tbuckley/cabot-search huggingface dataset:
Classification of somatic variants in solid tumors detected by next-generation sequencing (NGS) and the need for clinical guidelines.
Authors: Antonios Papanicolau-Sengos, Edward Hart, Wei Shen, Kenneth F. Grossmann, Cecily Vaughn, Wade Samowitz, Allie Grossmann
Journal: Journal of Clinical Oncology (2014)

1555 Background: NGS approaches to clinical mutation testing reveal previously uncharacterized, or poorly characterized, somatic variants. A major challenge in reporting is categorization of these variants in the absence of formal guidelines. The process is subjective and the potential for variation between molecular pathologists is significant. Methods: To better characterize variation between molecular pathologists we retrospectively reviewed 95 clinical cases sequenced with the Ion Ampliseq Cancer Hotspot Panel v2 at ARUP Laboratories. We focused on variants that were reclassified upon re-review by three molecular pathologists. Results: Ninety eight mutations and 31 variants of unknown significance (VUS) were reported in 72 total tumors. There were seven reclassifications (5% of total classifications) in seven different tumors (3 urothelial carcinomas, 1 bladder adenocarcinoma, 1 melanoma, 1 lung carcinoma, and 1 unknown). Most of these were point mutations and involved FGFR1 (x1), FGFR3 (x1), CTNNB1 (x1), RB1 (x1) and PIK3CA (x3). Six of seven were reclassified from mutation to VUS based upon insufficient evidence of oncogenicity. Conclusions: Five of the reclassifications involved actionable genes (FGFR1, FGFR3, and PIK3CA). The original classification of these as “mutation” was primarily based on in vitro data. A “mutation” classification implies there is sufficient evidence for an oncogenic change that may be amenable to targeted therapy. In vitro biochemical and cell biologic assays are artificial systems which may not fully recapitulate in vivo tumor behavior. This study emphasizes the subjective nature of variant classification and the need for the development of weighted criteria devised by a multidisciplinary panel of experts. Until then, it is of utmost importance that molecular pathologists develop systematic methods to determine the quality of available data. We propose a simple checklist to optimize the way variants are classified. We suggest that medical oncologists critically scrutinize the classification of variants as they appear in clinical reports.
Analysis of recurrence patterns in acral versus non-acral melanoma: Should histologic subtype influence treatment guidelines?
Authors: Priyanka Gumaste, Nathaniel H. Fleming, Ines Esteves Domingues Pires Da Silva, Richard L. Shapiro, Russell S. Berman, Judy Zhong, Iman Osman, Jennifer A Stein
Journal: Journal of Clinical Oncology (2014)

9052 Background: Current surgical treatment of primary melanoma is uniform for all histo-subtypes, although certain types of melanoma, such as acral lentiginous melanoma (ALM), are biologically distinct. To our knowledge, no study has explored the effectiveness of standard melanoma treatment guidelines in ALM compared to non-acral melanoma (NAM). Methods: Study subjects were selected from a prospectively enrolled cohort of primary melanoma patients at NYU. All patients received wide local excisions with standard margins and a sentinel node biopsy if indicated by accepted practice guidelines. ALM patients were matched to NAM patients (1:3) by gender and melanoma stage, including substage. Logistic regression models were used to compare recurrence and survival outcomes in both cohorts. Results: 244 patients were included in this study (ALM=61, NAM=183; median follow-up: ALM= 33 months, NAM=58 months). ALM histologic subtype was an independent negative predictor of recurrence-free survival (HR = 2.45, p < 0.001) and melanoma-specific survival (HR= 2.64, p = 0.001) compared to NAM. Recurrence was significantly more common in ALM compared to NAM (49% versus 30%, p=0.007). When comparing recurrence rates by tumor thickness in both groups, there was no significant difference in recurrence in tumors greater than 2mm (ALM: 64%, NAM: 47%, p= 0.12); in tumors less than 2mm, there was a significantly higher recurrence rate in ALM (28%) versus NAM (10%, p=0.048). Of note, the rate of loco-regional recurrence was nearly double in ALM (39%) compared to NAM (19%, p=0.001). Conclusions: Our data revealed a high rate of loco-regional failure in ALM compared to NAM when controlling for AJCC stage. ALM may require wider surgical margins than non- acral cutaneous melanomas of equal thickness, particularly in tumors less than 2mm thick. Revision of surgical margin recommendations based on larger multicenter cohorts may need to be considered.
