tbuckley/cabot-search huggingface dataset:
Is the mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin (ddTC) than to conventional taxane and carboplatin chemotherapy (TC) in high grade serous ovarian carcinoma? A survey of Japanese Gynecology Oncology Group study (JGOG3016A1).
Authors: Ryusuke Murakami, Noriomi Matsumura, Hiroshi Tanabe, Hirofumi Michimae, Mayu Yunokawa, Haruko Iwase, Motoi Sasagawa, Toshiaki Nakamura, Osamu Tokuyama, Masashi Takano, Toru Sugiyama, Takashi Sawasaki, Seiji Isonishi, Kazuhiro Takehara, Hidekatsu Nakai, Aikou Okamoto, Masaki Mandai, Ikuo Konishi
Journal: Journal of Clinical Oncology (2017)

5510 Background: High-grade serous ovarian cancer (HSOC) was divided into four transcriptome subtypes (i.e. Mesenchymal, Immunoreactive, Proliferative, and Differentiated). We established a new pathological classification based on these transcriptome subtypes: Mesenchymal Transition (MT) type, Immune Reactive (IR) type, Solid and Proliferative (SP) type and Papillo-Glandular (PG) type (PMID: 26993207). The MT type has the worst prognosis. We discovered the Mesenchymal transcriptome subtype might be sensitive to taxane chemotherapy. Therefore, we hypothesized that the MT type, which represents the Mesenchymal transcriptome subtype, may respond better to dose dense taxane combined with carboplatin (ddTC) rather than to conventional taxane and carboplatin (TC). Methods: We collected 207 HSOC slides registered in the Japanese Gynecology Oncology Group 3016 (JGOG3016) study. Two of the authors, R.M. and I.K., classified the samples into the four pathological subtypes (n=201). We categorized the patients into two groups based on the treatment they received: ddTC (n=95) or TC (n=106). Progression free survival (PFS) was compared between the two groups for each pathological subtype. Results: Among the MT patients, the ddTC group had a significantly better PFS than the TC group (n= 30 vs 42, median survival: 1.8 vs 1.2 years, p=0.01). Among the SP patients, the ddTC group had better PFS than the TC group, even though the difference was not statistically significant (n=22 vs 27, median survival: 3.2 vs 1.4 years, p=0.08). In contrast, among the IR patients, the two groups showed no significant difference in PFS (n=16 vs 16, median survival: 5.2 vs 5.8 years, p=0.64). The PG patients also showed no significant difference in PFS between the two groups (n=27 vs 21, median survival: 1.5 and 1.7 years, p=0.64). Conclusions: The HSOC of MT type is more responsive to ddTC than to TC. This new pathological classification reflecting HSOC transcriptome subtypes leads to individualization of chemotherapy treatments.
Acquired <i>BRAF</i> fusions as a mechanism of resistance to <i>EGFR</i> therapy.
Authors: Morana Vojnic, Christopher Kurzatkowski, Daisuke Kubota, Ken Suzawa, Zebing Liu, Marissa Mattar, Inna Khodos, John T. Poirier, Elisa de Stanchina, Charles M. Rudin, Gregory J. Riely, Helena Alexandra Yu, Maria E. Arcila, Marc Ladanyi, Romel Somwar
Journal: Journal of Clinical Oncology (2018)

12122 Background: While multiple genetic mechanisms have been identified in EGFR mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKI), either first generation (EGFR T790M), or third generation (EGFR C797S), or both (gains of MET or ERBB2), many cases lack a known mechanism of AR. Methods: To identify novel mechanisms of EGFR TKI, we performed targeted large panel sequencing (MSK-IMPACT assay; PMID: 28336552) on 374 consecutive patients with metastatic EGFR mutant lung cancer, including 200 tested prior to EGFR TKI, 136 tested after progression on EGFR TKI, and 38 patients with both types of samples. Genetic alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, PC9) using CRISPR-Cas9 genome editing. We also generated a cell line from a biopsy of a patient with AR (MSK-LX138cl). A kinase-focused inhibitor library was used to screen for agents that would overcome AR. Results: We identified 4 patients with a BRAF fusion (3 AGK/BRAF, 1 PJA2/BRAF) in a sample obtained at AR to EGFR TKI (2 post-erlotinib; 2 post-erlotinib and post-osimertinib). A pre-TKI sample was available in one of these 4 patients and was negative for BRAF fusion. In the 200 patients only studied pre-EGFR TKI, no BRAF fusions were identified, further supporting the acquired nature of the BRAF fusion. Induction of AGK/BRAF formation in H1975 (L858R+T790M), PC9 (ex19del) and HCC827 (ex19del) cells by genome editing increased phosphorylation of BRAF, MEK1/2, ERK1/2 and STAT3, and conferred resistance to growth inhibition by osimertinib. A patient-derived cell line, MSK-LX138cl, with ex19del and the PJA2/BRAF fusion, was confirmed to be resistant to EGFR TKIs and then used to screen a library of 61 drugs targeting the MAPK pathway in the absence or presence of osimertinib to derive a potential therapeutic strategy. This identified trametinib as an agent that reduced growth of MSK-LX138cl and H1975-AGK/BRAF cells in a synergistic manner with osimertinib. Conclusions: Our findings identify acquired BRAF fusion as a recurrent mechanism of AR to EGFR TKIs including osimertinib and suggest combined MEK and EGFR inhibition as a possible therapeutic strategy.
The role of surgery for stage I small cell lung cancer in recent years: an analysis of the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Dipesh Uprety, Lubina Arjyal, Yazhini Vallatharasu, Amit Khanal, Amir Bista
Journal: Journal of Clinical Oncology (2018)

