tbuckley/cabot-search huggingface dataset:
MMP-7 a potential biomarker of invasive cervix cancer: A prospective pilot study.
Authors: David Mysona, Adam Pyrzak, Jennifer Allen, Shan Bai, Ashok Sharma, Jin-Xiong She, Bunja Jane Rungruang, Sharad A. Ghamande
Journal: Journal of Clinical Oncology (2016)

e17005 Background: Cervical cancer is the second most common cancer of women worldwide. In this prospective study, we attempted to identify a set of serum biomarkers, which could identify patients who have invasive cervical cancer and monitor disease status (progression of disease (PD), remission (RM)). Biomarker selection focused on the matrix metalloproteinase (MMP) family and growth factors. Methods: In this IRB approved prospective study, luminex bead array was used to measure serum protein concentrations of 19 selected proteins in cervical cancer patients (CC) (n=23) compared to women with precancerous lesions (CIN2-3) (n=20), and patients with normal cervical cytology (n=20). Cervical cancer (adenocarcinoma and squamous carcinoma) patients had blood samples drawn within 30 days of diagnosis and repeat blood samples taken on follow up after completing therapy. Results were correlated to clinical data and outcomes. MMP7 expression was confirmed by immunohistochemistry (IHC). IHC scoring was done blindly by two pathologists independently. Results: Six proteins (CA153, OPG, CEA, IGFBP7, IGFBP4, and MMP-7) had significantly different levels in CC patients compared to controls and CIN (p < 0.05). MMP-7 had a sensitivity of 92% at 95% specificity. IHC revealed significant staining of MMP7 below the epithelial basement membrane of CC samples when compared to CINs and controls P<0.05. There was no difference in staining intensity between CINs, controls, and CC patients. MMP7 has significantly altered expression when comparing RM and PD (P<0.05). It also was an indicator of progression free survival (HR:4.5, P<0.05) and an indicator of overall survival at PD (P value = 0.04, HR= 7.5). Conclusions: MMP7 serum concentration is significantly altered when comparing CC patients to controls and CINs. This may be due to the overwhelming expression of MMP7 below the basement membrane in invasive CC. Further studies warrant investigating MMP7's role in CC. Protein AUC P value Sensitivity at 95% Specificity MMP7 0.98 (0.96-0.99) 5.29E-13 92 IGFBP4 0.84 (0.8-0.89) 2.36E-07 75 IGFBP7 0.83 (0.78-0.87) 6.23E-07 58 CEA 0.79 (0.74-0.84) 1.30E-05 42 OPG 0.77 (0.72-0.82) 3.80E-05 35 CA153 0.74 (0.69-0.8) 2.50E-04 8
Effects of the Endocrine-Disrupting Chemicals, Vinclozolin and Polychlorinated Biphenyls, on Physiological and Sociosexual Phenotypes in F2 Generation Sprague-Dawley Rats
Authors: Krittika Krishnan, Nitish Mittal, Lindsay M. Thompson, Mariana Rodriguez-Santiago, Christine L. Duvauchelle, David Crews, Andrea C. Gore
Journal: Environmental Health Perspectives (2018)

Background: Exposure to endocrine-disrupting chemicals (EDCs) during gestation influences development of the F1 generation offspring and can result in disease and dysfunction in adulthood. Limited evidence suggests consequences on the F2 generation, exposed as germ cells within the F1 fetus. These F2s provide a unique window into the programming effects of EDCs. Objective: This study assessed intergenerational effects of EDC exposure on adult physiology and behavior in Sprague-Dawley rats. Methods: Pregnant rats were exposed to either a polychlorinated biphenyl (PCB) mixture, Aroclor 1,221 (A1221), the fungicide vinclozolin (VIN), or the vehicle (VEH) (6% dimethylsulfoxide in sesame oil) alone. A1221 is weakly estrogenic, while VIN is antiandrogenic, enabling us to compare different classes of EDCs. The F1 male and female offspring were bred to generate the paternal- and maternal-lineage F2 generation. This F2 generation was assessed for physiological outcomes, ultrasonic vocalizations (USVs), and sexual behavior in adulthood. Results: Each EDC caused phenotypic effects in a sex- and lineage-dependent manner. The most robustly affected group was the paternal-lineage males. F2 VIN paternal male descendants had increased body weight throughout the lifespan, lower concentrations of circulating estradiol, and lower adrenal and testicular indices. Both VIN and A1221 paternal-lineage males also exhibited the greatest number of changes in the characteristics of USVs in response to an opposite-sex animal and changes in sexual behaviors in a mating test. Conclusion: Exposure of rats to EDCs at the germ cell stage led to differences in the physiological and behavioral phenotype later in life, especially in males. This finding has implications for multigenerational physiological and reproductive health in wildlife and humans. https://doi.org/10.1289/EHP3550
Healthcare costs among multiple myeloma (MM) patients (Pts) without stem cell transplant (SCT).
Authors: Sumeet Panjabi, May Hagiwara, Arati Sharma, Yaozhu (Juliette) J. Chen, Thomas E. Delea
Journal: Journal of Clinical Oncology (2016)

