tbuckley/cabot-search huggingface dataset:
It’s a Beautiful Thing
Authors: Shaurya Taran, Allan S. Detsky
Journal: JAMA (2017)

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Pathological complete response in HER2 positive breast cancer treated with trastuzumab and chemotherapy: Predictive factors report.
Authors: Ariadna Gasol Cudós, Serafin Morales, Anna Novell Alvarez, Anna Serrate Lopez, Ana Velasco Sanchez, Antonieta Salud Salvia
Journal: Journal of Clinical Oncology (2017)

e12133 Background: Achieving a pathological complete response (pCR) in HER2 positive disease is a surrogate of survival. Several factors were studied in order to predict pCR, but only negative estrogen receptor is correlated to pCR. Methods: 168 patients (March 2002-December 2016) with neoadjuvant trastuzumab-based treatment were retrospectively analyzed in order to find if common clinicopathological factors, HER2 expression and immune infiltrates could correlate with pCR. Results: Median age was 55 years (29-86), median tumor size of 39mm and 53% of tumors had initial nodal involvement. 45% of patients were estrogen and 71% progesterone receptor negative and median ki67 expression was of 43%. Otherwise HER2 expression was analyzed by immunohistochemistry, FISH amplification and mRNA expression; we also determined the presence of immune infiltrates stromal and intratumoral L45 lymphocytes, PD1 and PD-L1. A 38% pCR rate was found in whole population. In the univariate model we found and association with pCR and: estrogen receptor negative (p = 0.003; OR 2.5), high HER2 expression by mRNA in tissue &gt; 3.9 (p = 0.012; OR 8.4), stromal L45 expression &gt; 35% (p = 0.001; OR 5.3), stromal PD1 expression &gt; 10 (p = 0.004; OR 4.5). The most powerful factor associated with pCR is HER2 mRNA expression &gt; 3.9, with 82% of pCR rate in those tumors; followed of L45 stromal expression &gt; 35%, with 76% of pCR rate. Conclusions: Factors related to pCR are mostly estrogen receptor negative and high HER2 expression by mRNA and high L45 stromal infiltrates. With those variables, we could design a predictive model in order to perform the best neoadjuvant treatment to increase the pCR rate.
Incidence of esophageal and head and neck cancers among breast cancer survivors in the United States.
Authors: Krista Dollar, Albina Tyker, Matthew Simpson, Eric Adjei Boakye, John J. Dombrowski, Mark A Varvares, Nosayaba Osazuwa-Peters
Journal: Journal of Clinical Oncology (2017)

e12054 Background: Late sequelae of breast cancer therapies potentially impact morbidity and mortality with increasing numbers of survivors. Radiation exposure has been linked to increased incidence of second primary cancers (SPC). However, to date, there is limited literature describing incidence of head and neck (HN) and esophageal cancers in patients with an index breast cancer (BC). This study aimed to describe the incidence of esophageal and HN cancers following breast cancer diagnosis. Methods: Standardized incidence ratios (SIRs) were calculated using the Surveillance, Epidemiology, and End Results (SEER) 9 database for BC patients diagnosed from 1973-2013. SIRs compared incidence of HN and esophageal cancer after an initial BC diagnosis to the general population. HN included oral cavity, pharynx, and larynx. BC patients were grouped into those who received radiotherapy for their breast cancer (n = 216,045) and those who did not (n = 289,596). SIRs were calculated in 5-year intervals. SEER does not contain information on chemotherapy. Results: Less than 1% of BC patients developed HN (0.3%) or esophageal cancers (0.1%), irrespective of radiation treatment. However, among patients with an index BC who received radiation therapy, there was significant but small increased incidence of HN and esophageal cancers five to nine years following treatment (HN SIR: 1.22; 95% CI, 1.04-1.43 and esophagus SIR: 1.44; 95% CI, 1.09-1.87). Esophageal cancer incidence continued to increase through 15 years of follow-up, however incidence of HN was not significant beyond ten years after the index BC diagnosis and radiation treatment. Conclusions: Compared to the general population, breast cancer patients have elevated incidence of HN and esophageal cancers detected five to nine years after receiving radiation treatment, but only the incidence of second primary esophageal cancer remains elevated at 15 years. These findings warrant further investigations of breast cancer radiation and future malignancies.
Abstract 51: Nucleostemin Induced by Pim-1 Kinase Is Critical to Maintain Pluripotency and Enhance Regenerative Potential of Cardiac Progenitor Cells
Authors: Nirmala Hariharan, Anya Y Joyo, Kaitlen M Samse, Daniele Avitabile, Brandi Bailey, Sadia Mohsin, Mark A Sussman
Journal: Circulation Research (2012)

