tbuckley/cabot-search huggingface dataset:
Long-term results with combined treatment in adult localized extraskeletal Ewing's sarcoma (ES): A retrospective analysis of 51 patients (pts) from a single referral center
Authors: P. Dileo, R. Bertulli, C. Piovesan, A. Marrari, E. Puma, C. Spreafico, A. Gronchi, P. Olmi, L. Gandola, P. G. Casali
Journal: Journal of Clinical Oncology (2009)

10548 Background: After the first description in 1975, only small series of adult extraskeletal ES have been reported. In general, adulthood is claimed to be an adverse prognostic factor, while the meaning of extraskeletal origin is less established. Methods: We retrospectively reviewed adult pts with extraskeletal, localized ES, undergoing medical therapy between 1988 and 2004, who were included in the dataset of the current Adult Sarcoma Medical Unit at Istituto Nazionale Tumori, Milano, Italy, which serves as a reference center for adult soft tissue sarcoma. Fifty-one pts were treated with a combined approach, including chemotherapy, surgery when appropriate, and radiation therapy. Overall, 27/51 pts were male, and age ranged from 16 to 63 years. Site of primary lesions was: thorax 14 (27%), limbs 18 (35%), paravertebral region 5 (10%), pelvis 4 (8%), head&amp;neck 3 (6%), superficial trunk 6 (12%), other 1 (2%). Seven pts presented with locally advanced disease. Chemotherapy regimens included: vincristine (V), ifosfamide (I), epirubicin (E)/adriamycin (A), dacarbazine (D), actinomycinD (ActD), cisplatin (C), etoposide (Et). 35/51 pts (68%) underwent preoperative chemotherapy: 30 pts received IVE × 4–7 cycles; 5 pts received VAI alternating with IEt × 9 cycles. 42/51 pts underwent surgery; 38/51 pts received radiation therapy. Results: Response rate to induction chemotherapy including antracicline, ifosfamide + etoposide was 83%. Of these pts, 9 showed a complete response (CR), 17 a partial response (PR), 3 a minor response (MR), 3 stable disease (SD), and 3 progressive disease (PD). Overall, DFS at 10 years (y) was 55%. Pts with limb, head&amp;neck, or superficial trunk lesions had a better outcome compared to those with other primary sites (DFS at 10y is 71% vs 33%). Conclusions: In this series of adult pts with extraskeletal ES, response rate and DFS were comparable to those of ES of bone in conventional series. The primary site may identify a subset of pts with worse outcome and prognosis, for whom more intensive treatments could be investigated. No significant financial relationships to disclose.
Knowledge, attitudes and practice for Ebola virus disease in the national rapidly deployable isolation and treatment facility in Sierra Leone
Authors: Pelagia Reidy, Alie Wurie, Wayne Barnes, Emily Carr, David Kamau, Darrelle Marsden, Kerry Mundell, Lisa Watson, Megan Paveley, Buyiswa Lizzie Sithole, Tonny M. Sekikongo, Andrew M. Johnston, Tom E. Fletcher
Journal: Journal of Infection (2017)
Molecular correlates (EGFR status) and plasma VEGF levels associated with a phase II study of bevacizumab plus erlotinib (BE) for patients with recurrent ovarian cancer (OC) and fallopian tube (FT) cancer
Authors: H. S. Nimeiri, L. Faoro, A. M. Oza, R. J. Morgan, D. Gandara, V. Janamanchi, R. Salgia, W. M. Stadler, E. E. Vokes, G. F. Fleming
Journal: Journal of Clinical Oncology (2007)

