tbuckley/cabot-search huggingface dataset:
Mohs micrographic surgery in Uruguay: Our first 130 cases for skin cancer.
Authors: Julio César Magliano, Jorge Andrés Navarrete, Carlos Ignacio Bazzano, Miguel Angel Martínez
Journal: Journal of Clinical Oncology (2018)

e21617 Background: Mohs micrographic surgery is a technique for excision of skin cancers with histological examination of 100% of the surgical margins, achieving the highest cure rate with maximum preservation of healthy tissue. Objective: to perform a clinical-epidemiological description of our first 130 surgeries at the Hospital de Clínicas. Methods: Bidirectional descriptive analysis of all the patients operated by a single Mohs surgeon in our Dermatological Surgery Unit from November 2013 to June 2016. Clinical, tumoral and surgical data were recorded. Results: 130 surgeries were studied in 90 patients; 62.3% were performed in men and 37.7% in women. Mean age was 68 years (range: 33-90 years). 67.7% came from Montevideo (our capital) and 32.3% from other parts of the country. 68% corresponded to basal cell carcinoma and 32% to squamous cell carcinoma. 91.5% were primary tumors and 8.5% recurrences. 75.3% were located in the head and neck. The most frequent type of closure were flaps in 43% (56). Until now, 70 patients have completed a follow-up of at least one year, where tumor recurrence was seen in only one case (1/70, 1.43%). Conclusions: Mohs surgery is a safe and effective procedure, and our results coincide with those described in international reference centers. This is the first hospital in Uruguay with a Mohs surgeon, and we present the first study in Uruguayan patients.
Impacts of plasma EBV DNA load during different time-points of induction chemotherapy plus radiotherapy for nasopharyngeal carcinoma.
Authors: Jin-Ching Lin, Wen-Yi Wang, Yi-Chun Liu
Journal: Journal of Clinical Oncology (2018)

6058 Background: To investigate the prognostic impacts of plasma EBV DNA measured at different time-points in patients with advanced nasopharyngeal carcinoma who received induction chemotherapy (IndCT) plus radiotherapy (RT). Methods: We retrospectively review 206 previously untreated, biopsy-proven, and no distant metastasis NPC patients who received IndCT consisting of biweekly P-FL (cisplatin 60 mg/m2, day 1 and 5-fluorouracil 2500 mg/m2 + leucovorin 250 mg/m2, day 8) × 10 weeks, followed by RT 70-74 Gy. Quantification of EBV DNA was done before treatment, the 5th week (during-IndCT) and the 10th week (post-IndCT) in the IndCT period, one week after RT (post-RT). We set cut-off values as > vs. < 1500 copies/ml for pretreatment, and detectable ( > 0) vs. undetectable ( = 0) for other time-points (during-IndCT, post-IndCT and post-RT) and analyze the relationship between the EBV DNA status at different time-points and clinical outcome. Results: Pretreatment EBV DNA (median, 1550 copies/ml; interquantile range, 375-5688) was detectable in 95.1% (196/206) patients. The EBV DNA load decreased markedly as treatment going- 114 (55.3%), 84 (40.8%), and 30 (14.6%) patients showing detectable results during-IndCT, post-IndCT, and post-RT with a lower copy numbers (median 37, 18, and 236 copies/ml). The pretreatment, post-IndCT, and post-RT EBV DNA levels can discriminate relapse rates between the two subgroups (47.1% vs. 21.6%, P = 0.0001; 50.0% vs. 23.8%, P < 0.0001; 83.3% vs. 26.1%, P < 0.0001) whereas during-IndCT viral load cannot (37.7% vs. 30.4%, P = 0.2741). Overall survivals were significantly affected by the pretreatment (HR = 2.26, 95%CI = 1.45-3.52, P = 0.0002), post-IndCT (HR = 2.02, 95%CI = 1.32-3.09, P = 0.0010), and post-RT (HR = 4.86, 95%CI = 3.05-7.73, P < 0.0001) but not during-IndCT (HR = 1.27, 95%CI = 0.82-1.95, P = 0.2859) EBV DNA load. Relapse-free survivals showed the same results. Conclusions: Pre-treatment, post-IndCT, and post-RT EBV DNA are important variables to predict outcome for NPC patients. Those who had high pre-treatment levels, detectable after IndCT and one week after RT should be searched for more intensive post-RT adjuvant therapy in future trials.
Next-generation sequencing (NGS) in an advanced hepatocellular carcinoma (HCC) cohort: Analysis of common mutations, clinical covariates, and overall survival (OS).