Breast cancer subtypes according to body mass index and insulin resistance.
Authors: Grazia Arpino, Anna Crispo, Mario Giuliano, Carmine De Angelis, Maria Grimaldi, Ernesta Cavalcanti, Flaviano Di Paola, Immacolata Capasso, Emanuela Esposito, Massimiliano D'Aiuto, Giuseppe D'Aiuto, Flavia Nocerino, Giuseppe Buono, Gerardo Botti, Michelino De Laurentiis, Sabino De Placido, Maurizio Montella
Journal: Journal of Clinical Oncology (2014)

571 Background: High body mass index (BMI) is considered a risk factor for breast cancer (BC) onset and is correlated with bad prognosis and resistance to endocrine therapy in BC patients. Obesity is also cause of insulin resistance (IR), often associated to resistance to anti human epidermal growth factor receptor (HER) inhibitors. The aim of the present study was to assess the association of BMI levels and IR with BC immunohistochemically-defined subtypes. Methods: One thousand consecutive post-menopausal patients with early BC were included in our study. Clinical, metabolic and tumor characteristics were prospectively collected at the time of diagnosis. IR was defined by the homeostatic model assessment (HOMA), with a cut off value to define IR ≥ 3,4. BMI was categorized as low: ≤25; intermediate: 26-30; high: >25. Data were analysed by logistic regression model. Results: Patients with luminal (A and B) BC were more likely to be overweight (BMI = 26-30) (OR=2.96 95% CI 1.53-5.74; p=0.006) although they had low HOMA scores (< 3.4) (OR=0.57 95% CI 0.35-0.93; p=0.02). In contrast, patients with HER2+ subtype were at increased risk for elevated HOMA score (OR= 2.36 95% CI 1.27-4.4; p=0.007), whereas the association with BMI was not statistically significant. In additional, no significant association was found between triple negative (TN) BC and anthropometric and metabolic variables. Conclusions: Our data suggest that high BMI may be associated with endocrine sensitive BC, whereas high HOMA score, may be more frequent in patients with HER2+ subtype. These findings support the hypothesis that high estrogen exposure of breast tissue in women with higher BMI may drive growth of luminal cancers while insulin an resistance environment may increase the risk of growth factor receptor-dependent BC. If further confirmed, our data suggests that body weight reduction and glycemic control, respectively in these two subsets of women may help to prevent cancer development.
