tbuckley/cabot-search huggingface dataset:
PAPR1 expression in testicular germ cell tumors.
Authors: Michal Mego, Zuzana Cierna, Daniela Svetlovska, Dusan Macak, Katarina Machalekova, Viera Miskovska, Michal Chovanec, Vanda Usakova, Pavel Babal, Jozef Mardiak
Journal: Journal of Clinical Oncology (2012)

e15027 Background: Testicular germ-cell tumours (TGCTs) represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP inhibitors represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate poly(ADP-ribose)polymerase-1 (PARP1) expression in TGCTs and to correlate expression patterns with clinico-pathological variables. Methods: In this translational study, tumor specimens from 124 patients with GCTs were identified. PARP1 expression was detected by immunohistochemistry using monoclonal antibody, scored by the multiplicative quickscore (QS) method and compared to PARP1 expression in testicular tissue of normal testis. The QS was calculated by multiplying the percentage score by the staining intensity score to yield a minimum value of 0 and a maximum value of 18. Based on the QS nuclear PARP1 expression was graded as low (0–9) or high (10–18). Results: We observed higher expression of PARP1 in testicular tumors compared to normal tissue of testis (mean QS = 10.04 vs. 3.60, p &lt; 0.0000001). Mean QS ± SD for each histological subtype was following: intratubular germ cell neoplasia (ITGCN) = 18.00 ± 0.00, embryonal carcinoma = 9.62 ± 5.64, seminoma = 9.74 ± 6.51, yolc sac tumor = 7.8 ± 7.20, teratoma = 5.87 ± 5.34, and choriocarcinoma = 4.50 ± 8.33. The PARP1 overexpression (QS &gt; 9) was most often detected in ITGCN (100% of specimen with PARP1 overexpression), seminona (52.6%), embryonal carcinoma (47.0%), yolc sac tumor (33.3%), teratoma (26.7%), and choriocarcinoma (25.0%), compared to 1.9% of normal testicular tissue specimen. There was no association between PARP1 expression and clinical variables. Conclusions: PARP1 overexpression is an early event in the development of TGCTs. We suggest that PARP1 could represent a novel treatment target in TGCTs and the assessment of PARP1 expression in tumor samples may lead to the consideration of TGCTs patients for PARP inhibitor therapy.
Epigenetic and genetic alterations of <i>DYPD</i> in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer.
Authors: J. S. Bordalo Esa, J. Carvalho, M. Pinheiro, V. Costa, A. Rodrigues, I. Veiga, M. Teixeira, R. Henrique, C. Jeronimo
Journal: Journal of Clinical Oncology (2010)

e12005 Background: Deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) has been associated with the development of severe toxicity to 5-FU in gastrointestinal (GI) cancer patients. Promoter hypermethylation has been proposed as an alternative mechanism for DPD deficiency not explained by deleterious mutations. Moreover, thymidylate synthase (TYMS) activity also influences 5-FU cytotoxic effects. The primary objective of this study was to analyze the methylation status of dihydropyrimidine dehydrogenase gene (DPYD) promoter region by quantitative methylation-specific PCR in GI cancer patients who developed severe 5-FU toxicity. Secondary objectives were the analysis of large intragenic rearrangements of DPYD and the assessment of DPD and TYMS immunoexpression in tumor tissue samples. Methods: DPYD hypermethylation was evaluated through quantitative methylation-specific PCR in DNA extracted from peripheral blood (PB) samples and micro-dissected tumor tissue (MTT), using a colon cancer cell line as control. The screening for large DPYD intragenic rearrangements was performed with the MLPA method. Specific antibodies were used against DPD and TYMS to assess the immunoexpression of those enzymes in representative tissue sections. Results: DPYD promoter methylation was absent in all the PB and MTT samples from the 45 patients experiencing severe 5-FU toxicity and controls. Large DPYD intragenic rearrangements were also not detected in both groups. Severe 5-FU toxicity wasn't associated with DPD or TYMS immunoexpression either. Clinically, 5-FU toxicity was more frequent after 5-FU in bolus administration, as well as in gastric/esophageal primary site and in patients with a worse performance status score (p < 0.05). Conclusions: Promoter methylation and large intragenic rearrangements of DPYD do not contribute to the development of 5-FU severe toxicity. Additional studies are required to investigate other genetic and/or clinical factors, which might be responsible for severe forms of 5-FU toxicity in GI cancer patients. No significant financial relationships to disclose.
Clinical role of regulatory T cell in intraductal papillary mucinous neoplasms
Authors: Y. Morine, M. Shimada, S. Imura, H. Uchiyama, H. Uchiyama, H. Kanemura, Y. Arakawa, J. Hanaoka, K. Sugimoto
Journal: Journal of Clinical Oncology (2009)