e20576 Background: Concurrent chemoradiation has been the standard of care in limited stage small-cell-lung cancer (L-SCLC) because of its tendency to early dissemination. In a subset of patients with stage IA or IB disease, surgery followed by chemotherapy can be considered. The survival advantage of surgery in L-SCLC has not been evaluated in recent years. We therefore aimed to assess the impact of surgery in this subset of patients. Methods: We utilized SEER-18 database to identify adult patients with stage IA & IB SCLC between 2005 and 2013. Several cohorts were categorized by age ( < 65 and ≥65 years), sex and race. 2-year and 5-year overall survival (OS) and cancer-specific survival (CSS) were compared among various treatment groups: lobectomy alone (Lb), lobectomy with radiation therapy (Lb+RT), RT alone and neither Lb nor RT using Kaplan-Meier curve. Cox proportional hazard regression was used for multivariate analysis. Results: 1,461 patients with stage IA or IB were identified. Majority of them were whites (86.4%), elderly (66.5% of ≥65 years, median age of 69 years) and females (52.2%). 15.3% of them received Lb, 3.7% received Lb+RT, 49.7% received RT only and 31.3% received other treatments or details of treatment was not known. Survival was significantly better for those receiving Lb+RT followed by Lb and RT only (2-year OS: 89.1%, 70.5% and 51.8%; 5-year OS: 77.3%, 54.5% and 27.2%; 2-year CSS: 91.0%, 75.0% and 58.2%; 5-year CSS: 82.6%, 63.0% and 35.7% respectively, p < 0.001 by log rank test for both OS and CSS). On multivariate analysis, patients receiving Lb+RT had superior survival compared to Lb alone (HR of 0.39, p = 0.008 for OS; HR of 0.4, p = 0.02 for CSS) while patient receiving RT alone had worse survival compared to Lb (HR of 1.91, p < 0.001 for OS; HR of 2.0, p < 0.001 for CSS). Conclusions: There was significant survival benefit for those who received surgery (Lb with or without RT). Systemic therapy information is not available in SEER database which is a major limitation.
Cancer-related morbidity at the end of life in men with prostate cancer.
Authors: Divya Yerramilli, Eleanor Walsh, Emma Turner, Grace Young, Ryan David Nipp, Jenny Donovan, Freddie Hamdy, Neal David, Richard Martin, Jennifer S. Temel, Anthony L. Zietman
Journal: Journal of Clinical Oncology (2018)