Authors: Robin Kate Kelley, Paige M. Bracci, John Dozier Gordan, Kimberley Evason, Nancy M. Joseph, Andrea Grace Bocobo, Blake K. Rosenthal, Hubert J. Stoppler, Halla Sayed Nimeiri, Alan P. Venook
Journal: Journal of Clinical Oncology (2016)

e15641 Background: Mutations in TP53 and CTNNB1 are common in resected early stage HCC tumors. The frequency and prognostic impact of these and other mutations in advanced HCC is not known. We conducted this retrospective analysis using NGS to explore for association between tumor genetics, clinicopathologic features, and prognosis in an advanced HCC cohort. Methods: Archival samples were obtained from patients with unresectable HCC or mixed HCC-cholangiocarcinoma (CCA) enrolled on NCT01008917 or NCT01687673 clinical trials of sorafenib plus temsirolimus. Tumor and germline (blood) DNA pairs were sequenced using a capture-based 500+-gene NGS panel (UCSF500). Analysis was based on human reference sequence UCSC build hg19. Variants were called using GATK Unified Genotyper. Somatic, non-synonymous, exonic calls were curated using COSMIC, cBioPortal, and Pubmed. Overall survival (OS) was calculated from start of sorafenib. Results: Cohort (N = 26): HCC (n = 24), mixed HCC-CCA (n = 2); BCLC stage: B 11%, C 88%; male: 85%; race: Asian 35%, white 54%; etiology: HBV 31%, HCV 38%; source: liver 85%, metastasis 15%. NGS identified cardinal HCC mutations, some at higher frequency than reported in early stage cohorts (Table). There was no significant relationship between mutation and etiology, stage, or other clinical covariates. Median OS was 324 (95% CI: 203, 815) days, with no significant difference by mutation though CTNNB1 mutants had trend towards longer OS (452 vs. 203 days, p = 0.08). Conclusions: NGS in this advanced HCC cohort identified higher frequencies of TP53 and CDKN2Amutations than have been reported in early stage HCC resection cohorts, suggesting difference in biology between early and advanced stages. Tumor genetic biomarkers warrant further study in larger advanced HCC populations to determine if associated with prognosis or treatment response. Mutation Incidence Advanced v. early stage (Fisher’s exact) UCSF advanced HCC cohort (n = 24)* (95% CI) TCGA cohort (n = 198)1 TP53 67% (45, 84) 31% p = 0.0008 CTNNB1 29% (13, 51) 26% p = 0.81 CDKN2A 17% (5, 37 ) 1% p = 0.05 1TCGA cBioPortal: http://bit.ly/1MeZzuF; *Data for 2 additional cases pending.
RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature
Authors: Michael A. Chapman, Jonathan Sive, John Ambrose, Claire Roddie, Nicholas Counsell, Anna Lach, Mahnaz Abbasian, Rakesh Popat, Jamie D. Cavenagh, Heather Oakervee, Matthew J. Streetly, Stephen Schey, Mickey Koh, Fenella Willis, Andres E. Virchis, Josephine Crowe, Michael F. Quinn, Gordon Cook, Charles R. Crawley, Guy Pratt, Mark Cook, Nivette Braganza, Toyin Adedayo, Paul Smith, Laura Clifton-Hadley, Roger G. Owen, Pieter Sonneveld, Jonathan J. Keats, Javier Herrero, Kwee Yong
Journal: Blood (2018)
The neutrophil to albumin ratio as predictor of pCR in rectal cancer patients following neoadjuvant chemoradiation.