Molecular Profiling of Blastic Transformation in Chronic Myeloid Leukemia
Authors: Yotaro Ochi, Kenichi Yoshida, Ying-Jung Huang, Ming-Chung Kuo, Yusuke Shiozawa, Yasuhito Nannya, Yuichi Shiraishi, Ai Okada, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Akifumi Takaori-Kondo, Lee-Yung Shih, Seishi Ogawa
Journal: Blood (2018)
Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non–Small Cell Lung Cancer
Authors: Jose M. Pacheco, Dexiang Gao, Derek Smith, Thomas Purcell, Mark Hancock, Paul Bunn, Tyler Robin, Arthur Liu, Sana Karam, Laurie Gaspar, Brian Kavanagh, Chad Rusthoven, Dara Aisner, Robert Doebele, D. Ross Camidge
Journal: Journal of Thoracic Oncology (2018)
The Cone Opsin Repertoire of Osteoglossomorph Fishes: Gene Loss in Mormyrid Electric Fish and a Long Wavelength-Sensitive Cone Opsin That Survived 3R
Authors: Da-Wei Liu, Feng-Yu Wang, Jinn-Jy Lin, Ammon Thompson, Ying Lu, Derek Vo, Hong Young Yan, Harold Zakon
Journal: Molecular Biology and Evolution (2018)

Vertebrates have four classes of cone opsin genes derived from two rounds of genome duplication. These are short wavelength sensitive 1(SWS1), short wavelength sensitive 2(SWS2), medium wavelength sensitive (RH2), and long wavelength sensitive (LWS). Teleosts had another genome duplication at their origin and it is believed that only one of each cone opsin survived the ancestral teleost duplication event. We tested this by examining the retinal cones of a basal teleost group, the osteoglossomorphs. Surprisingly, this lineage has lost the typical vertebrate green-sensitive RH2 opsin gene and, instead, has a duplicate of the LWS opsin that is green sensitive. This parallels the situation in mammalian evolution in which the RH2 opsin gene was lost in basal mammals and a green-sensitive opsin re-evolved in Old World, and independently in some New World, primates from an LWS opsin gene. Another group of fish, the characins, possess green-sensitive LWS cones. Phylogenetic analysis shows that the evolution of green-sensitive LWS opsins in these two teleost groups derives from a common ancestral LWS opsin that acquired green sensitivity. Additionally, the nocturnally active African weakly electric fish (Mormyroideae), which are osteoglossomorphs, show a loss of the SWS1 opsin gene. In comparison with the independently evolved nocturnally active South American weakly electric fish (Gymnotiformes) with a functionally monochromatic LWS opsin cone retina, the presence of SWS2, LWS, and LWS2 cone opsins in mormyrids suggests the possibility of color vision.
Oncogenic Predictors of Outcome in Older AML Patients Treated Intensively. Analysis of the ALFA-1200 Trial
Authors: Raphael Itzykson, Elise Fournier, Thorsten Braun, Céline Berthon, Alice Marceau-Renaut, Cecile Pautas, Olivier Nibourel, Emilie Lemasle, Nicolas Duployez, Jean-Baptiste Micol, Lionel Ades, Jean-Pierre Marolleau, Jean Valère Malfuson, Lauris Gastaud, Emmanuel Raffoux, Philippe Rousselot, Xavier Thomas, Sylvain Chantepie, Thomas Cluzeau, Benjamin Papoular, Nicolas Boissel, Christine Terré, Karine Celli-Lebras, Herve Dombret, Claude Gardin, Claude Preudhomme
Journal: Blood (2018)
Impact of tumor burden on tyrosine kinase inhibitors (TKI) efficacy in advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations (EGFRm) and ALK rearrangement (ALK+).