5042 Background: Limited data exist regarding disease-related complications (DRCs), such as bone fractures and urinary obstruction (UO), near end of life of men who die with prostate cancer. We aimed to describe the burden of DRCs in these patients. Methods: As part of the Cancer Research-UK funded Clustered randomised trial of PSA testing for prostate cancer, we examined a cohort of 2603 men who died within 10 years of diagnosis. We collected clinical factors and DRCs. We used univariate analysis to examine association between diagnostic risk-group (low/intermediate, high, and metastatic, as defined by NCCN) and Kaplan-Meier analyses to compare median times to each DRC. We also explored a subgroup of men with metastatic disease who became castrate-resistant. Results: Men with higher risk disease at time of enrolment had higher frequency of DRCs and shorter time to each DRC (Table 1). 19% of high risk men developed cord compression, 16% had pathologic fracture, and 10% had renal failure. High risk men had bone metastases (BM) 2.9 months from diagnosis (IQR 1.7-4.9) versus men with low/int. risk disease (4.2 mos, 2.8-6.3), p < 0.001. Men with castrate resistance had higher odds of developing BM (OR 1.97, 95% CI (1.53-2.55), p < 0.001) and UO (OR 2.10, 95% CI (1.47-3.02), p < 0.001). Conclusions: In the largest contemporary cohort prostate cancer patients, we found that a significant proportion of men experience cancer-related morbidity prior to death. Men with localized disease at diagnosis can have long intervals until development of DRCs. Furthermore, men who become castrate resistance are particularly vulnerable to DRCs. Frequency & time to event at 10 years. Low/Int Risk (n = 490) High Risk (n = 616) T4,N1, or M1 (n = 1005) Proportion of Event % Median Time to 1st Event, Years (IQR) Any Bone Metastases 7.2 28.1 40.9 < 0.001 4.2 (2.8-6.3) 2.9 (1.7-4.9) 1.3 (0.6-2.4) < 0.001 Pathological Fracture 1.4 6.2 16.3 < 0.001 6.6 (4.8-7.5) 4.7 (2.0-5.9) 1.4 (0.7-3.0) < 0.001 Spinal Cord Compression 2.1 5.2 18.8 < 0.001 4.5 (3.4-5.9) 2.9 (1.3-4.8) 1.3 (0.8-2.4) < 0.001 Ureteric Obstruction 2.5 10.6 15.5 < 0.001 2.7 (2.4-6.5) 3.6 (2.1-5.6) 1.6 (0.7-3.1) < 0.001 Renal Failure Due to Ureteric Obstruction 0.6 6.5 10.3 < 0.001 4.3 (2.4-7.1) 3.5 (1.5-5.5) 1.3 (0.6-2.3) < 0.001
The genome patterns of prostate cancer in national cancer center in China.
Authors: Caixia Liang, Wen Luo, Lijuan Niu, Zejun Xiao, Yong Zhou, Yinchen Shen, Wenyuan Zheng, Yuankai Shi, Xiaohong Han
Journal: Journal of Clinical Oncology (2018)

e17090 Background: The disparity in genetic map of prostate carcinoma (PCa), the second most frequently diagnosed cancer in men, is less researched in China. Our study was to analyze the genomic complexity in Chinese PCa. Methods: We conducted a prospective study in 27 Chinese PCa. Tumour tissue and matched blood samples were obtained for whole genome and transcriptome sequencing. The mutational and rearrangement signatures were extracted by nonnegative matrix factorization and model selection approach. Results: We identified 112,528 somatic mutations with an average of 32 nonsilent mutations per tumor. Four mutational signatures were extracted from the samples based on the somatic single-nucleotide-variants. A previously unreported signature B was presented at 92.6% (25/27) samples with a strong link to several hotspot mutations of SPOP, suggesting that it could play a substantial role in PCa. And we also found the signature A (age signature) enriched in extracellular matrik (ECM) receptor interaction showing signature A may influence PCa development through ECM pathway.Copy number variations analysis showed high level amplification in chromosomal region 8q24.21 (22%) .We found that the amplification gene (ZBTB7B and SLC4A4) were overexpressed (P < 0.001) while the deletion gene (TBX18, CYSLTR2 and EFNA5) were lower expressed (P < 0.05) than normal which indicating that the five genes may relate to tumorigenesis. More importantly, four classifications (C1: translocation, 7.41%; C2: tandem duplicator, 25.93%; C3: small deletor with segment length ≤1kb, 33.33%; C4: large deletor with segment length > 1kb, 33.33%) with different phenotypes and characteristics based on six structural variation (SV) signatures were identified for the first time in PCa. Comparing with C3, we found C4 harbored more complex SV events (3.5 vs 23; P = 0.002) and chromoplexy events (4 vs 7; P = 0.037), but got smaller Gleason Score (9 vs 7; P < 0.001) and more elderly people (61 vs 69; P = 0.037). Interestingly, we found large proportion of signature B in C4. Conclusions: The genomic characteristics such as cluster C3 and C4, possibly interpret the pathogenesis and carcinogenesis. Our study reveals potentially disease relevant genomic alteration patterns of Chinese PCa.
Relationship of miR-140-5p expression and p53 function and contribution to prognosis prediction and treatment decision of patients with gastric cancer.
Authors: Meng Xie, Rachel Hargest, Jiafu Ji, Wenguo Jiang, Alwyn Dart
Journal: Journal of Clinical Oncology (2018)