Authors: Bernard Tawfik, Ali El-Mokdad, Hsiao Ching Li, Sergio Huerta, Prachi Patel
Journal: Journal of Clinical Oncology (2016)

e15139 Background: Pathologic complete response (pCR) following neoadjuvant chemoradiation (nCRT) and total mesorectal excision (TME), in patients with locally advanced rectal cancer, occurs in 15-27% of patients. Because blood cell counts and albumin are a direct indicator of the host environment, a response to nCRT might be predicted by these markers. This study was undertaken to determine if the Neutrophil to Albumin Ratio (NAR) was predictive of pCR in veteran patients. Methods: Ninety-eight patients with rectal cancer [distance from anal verge = 7.1±4.5 cm (SD)] who underwent standard nCRT followed by TME were analyzed. Pre- and post-CRT hematologic data were collected. Univariate and multivariate analyses were performed. Kaplan Meier Curves were calculated. Results: Demographics: male (99%), age 62.4±9.1 y/o, BMI = 27.4±5.9 Kg/m2, interval between nCRT and TME = 8 weeks, 55% patients = low anterior resection, 95% received 5-FU and all patients received radiation with 15% achieving a pCR. Univariate analysis demonstrated that pre- and post-CRT CEA (15.8±45.1 vs. 3.5±5.3 ng/dl; p = 0.002 and 4.5 ± 6.5 vs. 1.8 ± 1.2; p = 0.01; respectively); pre-CRT hemoglobin (13.0±2.3 vs. 13.9±5.3; p = 0.005); pre-CRT Neutrophil to Lymphocyte Ratio (NLR) [3.1±2.2 vs. 2.2±0.9; p = 0.01]; and the pre-CRT NAR [16.4 ± 4.8 vs. 14.2 ± 1.6; p = 0.002] were associated with pCR. On multivariate analysis pre-CRT CEA (OR = 0.41, 95% CI 0.22-0.77) and pre-CRT NAR (OR = 0.76, 95% CI 0.60-0.97) emerged as independent predictors of pCR. Overall survival between non responders and pCR patients at 1, 5 and 10 years was 96%, 62%, and 44% vs. 93%, 85%, 61%; p = 0.13; and disease free survival 95%, 60%, and 47% vs. 93%, 85%, 61%; p = 0.17; respectively. Conclusions: Our study shows that the pre-CRT NAR is an independent predictor of pCR. These findings should be applied to other cohorts to determine its validity and reliability to use as a potential predictor of pCR.
Single-cell RNA-sequencing and -imaging of melanoma ecosystems reveals sources of resistance to immune checkpoint blockade.
Authors: Benjamin Izar, Livnat Jerby-Arnon, Asaf Rotem, Parin Shah, David Liu, Gao Zhang, Bastian Schilling, Orit Rozenblatt-Rosen, Genevieve Marie Boland, F. Stephen Hodi, Keith Flaherty, Eliezer Mendel Van Allen, Bruce E. Johnson, Dirk Schadendorf, Charles Yoon, Levi A. Garraway, Aviv Regev
Journal: Journal of Clinical Oncology (2018)

3074 Background: While immune checkpoint blockade (ICB) produces durable responses in some patients with melanoma, most patients derive no clinical benefit, and the molecular underpinnings of ICB resistance (ICR) are elusive. Methods: We applied single-cell RNA-sequencing (scRNA-Seq) to > 10,000 malignant and non-malignant cells derived from 31 melanoma tumors, including 15 from patients with ICB, 15 treatment-naïve patients, and 1 patient with clinical response. We applied a novel data-driven method to systematically map cancer programs that promote ICR and T cell exclusion. Results: We demonstrate that cancer cell-autonomous ICR programs identified by scRNA-Seq predict comprise several putative mechanisms of resistance, including several that have previously not been described. In addition to functional implications, we generated a clinically applicable signature that was predictive of clinical response (per RECIST criteria) and progression-free survival (PFS): one of patients who underwent RNA-seq of matched pre-treatment and progression (ICR) specimens; and another of 112 melanoma patients with pre-treatment RNA-seq who receive anti-PD-1 monotherapy. This scRNA-Seq derived predictive signature was superior to all interrogated previously published signatures. Furthermore, we demonstrated that pharmacological reversal of these oncogenic cell states can be achieved by CDK4/6-inhibition, and explored the impact of this treatment in melanoma at the single cell level. To determine the role of T cell exclusion from the TME as a potential mechanism of ICR, we performed spatially resolved 30-plex single-cell protein analysis of matching FFPE specimens from 16 of patients who also underwent scRNA-seq. While the integration of these data sets is pending, the presented analytical platforms provide a promising approach to understanding drug resistance within preserved tumor ecosystems. Conclusions: Our study provides a high-resolution landscape of oncogenic ICR states, identifies clinically predictive signatures, and forms a basis to developing novel therapeutic strategies that could overcome immunotherapy resistance in melanoma.
Effect of sorafenib (S) starting dose and dose intensity on survival in patients with hepatocellular carcinoma (HCC): Results from a Canadian multicenter HCC database.