5554 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are commonly over- expressed in OC and may correlate with poor prognosis. EGFR mutations, although rare, have recently been reported in ovarian cancer. We examined these factors for prognostic value in the setting of treatment with BE. Results of a phase II trial of BE in recurrent OC pts have previously been reported; there were 1 CR and 1 PR among 13 patients. The trial was closed to accrual due to 2 bowel perforations. Methods: Pretreatment plasma VEGF, urine VEGF, and serum VEGFR2 levels are available on 9, 8, and 8 pts to date. VEGF levels were determined using an ELISA (R&amp; D Systems, Minneapolis, MN). Tumor from 8 pts: 1(CR), 1 (PR), 5 (SD), 1 (PD) was available for immunohistochemical analysis for EGFR. Genomic DNA was successfully isolated from 6 paraffin embedded tumor specimens. EGFR exons 18 to 21 were amplified by PCR using primary and secondary PCR primer pairs. PCR products were purified and submitted for DNA sequencing against forward and reverse primers (analyzed with Sequencher). Results: Mean baseline plasma VEGF level was 107.6 pg/ml (range, 52–198 pg/ml). For analysis, we combined CR+PR+SD versus PD. Wilcoxon rank-sum test was used to compare baseline plasma VEGF levels, urine VEGF and serum VEGFR2 between the two response groups. There were no significant differences between response and baseline VEGF levels (p=0.39), urine VEGF (p=0.56), and VEGFR2 (p=0.56) respectively. The pt with prolonged CR (18 mos) had the highest baseline VEGF level. Cox proportional hazards regression models was used to look at the association between overall survival (OS) and VEGF levels. There was no significant relationship between (OS) and baseline plasma VEGF (p= 0.38), urine VEGF (p=0.33) or serum VEGFR2 (p=0.63) respectively. No EGFR mutations were found in exon 19 (n=4) or exon 21 (n=6). EGFR expression is being evaluated. Conclusions: Our results indicate that there were no significant relationship between response or OS and baseline VEGF or VEGFR2 levels in our treated pts. The study was supported by NCI Grant N01-CM-17102. [Table: see text]
Comprehensive genetic definition of susceptibility to toxic side effects of irinotecan in mice.
Authors: Peter Demant, Karen Elizabeth Thudium, Maria Vittoria Sepporta, Hayley Affronti, Gustaaf Meijer, Laura Prendergast, Ron H.J. Mathijssen, William C Burhans, Wen Wee Ma, Alan Hutson, Gerald J Fetterly, Ashley J Dittmar
Journal: Journal of Clinical Oncology (2015)

e13566 Background: Adverse drug reactions (ADRs) are major obstacles of cancer therapy, but causes of their individual predisposition remain largely unknown. Irinotecan, an effective anti-cancer drug, causes frequent severe ADRs and their genetics has been a major paradigm for pharmacogenetics of anti-cancer drugs. UGT1A1 (UDP-glucuronosyltransferase) inactivates irinotecan’s cytotoxic metabolite SN-38. UGT1A1*28/*28 homozygous patients have low expression of UGT1A1, high plasma SN-38 levels, and in 50% develop grade 3-4 neutropenia. However, ±75% of such irinotecan-induced neutropenias occur in UGT1A1*1/*1 or UGT1A1*1/*28 patients independently of SN-38 levels. The causes of this majority of irinotecan-ADRs are unknown, suggesting effects of additional genes. Methods: To search for such additional genes we used a phenotype-driven linkage analysis of irinotecan-ADRs in mice. Such analysis, in contrast to candidate-gene studies, can detect genes of any functional class that control irinotecan-ADRs. We analyzed genetics of body-weight loss, mortality, myelotoxicity, and diarrhea. We compared kinetics of plasma levels of irinotecan and its metabolites SN-38 and SN-38G in ADR-susceptible and resistant strains. Results: We detected and mapped 11 new Adri (Adverse drug reaction irinotecan) genes controlling irinotecan-ADR susceptibility. They are distinct from the known irinotecan PK and PD genes and DNA-repair genes, do not affect SN-38 levels, determine cumulatively individual ADR-susceptibility, but not irinotecan tumor response or ADRs by other drugs. Adri genes affect either myelotoxicity or diarrhea. In the pathogenic pathway controlling diarrhea, Adri1 determines its incidence and Adri5 mortality. Conclusions: Irinotecan-ADR susceptibility is controlled in mice by multiple tissue specific Adri-genes. Unlike in UGT1A1*28/*28 homozygotes, causes of increased irinotecan toxicity in mice and likely also in most humans are not high systemic SN-38 levels, but probably increased sensitivity of normal tissues. Such ADRs may require a different clinical management. Adri genes likely represent novel regulators of local irinotecan effects and potential new pharmacological targets.
Adjuvant chemotherapy (AC) use and outcomes in stage II colon cancer (CC) with and without poor prognostic features.
Authors: Aalok Kumar, Hagen F. Kennecke, Howard John Lim, Daniel John Renouf, Ryan Woods, Caroline Speers, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2012)

