8th and 3rd most significant; p = 6.1x10-05 and p = 1.1x10-05 respectively). On multivariate analysis taking into account clinical variables PDL-1 mRNA remained significantly associated with LRR (p = 0.021). To validate this observation, we performed immunohistochemical analysis on tumors to examine tumor and stromal PDL-1 and PD-1 as well as the degree of CD8 and CD4 positive immune infiltrate. Only tumor PDL-1 was significantly associated with LRR (p = 0.003) on univariate analysis. On multivariate analysis taking into account clinical variables, tumor PDL-1 expression remained significantly associated with LRR (p = 0.021). In all cohorts, patients with high PDL-1 expression had between a 35-40% absolute increase in 2 year LRR rate compared to tumors with low expression. Further, PDL-1 expression was associated with LRR regardless of p53 mutation status. Conclusions: The current study demonstrates that tumor PDL-1 expression is highly associated with LRR in HNSCC and argues that targeting this immune checkpoint in combination with radiation could provide significant benefit.
Cost-effectiveness of ovarian cancer screening: An analysis of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) from a U.S. health system perspective.
Authors: Haley Moss, Evan Myers, Andrew Berchuck, Laura Jean Havrilesky
Journal: Journal of Clinical Oncology (2017)

6608 Background: UKCTOCS is the largest randomized controlled trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum CA125 interpreted with a risk algorithm; annual transvaginal ultrasound; or no screening (NS). There was a non-statistically significant 15% reduction in mortality over 11 years in MMS group. As most of the potential benefit of screening was seen after 7 years, follow-up is ongoing to determine if an observed stage shift translates into significant mortality reduction. The current study estimates the cost-effectiveness of an MMS screening program in the US. Methods: A modified Markov model was constructed using data from UKCTOCS to compare MMS to NS. Published estimates of the long term effect of MMS screening on ovarian cancer mortality were used to simulate mortality over 40 years from the start of screening. Base case costs included CA125, ultrasounds, clinical evaluations and false-positive surgeries, with an annual weighted cost of $35 in addition to an estimated risk algorithm cost of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2016 U.S. dollars per quality-adjusted year of life saved (QALY). Additional sensitivity analyses were performed. Results: MMS is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than NS. Screening women from age 50 to 75 with MMS reduced mortality by 24% with an ICER of $98,062/QALY. If screening begins at age 60, MMS reduces mortality by 12%, with ICER below the willingness to pay threshold of $100,000/QALY only if the algorithm costs &lt; $50. In probabilistic sensitivity analyses, the probability that screening from age 50-75 at an algorithm cost of $100 was less than $100,000/QALY was 41%. Conclusions: Ovarian cancer screening is potentially cost-effective in the US depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.
Total Medicare Costs Associated With Diagnosis and Treatment of Prostate Cancer in Elderly Men
Authors: Justin G. Trogdon, Aaron D. Falchook, Ramsankar Basak, William R. Carpenter, Ronald C. Chen
Journal: JAMA Oncology (2018)

Localized prostate cancer diagnosis and treatment among elderly men who are not likely to benefit represents a potential source of low-value health care services.To quantify the costs to the Medicare program associated with detection and treatment of prostate cancer among elderly men in the United States.This nationwide, population-based, retrospective cohort study uses the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify men 70 years or older diagnosed with localized prostate cancer between 2004 and 2007 and to ascertain Medicare costs associated with diagnosis and workup, treatment, follow-up, and morbidity management of the disease. National Medicare costs were estimated using per-person costs, stage-adjusted prostate cancer incidence rates by age from SEER 2007 through 2011, and 2010 Census population estimates by age.Estimated costs to the Medicare program overall, and in each (mutually exclusive) category related to diagnosis and workup, treatment, follow-up, and morbidity management.This nationwide, population-based, retrospective cohort study included 49 692 men with nonmetastatic prostate cancer from the SEER-Medicare database (all participants were 70 years or older; 25 981 [52.3%] were 76 years or older). The median per-patient cost within 3 years after prostate cancer diagnosis was $14 453 (interquartile range [IQR], $4887-$27 899). The majority of this cost was attributable to treatment costs (median, $10 558; IQR, $1990-$23 718). Patients with a Gleason score of 6 or lower who pursued initial conservative management (no treatment within 12 months of diagnosis) had a 3-year median total cost of $1914 per patient. The estimated total 3-year cost to the Medicare program associated with the annual detection of prostate cancer in men 70 years or older is approximately $1.2 billion. Increasing active surveillance use in those with Gleason score of 6 or lower could reduce this cost by $320 million.There is substantial cost to the Medicare program associated with the diagnosis and treatment of localized prostate cancer among elderly men in the United States, despite the fact that these men are unlikely to die of prostate cancer. The majority of costs are related to treatment. Reducing provision of low-value health care services among this patient population could result in significant health care savings.
Efficacy and safety of enzalutamide vs bicalutamide in European and North American men participating in the TERRAIN trial.
Authors: Simon Chowdhury, Neal D. Shore, Arnauld Villers, Laurence Klotz, D. Robert Siemens, Benoit Baron, Steve van Os, Nahla Hasabou, Fong Wang, David Forer, Axel Heidenreich
Journal: Journal of Clinical Oncology (2016)