8059 Background: The economic burden of MM is substantial. Treatment (Tx) costs for MM pts have been reported, however, gaps in understanding costs by line of therapy (LOT), service category, and time since Tx initiation remain. Methods: This was a retrospective observational study using the MarketScan database. Pts were adults with MM (ICD-9-CM code 203.0x) who initiated MM Tx between Jan 1, ‘06 and Dec 31, ‘14. LOT was defined by receipt of new MM Tx or a gap >90 days in MM Tx. Pts with prior SCT or insufficient continuous enrollment to determine LOT were excluded. Mean monthly healthcare costs were calculated by LOT, stratified by on- and off-tx periods, service category, and time since Tx initiation. LOT and on/off Tx periods mean costs were weighted by duration. Results: 9,464 pts met study criteria (mean age 67 y, 57% male). Mean costs during the 6 mos before 1L were $6,075/mo. On-Tx costs per mo were higher than off-tx costs in all lines. MM Tx medications represented 36%-45% of total costs across LOTs. MM complications and Tx-related AEs represented 26%-32% of total costs. Total costs per mo were highest at Tx initiation in all LOTs and declined over time. Conclusions: MM Tx medications and tx of MM complications/AEs represent the majority of healthcare costs in MM pts. Monthly MM Tx medication costs were greatest for 4L+ and monthly total costs at treatment initiation were greatest for 1L. In each LOT monthly costs declined over time. Therapies that extend PFS and the treatment-free interval may reduce the costs of MM treatment and likely defer costs of subsequent MM tx. Mean monthly health care cost by LOT, $. Costs 1L N=9,464 2L N=3,006 3L N=1,073 4L+ N=664 Total 9,771 9,664 9,823 11,760 On/Off Tx On 14,338 13,218 12,643 14,201 Off 5,794 5,557 5,659 7,736 MM-related by service category Tx – drugs 3,501 4,016 4,430 4,712 Tx – administration 156 129 124 176 Complications and Tx related AEs 3,149 2,743 2,573 3,721 Other outpatient 1,099 1,073 999 1,085 Other inpatient 836 755 776 1,028 Non-MM related 190 190 99 144 Time since Tx initiation Q1 17,234 15,741 15,223 16,211 Q2 12,873 11,086 9,934 11,704 Q3 9,109 8,509 8,868 9,401 Q4 7,456 7,418 8,093 8,292 Q5 6,164 7,118 7,117 8,924 Q6 5,220 6,720 7,451 7,915 Q7 4,913 6,390 6,652 6,917 Q8 4,804 5,757 6,287 5,455
Outcome of etoposide and mitoxantrone for relapsed or refractory acute myeloid leukemia (RR-AML) in the modern era.
Authors: Zelia Ramone Karema Bowman, Ryan James Caddell, Abraham Sebastian Kanate, Alex Shillingburg, Nilay Arvind Shah, Michael Craig, Aaron Cumpston
Journal: Journal of Clinical Oncology (2016)