e24185 Background: p53, the most commonly mutated gene in human gastric cancer (GC), acts as an important transcriptional regulator, regulates the cell cycle checkpoint and apoptosis signalling pathways. Its functional status was found to be a vital signature for GC molecular subtyping. MicroRNAs can target p53 directly or other factors in the p53 network, regulating the expression and function of wild-type (or the mutant) p53. Therefore, depending on the wild-type or mutant p53 context, the microRNAs’ changing profile may reflect the suppression or promotion of tumor development and even the tumor response to chemotherapy. Since molecular diagnosis has a great impact on precision medicine decisions, to define the function of p53 is of great importance in GC. Methods: We employed miRNA expression data from TCGA and GEO databases to search for candidate miRNAs which correlate with GC patients’ prognosis and treatment outcomes. qPCR was further carried out in two independent cohorts, one with neoadjuvant chemotherapy and one without, for chemotherapy response and prognosis analysis, respectively. Gene set enrichment analysis (GSEA) was conducted to explore the mechanism. GC cell lines AGS and NUGC4 (p53 wild-type), HGC27, MKN45, cells (p53 mutant-type) were assayed for proliferation, migration and cell viability determination with 5-FU treatment. Results: We identified that GC patients with higher miR-140-5p expression had a better overall survival and disease free survival in intestinal type GC, while an adverse trend in patients with diffuse type GC. GSEA indicated lower miR-140-5p correlated with higher expression of cell-cell adherens junction associated genes. However, upregulation of miR-140-5p in cancer cells with activated p53 increased IC50 of 5-FU. We also confirmed that MDM2 and RBBP6, both of which promote p53 degradation, are targets of miR-140-5p, and may contribute to the cell cycle arrest with drug treatment. Conclusions: These findings suggest that miR-140-5p mediates and reflects the function of p53, and thus may influence the progression and the response of chemotherapy in GC.
Cell free tumor DNA ( CfTDNA) in cervical carcinoma as diagnostic and prognostic marker: Pilot study.
Authors: H B Govardhan, Khaleel I a, Shubha Supriya
Journal: Journal of Clinical Oncology (2018)