Myocardial regeneration and repair in response to injury are governed in part by cell survival, proliferation and pluripotency. Proliferation and survival in cardiac progenitor cells (CPCs) are mediated by Pim-1, a serine threonine kinase, and nucleostemin (NS), a nucleolar stress sensor protein. The role of NS in regulating CPC pluripotency and the molecular mechanism of NS induction and action is largely unknown. The hypothesis of the study is that NS, induced by Pim-1 mediated stabilization of transcription factor c-Myc is critical to maintain CPC pluripotency and inhibits senescence. NS and c-Myc protein levels are increased in cultured CPCs overexpressing Pim-1 (3.1 and 5.5 fold, p&lt;0.01) while knockdown of Pim-1 using sh-RNA decreases c-Myc and NS expression (-60%, -54%, p&lt;0.05), similar to effects mediated by a Pim-1 kinase inhibitor (p&lt;0.01), indicating that Pim-1 regulates both c-Myc and NS. c-Myc is necessary and sufficient for NS regulation, as indicated by the increase (3.1 fold, p&lt;0.01) and decrease (-60.2%, p&lt;0.01) in NS expression upon lentiviral mediated over-expression or knockdown of c-Myc, respectively. Regulation of NS promoter by c-Myc is evident from loss of GFP expression and fluorescence following knock down of c-Myc in CPCs isolated from transgenic mice expressing eGFP driven by the NS promoter. The role of NS in regulating CPC pluripotency is determined by silencing NS. Change in morphology (flat, round cells vs spindle shape control CPCs), decreased expression of stem cell marker c-Kit (-55%, p&lt;0.05), up-regulation of cell cycle inhibitors p53 and p16 (4.2, 3.8 fold, p&lt;0.01) and decreased proliferation (p&lt;0.05) result from loss of NS in CPCs, suggestive of increased senescence and loss of pluripotency. NS-mediated regulation of CPC senescence is p53 dependent, as silencing p53 reverses CPC morphology and pluripotency lost by NS depletion. In conclusion, NS which is induced downstream of Pim-1 kinase maintains pluripotency and enhances regenerative potential in CPCs. These findings are consistent with cumulative evidence that Pim-1 induced cardiac regeneration is mediated in part by NS, providing an additional mechanistic basis for benefits of genetic engineering with Pim-1 to enhance NS expression in cardiac stem cells.
Accurate and precise targeted NGS with BRCA MASTR Plus Dx for <i>BRCA1</i> and <i>BRCA2</i> mutation detection in formalin-fixed paraffin-embedded tumor tissue-derived DNA.
Authors: Gaelle Boulet, Djana Van Barel, Annelies Rotthier, Dirk Goossens, Jurgen Del-Favero
Journal: Journal of Clinical Oncology (2017)