Authors: Charlotte Leduc, Nadia Moussa, Laura Faivre, Caroline Caramella, Jean-Charles Soria, Benjamin Besse
Journal: Journal of Clinical Oncology (2014)

e19021 Background: EGFRm and ALK+ are eligible to TKI. Predictive factors of response to TKI are poorly known, in particular the impact of the initial tumor burden. The objective of this study is to define if the initial tumor volume impacts TKI benefit in advanced NSCLC with EGFRm or ALK+. Methods: We retrospectively reviewed all consecutive patients with advanced NSCLC harboring EGFRm or ALK+ in a single center (Gustave Roussy). Baseline clinical characteristics were collected. CT images were centrally reviewed to assess initial tumor volume (volumetry software program lung VCAR, GE Healthcare), number, and type of metastatic lesions. EGFRm patients were treated with gefitinib or erlotinib, and ALK+ patients with crizotinib. Uni and multivariate Cox analyses were used to correlate with progression-free-survival (PFS) and overall survival (OS). Results: From 06/2006 to 11/2013, 97 patients (80 EGFRm, 14 ALK+, 3 both) were included: median follow up was 31 months (m), median age 57 years, 70% of female. Median PFS and OS were 8.5 (95% CI: 7.3-11) and 25 (16.2 - 28.7) m. Patients were divided in 3 groups according to their volume (n=33, 31 and 33). A significant decrease in PFS with increasing tumor volume was found (<35 cm3: median 9.0 m 95% CI (5.7-21.2); 35-74 cm3: 8.0 m (7.3-15.3); > 75 cm3: 7.3 m (4.3-10.1); p for trend=0.04). In multivariate analysis, results were similar when number of sites with metastasis and genomic alteration were included (<35 cm3: HR=1; 35-74 cm3: HR=1.54 95% CI [0.87-2.72]; > 75 cm3: HR=1.73 [1.01-2.96], p for trend=0. 04), but they were not significant when sex and presence of liver metastasis were included. Initial tumor volume was not associated to OS. Number of metastatic sites was associated with PFS and OS in multivariate analysis. Conclusions: In patients with EGFRm and ALK+ advanced NSCLC treated by TKI, PFS, but not OS, decreases with increasing tumor volume. Number of metastatic sites is a stronger survival predictor. Those results suggest that TKI onset should not be delayed after diagnosis or begun after a cytoreductive treatment such as chemotherapy. Updated data with 40 additional patients will be presented.
Efficacy of Transplantation of Combination of Noncultured Dermal and Epidermal Cell Suspension vs Epidermal Cell Suspension Alone in Vitiligo
Authors: Vishal Thakur, Sheetanshu Kumar, Muthu Sendhil Kumaran, Hitaishi Kaushik, Niharika Srivastava, Davinder Parsad
Journal: JAMA Dermatology (2019)

<h3>Importance</h3> Surgical interventions, notably noncultured epidermal suspension (NCES), are the next line of treatment in patients with vitiligo who fail to respond to medical therapy. Noncultured epidermal suspension is usually performed in patients with vitiligo with duration of clinical stability (DS) of 12 months or longer because DS is a vital parameter in determining outcome of NCES. In this pilot study, we planned to assess the efficacy of a novel combination of noncultured epidermal cell suspension and noncultured dermal cell suspension (NCES and NDCS) in patients with vitiligo with shorter DS (3-6 months). <h3>Objective</h3> To compare the efficacy of transplantation of NCES and NDCS vs NCES alone in patients with vitiligo with DS of 3 to 6 months. <h3>Design, Setting, and Participants</h3> A single-center randomized clinical trial including 40 patients with focal, segmental, or generalized vitiligo with DS of 3 to 6 months or more than 12 months was carried out. Based on DS, 2 groups including 20 patients each were recruited (DS in group 1, 3 to 6 months; DS in group 2, more than 12 months). Each group was further randomized into 2 subgroups, A and B. <h3>Intervention</h3> Patients in subgroups 1A and 2A underwent NCES alone, whereas patients in subgroups 1B and 2B underwent NCES and NDCS. <h3>Main Outcomes and Measures</h3> Extent of repigmentation, color match, and pattern of repigmentation at 24 weeks. <h3>Results</h3> Of the 40 study participants, mean (SD) age was 24.9 (4.0) years and 24 (60%) were women; in group 1 with DS for 3 to 6 months, more than 75% repigmentation at 24 weeks was observed in all 10 patients in subgroup 1B (NCES and NDCS) compared with 3 of 10 patients in subgroup 1A (NCES) (100% vs 30%,<i>P</i> = .003). In group 2 (DS &gt; 12 months), the same was observed in 6 of 10 patients in subgroup 2A and 7 of 10 patients in subgroup 2B (NCES) (60% vs 70%,<i>P</i> &gt; .99). The 2 groups and subgroups did not show any significant differences with respect to color matching and pattern of repigmentation. <h3>Conclusions and Relevance</h3> Combination of NCES and NDCS resulted in excellent response in patients with vitiligo with shorter duration of clinical stability compared with NCES alone. This combination may be used early in the course of stable vitiligo without waiting for a period of 12 months or more since last clinical activity. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT03013049
Correlation of childhood acute lymphoblastic leukemia subclones carrying intragenic IKZF1 deletions with relapse.