e18515 Background: Relapsed or refractory acute myeloid leukemia (RR-AML) carries a poor prognosis, requiring allogeneic transplant for durable remissions. The combination of Mitoxantrone and Etoposide (VP/Mito) is a common regimen utilized to obtain disease control prior to transplant. VP/Mito has been reported in several phase 2 studies, none of which were done in the current era of cytogenetic or gene mutation analysis. Methods: We present a retrospective review of 55 adult patients with RR-AML receiving VP/Mito (Etoposide 100mg/m2 QD x5 days and Mitoxantrone 10mg/m2 QD x5 days) from January 2003 to June 2014. All patients received antimicrobial prophylaxis and most patients received granulocyte-colony stimulating factor support. Results: Baseline characteristics are shown in Table 1. The ORR in patients who received VP/Mito was 31% with a complete response (CR) rate of 20% and CRi rate of 11%. OS and RFS were 5.0 and 5.8 months, respectively. A total of 17 patients (31%) were able to be bridged to an allogeneic HCT. Cytogenetic abnormalities were categorized into AML risk groups by the European LeukemiaNet (ELN) guidelines. Under this stratification, risk groups appeared to correlate with response rates with favorable being 57%, intermediate 42-40% and adverse risk 17%. Primary complications included neutropenic fever (40%), bacteremia (29%), pneumonia (13%), and mucositis (20%). Median duration of neutropenia and thrombocytopenia was 28 and 26 days, respectively. Conclusions: VP/Mito regimen is both a safe and effective therapy for RR-AML, with promising rates in favorable and intermediate risk patients. Efficacy in poor-risk patients is poor and other options should be explored for these patients. Patient characteristics. Total patients, n 55 Median age, years 50 (18-75) Male gender (%) 26 (47%) Prior MDS (%) 9 (16%) Prior # regimens (range) 2 (1-4) Prior regimen 7 + 3 48 (87%) HiDAC 47 (85%) Prior allogenic HCT (%) 11 (20%) ECOG PS, median 1 (0-2) AML risk group, n (%) Favorable 8 (15%) Intermediate I 20 (36%) Intermediate II 5 (9%) Adverse 22 (40%)
Development of combination therapy using radiation and cell-based immunotherapy.
Authors: Satoshi Wada
Journal: Journal of Clinical Oncology (2016)

e14522 Background: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colonystimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.
Oncogenic mutation within the β3-αC loop of EGFR/ERBB2/BRAF/MAP2K1.
Authors: Jie Gao, Jun Zhao, Liyun Miao, Shuanying Yang, Yu Chen, Jiaojiao Huan, Naixin Liang, Yu Zeng, Lianke Liu, Bin Yi, Yan-Fang Guan, Ling Yang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e24299 Background: Kinase domain β3-αC loop is highly conserved across oncogene families, exon 19 deletion within EGFR β3-αC loop affect kinase activity and drive lung cancer has been described. As β3-αC loop was immanent in ERBB2, BRAF and MAP2K1, the effect of these oncogenes and other mutation types including single nucleotide variants (SNVs), short insertions is not well understood. Here we analyze the spectrum of β3-αC loop mutations within these genes in Chinese patients. Methods: A total of 8819 samples were enrolled in the current study, tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based next generation sequencing. Results: We identified 988 mutations from 8819 samples within β3-αC loop in the cohort. 94.4% (933/988) mutations were located in EGFR, 2.4% (24/988) in ERBB2, 1.1% (11/988) in BRAF and 2.0% (20/988) in MAP2K1. EGFR β3-αC deletions were present in high frequency (895/933 = 96%), the most frequent mutation was ΔELREA, followed by lower frequencies of ∆LREATS P753S and ∆LREAT. We also detected 8 patients harboring rare EGFR β3-αC insertion (I740_K745dup), which was reported as TKI-sensitive mutation. Among 30 point mutations within this region, 33% (10/30) had influence on kinase activities and related to EGFR TKIs resistance. ERBB2 β3-αC deletions (ΔLRENT) were restricted to 3.7%(4/108) of ERBB2 mutation breast tumors, which were sensitive to EGFR/ERBB2 inhibitor neratinib and resistant to lapatinib. The percentage of drugs-relevant point mutations were 100% (9/9) and 63.6% (7/11) respectively in breast cancer and NSCLC. Moreover, 87.5% (14/16) deletions and 66.7% (10/15) point mutations located in BRAF/MAP2K1 β3-αC loop also preformed diverse drugs relevance. Conclusions: We show that oncogenic mutations within the β3-αC loop of ERBB2, MAP2K1 and BRAF are analogous to the EGFR. The multiple β3-αC loop mutations have profound effect on kinase activities and drug response. Understanding the spectrum within the β3-αC loop is critical to targeted therapies.
Retrospective study of age-adjusted growth patterns for height, weight and body mass index in pediatric acute leukemia and lymphoma.
Authors: Charles Phillips, Hanieh Razzaghi, Jing Huang, Charles Bailey
Journal: Journal of Clinical Oncology (2018)