Authors: Mohammed Abdullah Alghamdi, Richard Lee-Ying, Hao-Wen Sim, Haider Samawi, Jennifer J. Knox, Adriana Romagnino, Yoo-Joung Ko, Kelvin K. Chan, Mina Swiha, Eugene Batuyong, Winson Y. Cheung, Vincent C. Tam
Journal: Journal of Clinical Oncology (2017)

4084 Background: The SHARP trial showed that S improves survival in advanced HCC. Full dose (FD) S at 400mg bid can be difficult to tolerate, so some clinicians begin with a reduced dose (RD) &amp; escalate as tolerated to maximum dose. The purpose of this study was to determine whether starting dose or dose intensity of S affects survival. Methods: All patients treated with S for HCC from 01/2008 to 06/2016 in British Columbia, Alberta, Ontario (Princess Margaret Cancer Centre &amp; Sunnybrook Odette Cancer Centre), were included. Patient demographics, clinical, tumor characteristics, S starting dose &amp; mean dose intensity were collected &amp; analyzed. Patients were dichotomized into starting FD or RD of S. Mean dose intensity was categorized into &gt; 75%, 50-75% &amp; &lt; 50%. Survival outcomes were assessed with Kaplan-Meier curves &amp; compared with the log-rank test. A Cox-proportional hazard model was constructed with starting dose, dose intensity &amp; relevant clinical &amp; pathologic factors to assess their impact on survival. Results: We included 681 patients. Median age 64 years, 80% men, 37% East Asian, &amp; most frequent causes of liver disease were hepatitis B (33%) &amp; C (29%). ECOG performance status prior to starting S was 0 in 30% &amp; 1 in 60%. Most patients were Childs-Pugh A (86%) at start of S. Overall median survival was 9.1 months (m). S was started at FD in 42% of patients &amp; 31% had a dose intensity &gt; 75%. The median survival for starting FD &amp; RD was 9.4 m &amp; 8.9 m, respectively (p = 0.15). The median survival for a dose intensity &gt; 75% was 9.5 m, 50-75% was 12.9 m &amp; &lt; 50% was 7.1 m (p = 0.005). In multivariate models that adjusted for demographic, stage, performance status, AFP, prior treatment, toxicity &amp; liver function, starting dose (HR 1.1, 95%CI 0.86-1.3, p = 0.51) &amp; dose intensity (50-75% HR 0.93, 95% CI 0.73-1.2; &lt; 50% HR 0.89, 95% CI 0.69-1.1, p = 0.65) were not predictors of survival. Conclusions: Based on our multi-center database, starting HCC patients on a RD of S may be a reasonable since it does not appear to compromise survival. Patients receiving a dose intensity of S at 50-75% appear to have a superior median survival, though this is not significant after controlling for baseline characteristics.
Association BRCA mutation status between BMN 673 (talazoparib), an oral PARP inhibitor, in triple-negative breast cancer
Authors: G. Guney Eskiler, G. Cecener, U. Egeli, B. Tunca
Journal: Annals of Oncology (2018)

Background: The poly (ADP-ribose) polymerase (PARP) inhibitors appear to be a promising treatments strategy in BRCA-associated and/or sporadic triple-negative breast cancer (TNBC) due to the molecular heterogeneity of TNBC and the lack of defined molecular targets. However, there is no studies on the association between BMN 673 (talazoparib) efficacy, which is a novel and the most potent PARP1/2 inhibitor, and BRCA mutation status in TNBC. In the current study, we aimed to determine the cytotoxic and apoptotic effects of BMN 673 on TNBC cell lines according to BRCA mutational status. Methods: HCC1937 [BRCA1 mutant (5382insC)] and MDA-MB-231 (BRCA1 wild-type, TNBC cell lines were treated with 0.01-10 nM concentration of BMN 673 for 6 and 12 days and the cytotoxic effect was determined by WST-1 assay. Apoptosis induction by BMN 673 treatment was evaluated by Annexin V and cell cycle analysis, as well as the morphologic changes of the apoptotic cells were observed by AO/EtBr dual staining. Results: BMN 673 considerably inhibited HCC1937 and MDA-MB-231 cell viability in dose and time-dependent manner. The cell viability of HCC1937 and MDA-MB-231 cells reduced by 34.9% and 47.5% in concentration of 10 nM BMN 673, respectively (p < 0.01). After 12 days exposure to BMN 673, a significant increase of total apoptotic cells was determined compared to the untreated control. The total percentage of apoptotic cells was 77.8% and 58.3% in HCC1937 and MDA-MB-231 cells treated with 10 nM of BMN 673, respectively (p < 0.01). After the HCC1937 and MDA-MB-231 cells were incubated with 10 nM of BMN 673, the percentage of cells in the G2/M phase significantly increased to 49.5% and 43.5%, respectively (p < 0.01). Additionally, a loss of membrane integrity and the condensation of nucleus were observed in these cells by AO/EtBr staining. Conclusions: This study has suggested that BMN 673 demonstrates anti-cancer effects by inducing apoptosis in TNBC. However, BRCA mutated TNBC cells are far more sensitive to BMN 673 than to TNBC cells. Nevertheless, BMN 673 is greater potency than other PARP inhibitors at low nanomolar concentrations in TNBC cells. Legal entity responsible for the study: The Scientific Research Projects Foundation of the Uludag University in Turkey. Funding: This study was supported by a grant from the Scientific Research Projects Foundation (BAP) of the Uludag University of Turkey [Project No: BUAP(T)-2015/1]. Disclosure: All authors have declared no conflicts of interest.