Authors: Peter Hoogerbrugge, Esme Waanders, Anke den Engelsman, Simon van Reijmersdal, Jiangjan Yu, Edwin Sonneveld, Rob Pieters, Ad GeurtsvanKessel, Frank van Leeuwen, Roland Kuiper
Journal: Journal of Clinical Oncology (2014)

10043 Background: Relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), and further improvement of risk stratification is essential for obtaining better cure rates. We and others demonstrated that the presence at diagnosis of deletions in IKZF1, the gene encoding the lymphoid transcription factor IKAROS, is a strong risk factor for relapse. Furthermore, preliminary results show that these deletions can be present at subclonal levels, often undetectable by routine methodologies. These findings are in line with recent studies, which have shown a complex, dynamic architecture of clonal diversity in ALL, both at diagnosis and at relapse. This multiclonal diversity likely contributes to the selective outgrowth of therapy-resistant leukemic cells during or after chemotherapy treatment, resulting in relapse. Whether subclonal deletions in IKZF1 are also associated with relapse has not been thoroughly investigated. Methods: Several recurrent intragenic deletions in IKZF1 show clustering of their genomic breakpoints, which allows efficient detection of subclonal deletions by sensitive semi-quantitative breakpoint-spanning PCR. Using this method, we screened a cohort of 331 B-cell precursor ALL patients, treated according to the DCOG-ALL9 and ALL10 protocols, for the presence of subclonal exon 4-7 IKZF1 deletions (IKZF1Δ4-7) at diagnosis. The cohort was slightly enriched for relapsed cases (36.6%). Results: A total of 34 IKZF1Δ4-7 deletions were found, of which 17 were not detected by routine MLPA. All deletions carried unique breakpoints and TdT-mediated non-templated sequences. The 17 MLPA-negative cases had an allelic burden of the IKZF1Δ4-7 deletion varying from 28% to <1%. Whereas 12 cases with full clonal IKZF1Δ4-7 deletions eventually relapsed, only 6 cases with subclonal IKZF1Δ4-7 deletions developed a relapse. Remarkably, in none of the cases for which material was available for testing (n=4), these subclonal lesions were detected in the relapsed clone. Conclusions: Our data suggest that, in contrast to clonal IKZF1Δ4-7 deletions, subclonal deletions of IKZF1Δ4-7 rarely contribute to relapse development in ALL.
Immune Profiling of Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide and Low-Dose Dexamethasone in Combination with Daratumumab
Authors: William E. Pierceall, Nizar Bahlis, David S Siegel, Gary J. Schiller, Christy J. Samaras, Michael Sebag, Jesus G. Berdeja, Siddhartha Ganguly, Jeffrey V Matous, Kevin Song, Christopher S. Seet, Giampaolo Talamo, Shanti Srinivas, Mirelis Acosta-Rivera, Michael Bar, Donald P. Quick, Bertrand Anz, Gustavo Fonseca, Donna Reece, Weiyuan Chung, Natalya Serbina, Faiza Zafar, Amit Agarwal, Anjan Thakurta
Journal: Blood (2018)
Prospective multicenter study of the impact of the 12-gene assay recurrence score on adjuvant chemotherapy treatment recommendations for stage II/III colon cancer in the post-IDEA era: SUNRISE-Decision Impact study.