5063 Background: In the TERRAIN trial (NCT01288911), enzalutamide (ENZA) significantly increased progression-free survival (PFS) compared to bicalutamide (BIC) in patients (pts) with progressive metastatic castration-resistant prostate cancer. Pts were enrolled from clinical sites in North America (NA) and Europe (EU). Clinical management and treatment guidelines for these pts differ between the two regions. An analysis by geographic region was pre-specified in the TERRAIN study to investigate the efficacy of ENZA vs BIC. Efficacy and safety results are presented for both EU and NA pts. Methods: Pts were randomized 1:1 to ENZA (160 mg/day) or BIC (50 mg/day). The primary endpoint was PFS, defined as the time from randomization to first centrally confirmed radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy, or death from any cause. Other endpoints were time to prostate-specific antigen (PSA) progression, Functional Assessment of Cancer Treatment–Prostate deterioration, and safety. Results: Of375 randomized pts, 221 (58.9%) were from EU and 154 (41.1%) from NA. Of the EU and NA pts, 109/112 and 75/79 were randomized to ENZA/BIC respectively. Median PFS in EU patients was 16.6 months for ENZA and 5.8 months for BIC; hazard ratio (HR) (95%CI): 0.44 (0.31, 0.61), Logrank-p < 0.0001. Median PFS in NA patients was 14.9 months for ENZA and 6.2 months for BIC; HR (95%CI): 0.45 (0.30, 0.67), Logrank-p = 0.0001. Median time to PSA progression in EU and NA patients had not been reached for ENZA and was 16.4 months; HR (95% CI): 0.45 (0.28, 0.71) and 13.9 months; HR (95% CI): 0.63 (0.36, 1.10) for BIC in EU and NA pts respectively. Slightly more EU pts (91.7% ENZA and 93.7% BIC) than NA pts (77.0% ENZA and 85.9% BIC) reported adverse events (AEs), but more AEs per pt were reported in NA than EU. Quite similar distribution of AEs between treatment arms was observed in either region. Conclusions: Efficacy associated with ENZA use was similar comparing pts in EU and NA. In particular, treatment with ENZA was associated with significant improvement in PFS compared with BIC in pts from both continents. The distribution of AEs between treatment arms was quite consistent in the two regions. Clinical trial information: NCT01288911.
Phase IB/II study of lirilumab with azacytidine (AZA) in relapsed AML.
Authors: Naval Guastad Daver, Guillermo Garcia-Manero, Jorge E. Cortes, Sreyashi Basu, Farhad Ravandi, Tapan M. Kadia, Gautam Borthakur, Elias Jabbour, Courtney Denton Dinardo, Naveen Pemmaraju, Mark Brandt, Sherry Pierce, Nawar Hussin, Steven Mitchell Kornblau, Michael Andreeff, Marina Konopleva, Jing Ning, James Patrick Allison, Padmanee Sharma, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2017)

e18505 Background: Lack of KIR-HLA class I interactions has been associated with NK-mediated antitumor efficacy in AML patients (pts) in remission upon KIR-mismatched haploidentical stem cell transplantation (SCT) (Ruggeri L et al., Science 2002). Blockade of KIR2DL1, 2 and 3 receptors induced augmented NK-cell mediated lysis of tumor cells (Romagne F et al., Blood 2009). Hypomethylating agents possess anti-leukemia activity, increase MHC II expression, and interferon-gamma signature. Methods: Pts with AML who failed prior therapy, have adequate performance status (ECOG ≤ 2) and organ function are eligible. AZA 75mg/m 2 Days 1-7 was given with lirilumab on Day 8 at the dosage of 1 and 3 mg/kg in 2 consecutive cohorts of 6 pts each. Courses were repeated every 4-5 weeks. Lirilumab 3mg/kg established as recommended phase 2-dose with AZA. 13 additional pts treated at the RP2D. Responses evaluated at the end of 3 courses. Results: To date, 25 pts (16 de novo, 9 secondary AML), median age 64 years (range, 30 – 89), 52% adverse cytogenetics, median prior therapies 3 (range, 1-8), and prior alloSCT in 6 (28%) have been enrolled. All 25 pts had baseline next generation sequencing, common mutations included ASXL1 (n = 9), TP53 (n = 7), RAS (n = 4), TET2 (n = 4), and RUNX1 (n = 3). Two (8%) achieved CR/CRi (1 CR, 1 CRi) and 3 (12%) achieved hematologic improvement for an overall response rate of 20%. The median cycles to response was 3 (range, 1-11). The 8-week mortality is 12%, respectively. The median duration of response and overall survival were 2.0 months and 4.0 months, respectively (med f/u = 5.1 months). Grade 3/4 toxicities were similar to those seen with AZA based therapies in salvage including bloodstream infections in 15 (60%), 6 pneumonia, 1 UTI, 1 skin infection, 2 abdominal pain, and 1 mucositis. Immune mediated toxicities were observed in 4 (16%) pts (1 pneumonitis Grade 3, 2 colitis Grade 3, 1 colitis Grade 2). The immune mediated toxicities responded rapidly to steroids and 3 pts could be rechallenged safely with lirilumab. Six pts were postSCT and no Grade 3/4 GVHD flares were noted. Conclusions: Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML. The efficacy data are still preliminary and the study is ongoing. Clinical trial information: NCT02399917.
Panitumumab in platinum-sensitive epithelial ovarian cancer patients with KRAS wild-type: The PROVE-study, a phase II randomized multicenter study of the North-Eastern German Society of Gynaecologic Oncology<i>.</i>
Authors: Radoslav Chekerov, Peter Klare, Petra Krabisch, Jochem Potenberg, Georg Heinrich, Lothar Mueller, Christian M. Kurbacher, Eva-Maria Grischke, Elena Ioana Braicu, Pauline Wimberger, Jalid Sehouli
Journal: Journal of Clinical Oncology (2017)