10574 Background: Pediatric patients with acute lymphoblastic leukemia (ALL) have a significantly higher body mass index (BMI) than their peers with an expected increase in age-adjusted mean Z-score of 0.81 after completion of cancer treatment. Growth patterns are less well understood for other types of pediatric hematologic malignancies including acute myeloid leukemia (AML), Hodgkin’s Lymphoma (HL) and Non-Hodgkin’s Lymphoma (NHL). Understanding the differences in growth patterns between different pediatric malignancies is critical to discern who is most vulnerable to unhealthy weight changes and stunted growth. We describe a single institutional retrospective study of height, weight, and BMI patterns for patients with hematologic malignancies. Methods: Study population included patients at the Children’s Hospital of Philadelphia from 2011-2017. Anthropomorphic measurements were abstracted from the electronic health record and contained in an electronic health record derived research network, PEDSnet. All acute leukemia and lymphoma patients who received at least one dose of chemotherapy were included. Anthropomorphic measurements were standardized with day 0 corresponding to the day of first chemotherapy administration and followed for 1 year. Results: A total of 650 patients met inclusion criteria with the following diagnosis frequency: ALL 377, AML 83, HL 93, NHL 97. As expected, mean BMI Z-score for ALL patients increased during therapy and increased by 0.5 at 1 year. At 1 year, mean BMI Z-score decreased for AML patients by 0.4, increased for NHL by 0.5, and was unchanged for HL. All four cancer groups had a mean weight Z-score change of < 0.3. HL was the only cancer not to have a mean weight Z-score fall during the first 6 months of treatment. Regarding height, ALL and AML patients had a decrease in mean height Z-score of about 0.4 while HL and NHL had no change. Conclusions: Acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin’s Lymphoma, and Non-Hodgkin’s Lymphoma have unique growth patterns in the first year after cancer diagnosis. Hodgkin’s lymphoma had the smallest changes in mean height, weigh and BMI Z-scores while acute myeloid leukemia had the largest changes.
A phase III, double-blind, randomized clinical trial comparing S-1 in combination with DC vaccine loaded with WT1 peptides (TLP0-001) or placebo for the patients with advanced pancreatic cancer refractory to standard chemotherapy.
Authors: Masahiro Katsuda, Motoki Miyazawa, Manabu Kawai, Seiko Hirono, Ken-Ichi Okada, Atsushi Shimizu, Yuji Kitahata, Hiroki Yamaue
Journal: Journal of Clinical Oncology (2017)

TPS4153 Background: The development of new potent therapeutic is strongly called for treating pancreatic cancer. Dendritic cells (DCs) are a type of antigen-presenting cells that play an important role in adaptive immune system, and this property has prompted their recent application to therapeutic cancer vaccines. DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce therapeutic anti-tumor immunity. Wilms' tumor gene WT1 is expressed in various kinds of cancers including pancreatic cancer. In pilot clinical trials of DC vaccination loaded with WT1 peptides for patients with advanced pancreatic cancer, induction of anti-tumor WT1 specific immune responses and tumor regressions have been observed (Kimura et al, Pancreas, 2012 / Kobayashi et al, Cancer Immunol Immunother, 2014 / Mayanagi et al Cancer Sci, 2015). TLP0-001 is activated Dendritic cells loaded with epitope peptides derived from WT-1. Methods: This is an investigator initiated, phaseIII, multicenter, double-blind, randomized trial of TLP0-001+S-1 versus placebo+S-1 for the patients with locally advanced or metastatic pancreatic cancer refractory to standard chemotherapy. Patients are allocated to either DC vaccine (TLP0-001) + S-1 group or placebo + S-1 in 1:1 ratio by dynamic allocation method. The primary endpoint is overall survival. Sample size is estimated presuming the effects will be observed from the time point of 50% cumulative survival rate. Assuming a type I error alpha (two-sided) level of 5% and a power of 80% or more for hazard ratio 0.644, sample size necessary is estimated as 174 patients. When the first 6 patients are administerd TLP0-001, the independent Data Monitoring Commitee checks safety data to assess continuation of the study. Enrollment begins in March 2017.
Impact of care at Memorial Sloan Kettering Cancer Center (MSKCC): A comprehensive cancer center on overall survival (OS) in patients (pts) with AJCC stage IV pancreas adenocarcinoma (PDAC).
Authors: Fiona Boland, Ahmad Cheema, Maeve Aine Lowery, Kenneth H. Yu, Anna M. Varghese, Andrew S. Epstein, Ghassan K. Abou-Alfa, David Paul Kelsen, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