OS1.4 Induction of mitotic cell death: a novel therapeutic strategy for glioblastoma
Authors: N Gomez-Roman, A J Chalmers
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and lethal adult brain tumour. Tumours typically contain large numbers of binuclear and multinucleated cells, and a subpopulation of relatively quiescent glioma stem-like cells (GSC) that are thought to be responsible for treatment resistance and tumour recurrence. GSC display robust G2/M arrest following ionising radiation (IR) yet are highly prone to aberrant cell division and are sensitive to mitotic spindle checkpoint inhibitors. The aim of this study was to investigate the therapeutic activity of mitotic inducers in preclinical models of GBM. Bioinformatic analysis of mRNA expression data was used to confirm the relevance of mitotic activity following irradiation of GSC in a 3D patient-derived GBM stem cell model. Immunofluorescence, clonogenic survival and cell viability assays were used to evaluate the therapeutic potential of mitotic inducers (ME-344; Wee1 inhibitor AZ1775) in 2D and 3D U87MGLuc and E2, G1, G7, S2 and R15 patient-derived GSC cell culture models. either alone or in combination with IR. In vivo validation was determined in U87-MGLuc orthotopic GBM mouse model. Radiation induced downregulation of mRNA expression of several mitotic genes was observed in G7 and E2 cell lines confirming mitotic relevance. In cell viability and clonogenic survival assays, AZ1775 and ME-344 showed potent cytotoxicity against all GSC cell lines in both 2D and 3D, with EC50 values of 0.2 to 0.4 μM for AZ1775 and 0.003 to 0.02 μM for ME-344. ME-344 and AZ1775 triggered profound morphological and cell cycle effects including mitotic induction and arrest, increased mitotic fraction, reduced nuclear tubulin in mitotic cells and, induced mitotic catastrophe in the most sensitive cell lines U87MGLuc and E2. These events were apoptosis-independent. Combination with IR increased GSC cell death in the two GSC models tested to date. Accumulation of cells in mitosis following ME-344 treatment was recapitulated in orthotopic GBM xenografts in vivo, although few mitotic catastrophe events were observed 24 h after treatment. ME-344 demonstrated therapeutic efficacy as a single agent in U87MGLuc2 orthotopic xenografts by extending mouse survival compared to vehicle (p=0.043). Two agents that induce mitosis through different mechanisms have promising single agent activity against all GBM cell lines tested in vitro and in vivo. Further preclinical evaluation in combination with IR and/or temozolomide is underway. Results indicate that this therapeutic strategy for GBM has clinical potential.
Characterization of URST1 as a prognostic biomarker and therapeutic target for lung and oral cancers.
Authors: Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yohei Miyagi, Yataro Daigo
Journal: Journal of Clinical Oncology (2017)

e14057 Background:Lung cancer and oral cavity cancer belong to aerodigestive cancers whose clinical outcome after multimodal therapy remains poor. Methods:To identify new biomarkers and therapeutic targets for lung and oral cancers, we screened genes using our original gene expression profile database for various solid cancers, and characterized clinical and oncogenic values of up-regulated in solid tumor 1 (URST1) protein as a candidate. Results: URST1 was highly expressed in the most of lung or oral cancer cell lines and tumor tissues, but was hardly detected in normal lung or oral epithelial cells and tissues as detected by real-time PCR and western blot analyses. Immunocytochemical analysis revealed that URST1 was mainly localized in the nucleus and cytoplasm of lung or oral cancer cell lines. Immunohistochemical analysis using tissue microarray showed that positive staining of URST1 was observed in 231 of 358 (64.5%) lung cancers, but not in normal lung, and it was significantly associated with poor prognosis after curative surgery. In addition, URST1 was expressed in 64 of 96 (66.7%) oral cancers, but not in oral mucosa, and it was significantly correlated with poor clinical outocome after surgery. Multivariate analysis confirmed that URST1 expression was an independent prognostic factor for oral cancer. Suppression of URST1 expression by siRNA or treatment with synthesized inhibitor specific for URST1 activity inhibited mitosis and growth of lung or oral cancer cell lines. Conclusions:URST1 is likely to be a prognostic biomarker and therapeutic target for aerodigestive cancers such as lung and oral cancers.