e24100 Background: To study a non-invasive genetic panel for timely detection of cervical carcinoma and its prognostication by using cell-free circulating tumor DNA (cfTDNA). Methods: A total of 25 patients with locally advanced squamous cell carcinoma of cervix (Stage IB-IIIB) were tested prospectively with 50 tumor gene panel in a NABL accredited laboratory. Four ml serum was collected, CfTDNA was isolated and they were checked for single nucleotide variants (SNVs) / copy number variants (CNVs) by using Next Generation Sequencing (NGS).All Patients underwent EBRT and Brachytherapy according to the institutional protocol and were on regular follow up.And patients were followed upto 30 months - survival and local control were assessed. Results: In 21/25(84%) patients, CFTDNA was detected and sufficient to carry under NGS. Out of 50 genes, around 32 genetic alteration were detected. Mean genetic alteration was 4.08(2-14). Most common SNVs detected included were, , TP53 -11/21 (52.3%) patients, CDKN2A- 10/21(47.6%)patients, PTEN and STK11 -7/21 (33.3%)patients, BRAF and VHL -6/21 (28.5%)patients , EGFR and SMAD4 -4/21(19%). On combination of these genetic alterations - EGFR, KIT,PTEN, PIK3CA,TP 53, VHL are the main alterations and combination of these gene (Diagnostic GENETIC MODULE) , at least one genetic alteration among combination was found in 100% patients at any point of time. Further follow up data regarding correlation of this genetic alteration with prognosis will follows. On follow up data – median survival was 19 months. 12 out of 21 cases were alive and remaining 9 patients were dead at the end of the study. Patients with VHL; PTPN11; KIT; JAK3; HRAS; FLT3; EGFR; CSF1R; ATM; APC; BRAF; CDKN2A; PTEN; STK11 and TP53 genes will have a more aggressive disease. Patients with SMO; KRAS; NPM1; NOTCH1; FGFR3; FBXW7; ERBB4; CTNNB1 genes associated with good prognosis genes . Conclusions: CfTDNA can be easily demonstrable and can be used as a minimally invasive diagnostic and therapeutic response tool in cervical carcinoma. With available genetic panel showed good and bad prognostic modules on follow up data.
Abstract B061: Alternative RNA splicing and prostate cancer aggressiveness
Authors: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the most common cancer in men in the United States. Aggressive pathology, metastasis, and drug resistance of cancer cells are the most important prognostic factors for patients with PCa. African Americans (AAs) suffer disproportionately from PCa, with higher aggressiveness, progression, and mortality. A recently published analysis involving our laboratory reported more than 2,500 alternatively RNA spliced (ARS) genes between AA and white PCa biopsy tissue specimens. Subsequent analysis revealed that, among the race-related ARS genes in PCa tissue, 19 are also ARS in breast, lung, and liver cancer. Several of the genes that are ARS across multiple tumor types are important for cancer aggressiveness, including CD44, FN1, and LMO7. We designed PCR primers to further explore the expression of LMO7 variants in preclinical models of white and AA PCa, and found that a LMO7 variant that skips exons 10, 11, and 12 is predominantly expressed in VCaP (white) and MDA PCA 2b (AA) PCa cell lines. In addition, we detected a unique race-related LMO7 splicing event that excludes exons 10 and 11, but preserves exon 12. This event is detected in MDA PCA 2b cells, but not in VCaP cells. Importantly, both of these LMO7 splicing events are in-frame and are not frameshifts leading to truncated or extended C-terminal proteins. These LMO7 variants translate to proteins of 1297 amino acids (missing 344 amino acids coded by skipped exons 10, 11, and 12) and 1287 amino acids (missing 334 amino acids coded by skipped exons 10 and 11), which differ from the full-length LMO7 variant that translates to a protein of 1631 amino acids. Interestingly, the enrichment of these variants in cancer cells suggests an important regulatory role for the amino acids encoded by the skipped exons. Further work to study the impact of LMO7 variants as well as other candidate RNA splice variants on PCa aggressiveness is ongoing, using gene overexpression, gene depletion, and splicing manipulation by siRNA or CRISPR-cas, followed by assessment of resulting alterations in growth, migration, invasion, and drug sensitivity. In summary, we have identified genes that undergo race-related ARS in multiple tumor types and novel ARS events that may functionally contribute to increased tumor aggressiveness, including that of PCa in AA men. Citation Format: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman. Alternative RNA splicing and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B061.
Sandwich-like gemcitabine, dexamethasone, and cisplatin(GDP) chemotherapy with radiotherapy in newly diagnosed, stage IE to IIE, upper aerodigestive tract natural killer/T-cell lymphoma.
Authors: Shu Tian, Li fen Zou, Wei fang Wang, Wei Yuan, Sheng zi Wang, Hao Ding
Journal: Journal of Clinical Oncology (2016)

7561 Background: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal-type is highly aggressive with rather poor prognosis. Combined chemoradiotherapy is necessary for those having fever and/or extensive lesions. It is imperative to develop an effective chemotherapy regimen as ENKTL is often refractory to CHOP. This study was conducted to evaluate the efficacy and safety profiles of gemcitabine, dexamethasone, and cisplatin (GDP) as initial treatment combined with radiotherapy for patients with stage IE/IIE ENKTL. Methods: This study was conducted of
Risk of first‐time and recurrent depression in patients with psoriasis: a population‐based cohort study
Authors: A. Egeberg, J.P. Thyssen, J.J. Wu, L. Skov
Journal: British Journal of Dermatology (2018)

Psoriasis impairs quality of life, but it is unknown whether psoriasis is also an independent risk factor for depression.To evaluate the incidence and risk of new and recurrent depression in patients with psoriasis.We used individual-level linkage of Danish administrative registers. Patients with psoriasis aged ≥ 18 years between 1 January 1997 and 31 December 2016 were matched 1 : 1 with individuals without psoriasis. Incidence rates were calculated and adjusted hazard ratios (HRs) estimated by Cox regression.There were 247 755 patients with psoriasis: 220 721 were treated with topicals (mild psoriasis), 24 771 with systemic nonbiologics (moderate psoriasis) and 2263 with biological therapy (severe psoriasis). The same number of matched referents without psoriasis were also analysed. During a maximum 20 years of follow-up, 45 641 patients with psoriasis and 36 299 referents developed depression. In adjusted models, the HRs (95% confidence interval) of depression were 1·19 (1·17-1·20), 1·19 (1·15-1·23) and 1·50 (1·23-1·84) for mild, moderate and severe psoriasis, respectively. The highest risk was observed among patients with severe psoriasis aged 40-50 years. Concurrent inflammatory bowel disease, but not psoriatic arthritis, was associated with increased risk of depression. The incidence of depression was markedly higher among patients with previous depression.Psoriasis was independently associated with risk of depression. These results may help clinicians identify particularly high-risk individuals.