e23116 Background: Targeted next-generation sequencing (NGS) has tremendous potential in clinical diagnostics as it allows oncogenetic profiling to steer therapy. Inhibitors of poly-(ADP-ribose) polymerase (PARPi) have emerged as a new class of targeted anti-cancer drugs, specifically for tumors showing homologous recombination repair deficiency, including BRCA1- and BRCA2-mutated ovarian and breast cancers. This multicentre study evaluated the performance of BRCA Tumor MASTR Plus Dx * (Multiplicom) to routinely diagnose somatic and germline BRCA mutations in formalin-fixed paraffin-embedded (FFPE) tumor tissue-derived DNA. Methods: Three genetic centres participated in this performance evaluation study (PES) to detect single nucleotide variants (SNV) and small indels in the BRCA genes at a variant allele frequency down to 5%. The sample population comprised 54 FFPE-derived DNA extracts from 51 clinical and 3 reference samples. DNA extracts were subjected to quality control using Multiplicom’s QC plex assay. The clinical samples were characterized using an independent targeted NGS method and Integrative Genomics Viewer (IGV) analysis of the mapped raw reads. SNV calling was performed using third-party bioinformatics platforms in the BRCA coding regions +/- 2 intronic bp. Results: BRCA MASTR Plus Dx * showed a uniformity of 93.9%, i.e. the percentage of amplicons with at least 0.2x the mean amplicon coverage, and a target specificity of 99.1%. The limit of detection (LOD) proved to be as low as 1%. The diagnostic accuracy was ≥ 99.99% [95% CI ≥ 99.98%] (100% sensitivity [95% CI ≥ 99.02%] and ≥ 99.99% specificity [95% CI ≥ 99.98%]). Both repeatability and reproducibility were ≥ 99.99% [95% CI ≥ 99.98%]. Lot equivalence was 100% [95% CI ≥ 99.99%]. Conclusions: This multicentre study demonstrated that BRCA MASTR Plus Dx * can be routinely applied as an accurate and precise method with an LOD of 1%. The assay can be used to direct patients with somatic or germline BRCA mutations to PARPi therapy. Currently, a PES for BRCA MASTR Plus Dx * and Multiplicom’s MASTR Reporter software is ongoing. * Products described above are CE-IVD and not available for sale in the US
Myocardial Damage in Patients With Deferred Stenting After STEMI
Authors: Jacob Lønborg, Thomas Engstrøm, Kiril Aleksov Ahtarovski, Lars Nepper-Christensen, Steffen Helqvist, Niels Vejlstrup, Kasper Kyhl, Mikkel Malby Schoos, Ali Ghotbi, Christoffer Göransson, Litten Bertelsen, Lene Holmvang, Frants Pedersen, Erik Jørgensen, Kari Saunamäki, Peter Clemmensen, Ole De Backer, Lene Kløvgaard, Dan Eik Høfsten, Lars Køber, Henning Kelbæk
Journal: Journal of the American College of Cardiology (2017)
Systematic analysis of parameters predicting pathological axillary status (ypN0 vs. ypN+) in patients converting from cN+ to ycN0 through primary systemic therapy (PST).
Authors: Cornelia Liedtke, Hans-Christian Kolberg, Laura Kerschke, Dennis Goerlich, Ingo Bauerfeind, Tanja N. Fehm, Barbara Fleige, Maik Hauschild, Gisela Helms, Annette Lebeau, Sabine Schmatloch, Peter Schrenk, Lukas Schwentner, Annette Staebler, Gunter Von Minckwitz, Sibylle Loibl, Michael Untch, Thorsten Kuehn
Journal: Journal of Clinical Oncology (2017)

560 Background: Optimization of axillary staging in patients converting from cN+ to ycN0 through PST is needed. The aim of this analysis was to develop a nomogram predicting the probability of ypN+ after PST based on clinical/pathological parameters. Methods: Patients converting from cN+ to ycN0 through PST from a prospective study (SENTINA arm C) were included. Univariate/multivariate analyses were carried out for 14 clinical/pathological parameters to predict ypN+ using logistic regression models. Odds ratios and 95% confidence intervals were reported. Model performance was assessed by leave-one-out cross-validation (LOOCV at .5 cut-offs) and ROC analyses. Calculations were performed using the SAS Software (Version 9.4). Results: 553 patients were assessed. Stepwise backward variable selection based on a multivariate analysis of all significant parameters resulted in a model (5M, Table, N = 369 evaluable) including ER (3.81; 2.25-6.44), multifocality (2.22; 1.26-3.92), LVI (9.16; 4.68-17.90), detection of SLN after PST (.50; .26-.95) and ycT (1.03; 1.01-1.06). In LOOCV, this model had an area under the curve of .81. Multivariate analysis of parameters available preoperatively showed an association between ypN0/ypN+, ER and ycT. Full subset selection resulted in a model (2M, N = 414) containing only ER (4.36; 2.80, 6.81) and ycT (1.04; 1.02, 1.07). Conclusions: A prediction model including parameters evaluable before/after definitive surgery resulted in a nomogram with acceptable accuracy. Limitation to parameters evaluable before surgery (i.e. ER, ycT) showed reduced accuracy that was comparable/superior to accuracy of using individual parameters. Since tumor biology was the strongest parameter in our models, we hypothesize that modern tumor biologic parameters such as gene expression profiling might optimize prediction of axillary status after PST improving patient counseling. [Table: see text]
Phase III, randomized study of first-line trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs. trastuzumab + taxane (HT) treatment of HER2-positive MBC: Final overall survival (OS) and safety from MARIANNE.
Authors: Edith A. Perez, Carlos H. Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B. Pivot, Howard A. Burris, Silke Hoersch, Monika Patre, Paul Anthony Ellis
Journal: Journal of Clinical Oncology (2017)