e18128 Background: PDAC has a rising incidence and relatively static mortality rates. Current cytotoxic regimens confer median survivals of 8.5- 11 months (Von Hoff, Conroy, et al. NEJM 2013, 2011). National Cancer Institute-designated Comprehensive Cancer Centers potentially allow greater access to multidisciplinary consultation for complex cancer care. Although the widespread benefits of NCICCCs are acknowledged, there is limited data demonstrating superior outcomes for patients treated at these centers. Methods: Patients with stage IV PDAC, diagnosed between 01/01/13 and 12/31/14, were identified and followed until death or 12/31/2016. These patients had care centralized to MSKCC and the analysis was conducted to evaluate key patient (pt) and disease characteristics, systemic therapies and outcomes.Survival times were calculated from the date of diagnosis. Results: N=391 pts identified, 210 males (54%), 181 females (46%). Median age 66 years (range 27-91). Table 1 outlines key points. For entire cohort, median overall survival (mOS): 11.4 + 9 months, 1-year (yr) and 2-yr survival rates (SR) of 48% and 15.1% respectively. N= 165 (42%) received mFOLFIRINOX-based regimen as 1st-line therapy with mOS 13.2 + 8.9 months, 1-yr and 2-yr SR of 59.4.% and 20% respectively. N= 118 (30.1%) received gemcitabine + nab-paclitaxel- based regimen as 1st line therapy had a mOS of 11.6 + 9 months with 1-yr and 2-yr SR of 49.1% and 16.2% respectively. Conclusions: At MSKCC, a major referral center for PDAC, outcomes for stage IV disease compare favorably to contemporary trial outcomes with notable 2-yr survivorship (long-term survival analysis of MPACT trial showed 1-yr and 2-yr SR of 35% and 10% respectively). Contributing factors likely reflect multidisciplinary expertize, patient selection and biases. Centralized care for complex illnesses may improve outcomes. [Table: see text]
NCOG-12. COMPREHENSIVE GERIATRIC ASSESSMENT (CGA) FOR OUTCOME PREDICTION IN ELDERLY PATIENTS (PTS)WITH GLIOBLASTOMA (GBM): A MONO-INSTITUTIONAL EXPERIENCE
Authors: Giuseppe Lombardi, Eleonora Bergo, Luisa Bellu, Mario Caccese, Annunziata Lettiero, Giuseppina Tierno, Ardi Pambuku, Antonella Brunello, Vittorina Zagonel
Journal: Neuro-Oncology (2018)

Treatment for GBM elderly PTS is still a challenge in neuro-oncology. Clinical tools, including CGA, are needed for improving treatment decision and outcome. The aim of this study was to evaluate CGA as a prognostic tool in terms of PFS and OS in elderly GBM PTS. We performed a retrospective analysis of elderly PTS ≥ 65 years, treated at Veneto Institute of Oncology between January 2011 and January 2018, with newly histologically diagnosed GBM and receiving a baseline CGA after 3–4 weeks from surgery. CGA included the following domains: age, activities and instrumental activities of daily living (ADL, IADL), cognitive status (MMSE), mood (GDS), nutritional status (MNA), number of drugs, comorbidity (cumulative Illness Rating Scale-CIRS), presence of geriatric syndromes, presence of caregiver. PTS were classified according to Balducci’s criteria into Fit or Unfit (Frail and Vulnerable). 113 PTS were enrolled: 72(64%) were male, KPS were ≥ 70 in 90 PTS(80%); 37 PTS(33%) had a radical surgery, 63% partial surgery and 4% received a biopsy. 90 PTS(80%) received Stupp treatment, 16 (14%) temozolomide or radiotherapy alone and, only 7(6%) received no treatment. MGMT methylation status was analyzed in 96 PTS: 44% were metMGMT. According to CGA evaluation: 40 PTS(35.4%) were classified as Fit and 73 PTS(64.6%) Unfit. PFS was 11.2(95% CI 6.0–16.4) and 7.2(95% CI 5.8–8.6) months for Fit and Unfit PTS (p=0.1). On multivariate analysis, adjusted for type of surgery, MGMT methylation status and type of therapy, PFS was significantly different between the two groups (HR=0.6, 95% CI 0.2–0.9; p=0.04). OS was 16.4(95% CI 14.6–18.2) and 10.6(95% CI 8.3–12.8) ms for Fit and Unfit PTS (p=0.04); on multivariate analysis the HR was 0.51(95% CI 0.2–0.9; p=0.04). CONCLUSIONS: CGA demonstrated significant outcome prediction in terms of OS and PFS, regardless of therapy and it could be a useful treatment decision-tool.