3527 Background: AC is frequently considered inpatients (pts) with "high risk" stage II CC, defined by the presence of &gt;/=1 poor prognostic features, such as obstruction or perforation, T4 stage, &lt;12 lymph nodes retrieved, positive margins, and lymphovascular or perineural invasion. However, survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to 1) examine patterns of AC use in stage II CC and 2) explore the relationship between AC use and survival in high vs low risk pts. Methods: All pts diagnosed with stage II CC in British Columbia from 1999 to 2008 and evaluated at any 1 of 5 regional centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate a) high vs low risk status and b) receipt of AC with relapse-free (RFS), disease specific (DSS) and overall survival (OS). Results: We identified 1,697 stage II CC pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk features who received AC were younger (median 62 vs 72 years, p&lt;0.001) and had better performance status (ECOG 0/1 47% vs 34%%, p=0.02). In the high risk group, AC was associated with improved 5-year OS, but not with RFS or DSS (Table). After adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), but no significant RFS or DSS benefits were seen (HR 0.76, 95CI 0.58-0.99, p=0.05 and HR 0.75, 95CI 0.55-1.02, p=0.11, respectively). Subgroup analyses showed that individuals with T4 lesions had improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.02), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). Conclusions: In this population-based cohort of stage II CC, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk based on clinical and pathological factors. Risk stratification based on molecular testing should be further explored. [Table: see text]
Combining pembrolizumab and palliative radiotherapy in gastroesophageal cancer to enhance anti-tumor T-cell response and augment the abscopal effect.
Authors: Joseph Chao, Yi-Jen Chen, Paul Henry Frankel, Vincent M. Chung, Dean Lim, Daneng Li, Marwan Fakih, Peter P. Lee
Journal: Journal of Clinical Oncology (2017)

TPS220 Background: Pembrolizumab has demonstrated encouraging preliminary evidence of activity in small cohorts of gastroesophageal cancer patients (pts) when selected for tumor PD-L1 overexpression. Strategies should be further developed to enhance the potency of PD-1 inhibitors, even in pts whose tumors are not considered to have detectable PD-L1 expression. The abscopal effect is a rarely observed though well annotated clinical phenomenon in cancer radiotherapy (RT), in which non-irradiated metastatic lesions are noted to regress after radiation to the primary tumor site. In preclinical models, this phenomenon has been attributed to immune-mediated effects, while RT has been observed to increase tumor PD-L1 expression. This lends credence to ongoing efforts to combine RT and immune checkpoint inhibition. We present the study design for a phase II trial combining pembrolizumab and palliative RT in metastatic gastroesophageal squamous cell and adenocarcinoma pts. Methods: A target accrual of 14 pts will be assigned to palliative RT of 30 Gy over 10 fractions for symptoms from their primary tumor or a single target metastatic site in combination with fixed dose pembrolizumab 200 mg every 3 weeks. Symptomatic brain metastases will be excluded. Pembrolizumab will be continued until disease progression, intolerable toxicity, or 35 administrations (~2 years). Pts will be required to undergo sequential biopsies of a non-target metastatic site (inclusive of malignant ascites) with timepoints occurring pre-treatment and ~21 days after completion of RT. Biomarkers of immune response and overall response rate (RECIST1.1, irRECIST) will be a composite primary endpoint; progression-free and overall survival, and toxicities will be secondary endpoints. Quantitative spatial image analyses of biopsy samples will be performed to examine changes in tumor cell-stromal interactions inclusive of CD4, CD8, Treg, and MDSC populations as well as tumor PD-L1/PD-1 expression levels. The results will assist in determining mechanisms of response and resistance to combination RT and PD-1 targeting strategies. Clinical trial information: NCT02830594.
Excision repair cross-complementary group 1 (ERCC1) as a prognostic biomarker in patients (pts) with solid tumors: A meta-analysis on detection methods.
Authors: Milena Perez Mak, Tiago Kenji Takahashi, Paulo Marcelo Hoff, Gilberto Castro, Igor M. L. Snitcovsky
Journal: Journal of Clinical Oncology (2012)