1003 Background: In MARIANNE (NCT01120184), patients with HER2-positive advanced breast cancer were randomized to trastuzumab + docetaxel or paclitaxel (HT; n=365), T-DM1 + placebo (T-DM1; n=367), or T-DM1 + P (T-DM1 + P; n=363) as first-line therapy. In the primary analysis, T-DM1–based treatment exhibited noninferior, but not superior, progression-free survival relative to HT (Perez EA, et al. J Clin Oncol 2016). OS was similar between treatments in the first interim analysis. Here we report OS from the final descriptive analysis. Methods: Enrolled patients had centrally assessed HER2-positive (IHC3+ or ISH+) progressive/recurrent locally advanced breast cancer or previously untreated MBC with a ≥6-month interval since (neo)adjuvant treatment with taxanes or vinca alkaloids. Results: At the clinical cutoff date of May 15, 2016, median follow-up was 54 months and 512 patients had died. Median OS was 50.9, 53.7, and 51.8 months with HT, T-DM1, and T-DM1 + P, respectively (Table). A sensitivity analysis in which HT-treated patients who received T-DM1 and/or P after disease progression (n=85) were censored prior to treatment switch found similar results. There were numerically fewer grade ≥3 adverse events (AEs) with T-DM1. Conclusions: With this longer follow-up, the T-DM1 safety profile was consistent with the primary analysis and prior experience. While OS was similar across treatment arms, a median OS of 53.7 months and fewer grade ≥3 AEs (vs other arms) supports T-DM1 as an effective and tolerable alternative first-line treatment for HER2-positive MBC patients. Clinical trial information: NCT01120184. [Table: see text]
Association of HER2 and IGF1 germline polymorphisms with outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR) with or without cetuximab (CB): The EPIC experience.
Authors: Dongyun Yang, Pierre Oliver Bohanes, Wu Zhang, Christopher Harbison, Ovidiu C. Trifan, Yan Ning, Leonor Benhaim, Takeru Wakatsuki, Anthony B. El-Khoueiry, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

3615 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated 6 functional germline polymorphisms involved in the IGF1 and HER2 for their potential role as molecular predictors of clinical outcome in pts treated in the EPIC study. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the EPIC trial. Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Univariate analysis (Fisher's exact test for RR; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. Multivariate analysis (Logistic regression or Cox regression model) was conducted to control baseline patient characteristics and treatment. Results: 186 pts with available samples were treated either with IR/CB (arm A, 84 pts) or IR alone (arm B, 102 pts). Median age was 59 yrs (range 34-85yrs) for arm A and 61 yrs (range 25-90 yrs) for arm B. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS for arm A was 3.0 months (95%CI 2.4- 4.1 months) vs 2.7 months (95%CI 2.2-2.9 months) for arm B; median OS was 9.3 months (95%CI 7.1-21.1 months) for arm A vs 12.3 months (95%CI 10.4- 17.9 months) for arm B. KRAS mutation status was not significantly associated with outcome in our patient cohort. We found that HER2 rs 1136201 was significantly associated with response (RR: AA 6.5%, AG 12.5%, and GG 27.3%, Fisher’s exact test p=0.045). IGF1 rs 2946834 was significantly associated with PFS in both univariate and multivariate analyses (median PFS was 2.8 months in patients with CC or CT vs 1.8 months in patients with TT; log-rank p=0.009; Wald test p=0.008). Conclusions: Our study suggests the prognostic value of polymorphisms in the IGF1 and HER2-pathway in mCRC pts treated with IR± CB. Prospective validation of these findings in clinical trials is warranted.
Tumor genomics and response to CDK 4/6 inhibitors for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Laura Spring, Andrzej Niemierko, Dejan Juric, Mark Zangardi, Elizabeth Abraham, Dora Dias-Santagata, Leif W. Ellisen, Steven J. Isakoff, A. John Iafrate, Beverly Moy, Aditya Bardia
Journal: Journal of Clinical Oncology (2017)