Authors: Takeharu Yamanaka, Takeo Sato, Sayoko Nakashima, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2018)

TPS868 Background: The results of IDEA collaboration study in ASCO 2017 suggested that adjusting the duration of adjuvant chemotherapy (CTx) for stage III colon cancer may be possible according to patient’s risk (T and N factors) and treatment regimen (FOLFOX and CAPOX) in order to balance the benefit and neurotoxicity of oxaliplatin-based CTx. The 12-Gene Assay Recurrence Score (12-gene RS), known as Oncotype DX, has been validated to predict the recurrence risk of stage II/III colon cancer patients through several studies, including our SUNRISE study (J Clin Oncol, 2016), and thus to personalize adjuvant CTx taking account of individual recurrence risk. The objective of this SUNRISE-DI study is to determine the impact of the 12-gene RS on adjuvant CTx treatment recommendations, including the decision for the duration of oxaliplatin-based CTx in stage III patients as well as that for oxaliplatin-based CTx versus 5FU-based monotherapy in stage II/III patients. This study enables us to evaluate how physicians employ the IDEA collaboration results combined with the 12-gene RS to determine the regimen. Methods: Patients who have a curatively resected Stage II/IIIA/IIIB colon cancer, an age of more than 20, and an ECOG PS of 0-1 are eligible. Treating physicians will formulate a treatment recommendation and complete a pre-assay questionnaire, and the 12-gene assay will be performed. Following receipt of the RS result, the treatment recommendation will be revised and a post-assay questionnaire completed. The primary endpoint is the proportion of changes in treatment recommendations between pre- and post-assay across all patients. Secondary endpoints include the proportion of changes by stage; the proportion of changes in the duration of oxaliplatin-based CTx (3 months vs 6 months); the proportion switched to observation only, 5-FU mono, or 5-FU plus oxaliplatin; and changes in expressed physician confidence level. The enrollment target is 200 patients with stage IIIA/IIIB and 100 patients with stage II from 15 centers in Japan. Clinical trial registry number: UMIN000028784
<i>RAD51</i> 135 G&gt;C polymorphism and risk for ovarian cancer in Serbian women.
Authors: Radmila Jankovic, Emina Malisic, Ana Krivokuca, Ivana Boljevic, Sinisa Radulovic
Journal: Journal of Clinical Oncology (2014)

e16517 Background: Defective repair of double strand DNA breaks leads to genomic instability and neoplastic transformation. RAD51 protein is one of the essential proteins for the repair of these DNA lesions. Single nucleotide polymorphism 135G>C (rs1801320) in the 5′-untranslated region of the RAD51 gene could affect mRNA splicing, transcription activity, translation efficiency, mRNA stability and alter RAD51 protein level. The role of this polymorphism in ovarian cancer development in different population is still inconclusive. We aimed to evaluate association of RAD51 135G>C polymorphism and risk of ovarian cancer in Serbian women. Methods: The case-control study included 50 fresh frozen ovarian cancer samples and 78 cervical swabs from age-matched controls. RAD51135G>C polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP). Deviations of the genotype frequencies from those expected under Hardy-Weinberg equilibrium were assessed using the χ2 test. The allele- and genotypic-specific risks were estimated as odds ratios (ORs) with associated 95% confidence intervals (CIs). Results: The distribution of genotypes for 135G>C RAD51 polymorphism in ovarian cancers vs. controls was: 66% vs. 84.6% for GG, 28% vs. 12.8% for GC, and 6% vs. 2.6% for CC genotype, respectively. All genotype distributions in cases and controls did not differ significantly (P > 0.05) from those expected by the Hardy–Weinberg equilibrium (χ2=0.781 and χ2=3.595, respectively). We found that RAD51 135C allele is associated with ovarian cancer (OR= 2.536 for C vs. G with 95% CI of 1.215 to 5.293). The C allele exerts its effect on increased risk for ovarian cancer development in dominant model (CC plus GC vs. GG) with OR (and 95% CI) of 2.833 (1.212 to 6.622). Conclusions: Our results suggest that the 135G>C polymorphism of the RAD51 gene, could be a biomarker of increased risk for ovarian cancer development in Serbian women. These results require further study on larger case-control group.