e21040 Background: ERCC1 overexpression is associated with better outcomes in some cancers. The best method to assess its expression, immunohistochemistry (IHC) or polymerase chain reaction (PCR), is not established. To clarify such question, this meta-analysis was conducted. Methods: PUBMED, EMBASE and Cochrane databases were searched with terms: “ERCC1” and “IHC” and/or “PCR” and/or “mRNA”. Inclusion criteria: full papers in English, solid tumor pts, ERCC1 evaluated by IHC and PCR on the same samples, reported correlation between ERCC1 expression and overall survival (OS) – the primary endpoint. As secondary endpoint, correlation between IHC and PCR expression was assessed. Exclusion criteria: review articles and no reported endpoint. Two authors reviewed and classified all papers. Pooled HR and variance were calculated by standard methods, using CMA v2.2.064 (Englewood, USA). Results: 25 articles were retrieved, with 4 included for the primary endpoint (224 pts) and 4 (191) for the secondary endpoint. All were retrospective, with diverse primary sites. Except for one, platinum chemotherapy was employed. All studies used 8F1 clone, and in 2, FL297 clone was also evaluated. ERCC1 positivity was determined by H-score in 2 studies and by AQUA in 2. mRNA ERCC1 positivity was variably defined. In general, ERCC1 overexpression was correlated with longer OS (HR 0.569, 95% CI 0.436 - 0.743, p &lt;0.001). Similar results were found in terms of OS either by IHC or PCR (HR 0.626, 95% CI 0.46 – 0.853, p 0.003 and HR 0.434, 95% CI 0.257 – 0.730, p 0.002; respectively). No correlation between IHC and PCR overexpression was found (coefficient 0.098 p 0.444, random effect). Heterogeneity was detected only in IHC analysis, when expression was detected by both FL297 and 8F1 antibodies (p 0.001, fixed effect). Conclusions: ERCC1 overexpression is associated with better OS, regardless of employed methodology. However, protein and mRNA expression are not correlated. Major limitations to our analysis include the variety of employed ERCC1 detection methods and retrospective nature of data. Definitive conclusions on the prognostic role of ERCC1 and best methodology remain to be answered.
Advanced Materials for Health Monitoring with Skin‐Based Wearable Devices
Authors: Han Jin, Yasmin Shibli Abu‐Raya, Hossam Haick
Journal: Advanced Healthcare Materials (2017)

Skin‐based wearable devices have a great potential that could result in a revolutionary approach to health monitoring and diagnosing disease. With continued innovation and intensive attention to the materials and fabrication technologies, development of these healthcare devices is progressively encouraged. This article gives a concise, although admittedly non‐exhaustive, didactic review of some of the main concepts and approaches related to recent advances and developments in the scope of skin‐based wearable devices (e.g. temperature, strain, biomarker‐analysis werable devices, etc.), with an emphasis on emerging materials and fabrication techniques in the relevant fields. To give a comprehensive statement, part of the review presents and discusses different aspects of these advanced materials, such as the sensitivity, biocompatibility and durability as well as the major approaches proposed for enhancing their chemical and physical properties. A complementary section of the review linking these advanced materials with wearable device technologies is particularly specified. Some of the strong and weak points in development of each wearable material/device are highlighted and criticized. Several ideas regarding further improvement of skin‐based wearable devices are also discussed.
The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL
Authors: A M Savino, J Sarno, L Trentin, M Vieri, G Fazio, M Bardini, C Bugarin, G Fossati, K L Davis, G Gaipa, S Izraeli, L H Meyer, G P Nolan, A Biondi, G Te Kronnie, C Palmi, G Cazzaniga
Journal: Leukemia (2017)
The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers.
Authors: Kara Noelle Maxwell, Daniel De Sloover, Lyndsey Emery, Bradley Wubbenhorst, Kurt P D'Andrea, Jessica Long, Rebecca Mueller, Jacqueline Powers, Jill Stopfer, Michael D Feldman, Susan M. Domchek, Robert Daber, Katherine L. Nathanson
Journal: Journal of Clinical Oncology (2013)