5558 Background: For ovarian cancer (OC) patients with platinum-sensitive recurrence the addition of new biologic agents to chemotherapy may improve survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). The purpose of this trial was to investigate the therapeutic efficacy of panitumumab in the combination with carboplatin-based chemotherapy in relation to the respective standard combination in patients with a KRAS wildtype with platinum-sensitive recurrent ovarian cancer (NCT01388621). Methods: Major eligibility criteria were pretreated platinum-sensitive epithelial ovarian/ fallopian/ peritoneal cancer and no more than 2 prior treatments for this disease. Only patients with measurable disease or elevated CA125 and with KRAS wild type were eligible. Patients were treated with Carboplatin AUC4/Gemcitabine 1000 mg/m² or Carboplatin AUC5/PLD 40 mg/m² and randomized to panitumumab 6 mg/kg day 1 and day 15, every 3 or 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CT-scan and CA-125 criteria. Results: In this multi-institutional phase II trial 102 patients were randomized and 96 enrolled for the final analysis. Progression-free survival in the intention-to-treat population (N=96) was 9.5 vs. 10.7 months (HR 0.829, 95%CI of 8.5-11.6 months vs 8.5-13.1 months) for the experimental vs. standard arm, p=0.45. Data of overall survival are not jet evaluable. The most common treatment related grade 3+ toxicities included hematologic toxicity (54%), skin reactions (18%) and gastrointestinal events (16%). Conclusions: The addition of panitumumab to platinum-based chemotherapy for recurrent ovarian cancer does not influence efficacy and progression-free survival in platinum sensitive patients, while no new additional toxicity aspects for panitumumab were evaluated. Clinical trial information: NCT01388621.
Genomic profiling using a 435-gene panel provides a vision for precision medicine in Japanese gastric cancer.
Authors: Hiroshi Ichikawa, Masayuki Nagahashi, Yuko Kitagawa, Kazuhiro Yoshida, Eiji Oki, Hiroshi Yabusaki, Satoru Nakagawa, Nobuaki Sato, Takaaki Hanyu, Takashi Ishikawa, Yusuke Muneoka, Kizuki Yuza, Yoshifumi Shimada, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2017)

e15592 Background: Molecular heterogeneity represents a significant hurdle in realizing precision medicine for gastric cancer (GC). Large-scale whole exome sequencing projects have identified distinct molecular subtypes to help define the heterogeneity of GC. However, it remains unclear whether the targeted gene panel-based sequencing can provide optimum targeted therapies and clinical utility in GC. The aim of this study is to generate comprehensive genomic profiling data and classify Japanese GC into actionable clusters associated with targeted therapies. Methods: FFPE tumor tissues were obtained from surgical or biopsy specimens of 207 Japanese patients with GC. Extracted DNA was subjected to genomic sequencing for 435 cancer related genes including 69 druggable genes with FDA approved targeted therapies. Somatic mutations, copy number alterations (SCNA), microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection were evaluated using sequencing data. Results: Genomic sequencing identified at least one alteration of 435 genes in 194 pts (94%), and that of 69 druggable genes in 141 pts (68%). The most frequently altered druggable gene was ERBB2 (14%), following BRCA2 (11%) and ATM (10%). We successfully classified 207 tumors into four molecular subtypes, similar to the previously report; EBV (4%), MSI (8%), chromosomal instability (58%) and genomically stable subtype (30%). Frequent alterations of druggable genes ( &gt; 5%) were widely observed through these subtypes. To discover the novel classifications associated with targeted therapies, we classified 207 tumors using mutation rate and hierarchical clustering. We identified a hypermutated group (n = 32), and a remaining non-hypermutated group (n = 175) which were sub-divided into six clusters including five actionable ones; ERBB2 (n = 25), CDKN2A and CDKN2B (n = 10), KRAS (n = 10), BRCA2 (n = 9) and ATM cluster (n = 12). Interestingly, we experienced a case of unresectable GC with a remarkable response for anti-HER2 therapy in the ERBB2 cluster. Conclusions: Genomic sequencing using a 435-gene panel has the potential to provide the information of optimum targeted therapies for upcoming precision medicine in Japanese GC.