1046 Background: The combination of endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor, such as palbociclib, has changed the treatment paradigm of HR+ MBC, particularly as 1 st line therapy. However, there are no predictive biomarkers at present, and little is known about the impact of tumor genomics on outcomes. For example, mutations in TP53 could impact the ability of p53 to negatively regulate p21, thereby promoting cell cycle progression despite CDK 4/6 inhibition. The aim of this study was to evaluate the association between tumor genomics, particularly PIK3CA and TP53 mutations, and response to CDK 4/6 inhibitors in HR+ MBC. Methods: All HR+/HER2- MBC patients at our institution receiving a CDK 4/6 inhibitor in the second line or beyond were identified. Tumor genomics were analyzed utilizing the institutional tumor genotyping next generation sequencing (NGS) assay known as “Snapshot-NGS assay” on DNA isolated from the tumor, covering key oncogenic driver mutations and tumor suppressor genes. The log-rank test was used for statistical analysis. Results: A total of 83 patients with HR+/HER2- MBC were identified, of which 61 had available tumor genotyping results available (52 metastatic specimens). The median line of therapy was three. Median progression-free survival (PFS) on CDK 4/6 inhibitor-based therapy, as second line or beyond, was 9.2 months (mo) overall. No significant difference in PFS was seen among patients with PIK3CA (n = 31) mutations (7.1 vs. 9.7 mo; p = 0.28) or with any alteration in the PI3K/Akt/mTOR (n = 36) pathway (8.2 vs. 9.3 mo; p = 0.40). The presence of a p53 mutation (n = 9) or complex tumor genomics (n = 14) demonstrated a trend towards shorter PFS (5.5 vs. 9.2 mo; 5.5 vs. 9.5 mo, respectively), although statistical significance was not reached due to small numbers (p = 0.76; p = 0.31). In a multivariable analysis adjusting for age and prior lines of therapy, similar results were observed. Conclusions: This study suggests patients with HR+ MBC harboring p53 mutations or complex tumor genomics may experience shorter PFS on CDK 4/6 inhibitor-based therapy in the second line and beyond, and these novel findings require validation in additional studies.
Skeletal Muscle Involvement in Antisynthetase Syndrome
Authors: Eri Noguchi, Akinori Uruha, Shigeaki Suzuki, Kohei Hamanaka, Yuko Ohnuki, Jun Tsugawa, Yurika Watanabe, Jin Nakahara, Takashi Shiina, Norihiro Suzuki, Ichizo Nishino
Journal: JAMA Neurology (2017)

<h3>Importance</h3> Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients’ serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies. <h3>Objective</h3> To elucidate the clinical features of myositis in patients with antisynthetase syndrome. <h3>Design, Setting, and Participants</h3> In this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016. <h3>Exposures</h3> Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed.<i>HLA-DRB1</i>alleles were genotyped. <h3>Main Outcomes and Measures</h3> The main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied. <h3>Results</h3> Of 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1—the anti-OJ antibody—was not detected by line blot assay but by RNA immunoprecipitation. There were no significant<i>HLA-DRB1</i>alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis. <h3>Conclusions and Relevance</h3> Although clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.
Workplace Accommodation for Persons With IBD: What Is Needed and What Is Accessed
Authors: Tarun Chhibba, John R. Walker, Kathryn Sexton, Gayle Restall, Melony Ivekovic, Leigh Ann Shafer, Harminder Singh, Laura E. Targownik, Charles N. Bernstein
Journal: Clinical Gastroenterology and Hepatology (2017)