1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.
Migration to next-generation sequencing and the identification of <i>RET</i> and <i>ROS1</i> rearrangements plus PTEN and MET protein expression in tumor specimens from patients with lung adenocarcinomas: Lung Cancer Mutation Consortium (LCMC 2.0).
Authors: Mark G. Kris, Bruce E. Johnson, David J. Kwiatkowski, Ignacio Ivan Wistuba, Lynne D Berry, Eric B. Haura, Mark A. Socinski, Suresh S. Ramalingam, Bonnie S. Glisson, Saiama Naheed Waqar, Gregory Alan Otterson, Joan H. Schiller, Edward B. Garon, Jeremy Paul Cetnar, Katerina A Politi, Julie R. Brahmer, Lecia V. Sequist, Christine Marie Lovly, Kelly Kugler, Paul A. Bunn
Journal: Journal of Clinical Oncology (2015)

8094 Background: LCMC 1.0 demonstrated that multiplexed genomic platforms can assay 10 oncogenic drivers at diagnosis in tumor specimens from patients with lung adenocarcinomas and this information can guide care. (Kris JAMA 2014) The number of molecular lesions that can be targeted with drugs continues to grow and Next-Generation Sequencing permits more comprehensive testing of more aberrations with less tumor tissue. To translate these advances, we initiated LCMC 2.0 to test initial tumor specimens for 12 oncogenic drivers and to provide the results to clinicians for treatment decisions and research. Methods: The 16 site LCMC 2.0 is testing tumors from 1000 patients with lung adenocarcinomas in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, MAP2K1, AKT1, and NRAS mutations, MET amplification, rearrangements in ALK, RET, and ROS1,and PTEN (MAb 138G4) and MET (MAb SP44) expression by immunohistochemistry. All patients were diagnosed with stage IIIB/IV after May 2012, had a performance status 0-2 and available tumor tissue. Results: Of 986 patients registered, data is now reported for 617. An oncogenic driver has been found in 52% (95% CI 49 to 56%). Drivers detected 13 RET (2%, 95% CI 1 to 3%) , 17 ROS (1%, 95% CI < 1 to 2%), 135 KRAS (22%, 95% CI 19 to 25%), 77 EGFR (13%, 95% CI 13 to 15%), 20 ALK (3%, 95% CI 2 to 5%), 18 BRAF (3%, 95% CI 2 to 4%), 4 PIK3CA ( < 1%, 95% CI < 1to 1%), 9 HER2 (2%, 95% CI < 1 to 3%), 12 MET amplification (2%, 95% CI 1 to 3%), 3 NRAS ( < 1%, 95% CI < 1 to 1%), 1 MAP2K1 ( < 1%, 95% CI < 1 to 1%), 0 AKT1, 26 had ≥ 2 findings (4%, 95% CI 3 to 6%). PTEN loss was detected in15% (95% CI 12 to 17%) and MET expression in 54% (95% CI 50 to 58%). Next-Generation platforms were used at 81% of LCMC 2.0 sites. Results were used to select a targeted therapy or trial in 16%. Conclusions: Next-Generation Sequencing is rapidly becoming routine practice at LCMC 2.0 centers with use going from 0 to 81% of sites since 2012. LCMC 2.0 identified additional targets (RET and ROS1 rearrangements and PTEN loss) and detected an actionable oncogenic driver in the majority of initial lung adenocarcinoma specimens. Supported by Free to Breathe Clinical trial information: NCT01014286.