e15537 Background: Intraductal papillary mucinous neoplasms of pancreas (IPMNs) have malignant potential and exhibit a broad histologic spectrum, ranging from adenoma to invasive carcinoma. Recently, several investigators have reported that regulatory T cells (Foxp3+CD4+ T cells including CD4+CD25+ T cells and CD4+CD25- T cells) play important roles in anti-tumor immunity. We previously reported clinical role of increased populations of Foxp3+CD4+ T cells (Treg) in peripheral blood from advanced pancreatic cancer patients (Pancreas 2006). This study was conducted to clarify the clinical role of Treg for surveillance of IPMNs. Methods: Thirty-five patients with IPMNs (IPMC: n=8, IPMB: n=2, IPMA: n=5) and pancreas cancer (n=20) who underwent surgical resection were included in this study. Peripheral blood was withdrawn from IPMN patients (IPMC: n=5, IPMA: n=2) and PC patients (n=20), as well as healthy volunteer donors (n=20) as controls. The peripheral blood mononuclear cells (PBMCs) were subjected to FACScan analysis after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Immunohistochemical expression of Foxp3 (abcam: FOXP3 antibody, 236A/E7), Fascin (Dako: Fascin antibody, 55K-2) and TGF-β (Santa Cruz: TGF-β1 antibody, SC146) in main tumor was assessed in all IPMN patients. Results: The Treg population among the PBMCs was significantly increased in IPMC patients (median: 4.50%) and PC patients (median: 3.06%) compared with healthy donors (median: 1.30%). No significant difference in the Treg population among the PBMCs was observed between IPMC and PC patients. On the other hand, in IPMA patients (n=2), the Treg population among the PBMCs was equivarent to healthy donors (2.40 and 1.85% respectively). In immnohistochemical staining, the positive expression of Foxp3 was 87.5% (7 of 8) in IPMC patients, while in IPMA and IPMB patients, the expression of Foxp3 was not observed. The expression of Fascin and TGF-β was not correlated to malignant potential of IPMNs Conclusions: Increase of Foxp3+CD4+ T cells in the PBMCs is a new promising marker for malignant potential in IPMNs patients. No significant financial relationships to disclose.
A randomized phase II study of AZ2014 versus everolimus in patients with VEGF refractory metastatic clear cell renal cancer (mRCC).
Authors: Thomas Powles, Matthew James Wheater, Omar Din, Thomas R. Geldart, Ekaterini Boleti, Andrew Stockdale, Santhanam Sundar, Angus Robinson, Imtiaz Ahmed, Shah-Jalal Sarker, Syed A. Hussain, Christy Ralph
Journal: Journal of Clinical Oncology (2015)

409 Background: Dual TORC1 and 2 inhibitors such as AZD2014 have theoretical advantages over isolated TORC1 inhibitors such as everolimus in the treatment of mRCC. In this study we compare the activity of these drugs in patients with vascular endothelial growth factor (VEFG) refractory mRCC. Methods: Patients with measurable VEGF refractory mRCC were randomised (1:1) to AZD2014 or everolimus stratified by MSKCC prognostic score and 1st line targeted therapy. Progression free survival (PFS) measured by RECIST v1.1 was the primary endpoint. Adverse events (AE) (CTCAE v4.03), response rates (RR) and overall survival (OS) were reported. This was an investigator led study and had appropriate ethical approval. Results: The study was stopped early (May 2014) with the recommendation of the IDMC. At this point 48 patients were recruited and 40 (AZD2014 23 :everolimus 17) patients were assessable for efficacy. Patient’s demographics were similar in the 2 groups. The median PFS was shorter for AZD2014 than everolimus (2.0 [95% CI 1.6-3.2] months vs. 5.8 [95% CI 2.8-11.2] months: stratified HR [2.4 95% CI:1.0-5.7; p&lt;0.05]). Progression of disease as a best response was higher for AZD2014 than everolimus (65% vs. 18%: p=0.03). Response rates for AZD2014 and everolimus were 0% and 12% respectively. There were 9 deaths in this patient group, 7 in AZD2014 and 2 in everolimus group, all were due to disease progression. Grade III-IV adverse events (AEs) occurred with AZD2014 and everolimus in 30% and 59% of patients respectively. Discontinuation for AEs did not occur with AZD. PK analysis revealed AZD2014 doses within therapeutic window. Results for the 48 patient will be presented along with the survival data. Conclusions: The PFS for AZD2014 is inferior to everolimus in this setting despite excellent tolerability. These results are consistent with previous results with broader spectrum mTOR inhibitors in VEGF refractory mRCC (GDC0890: HR2.04 [Powles et al ASCO 2014]). This approach appears to be flawed. Clinical trial information: NCT01793636.
Abstract 12073: Compound K811 Prevents Vascular Cognitive Impairment by Inhibiting Apoptosis Signal-Regulating Kinase 1
Authors: Kensuke Toyama, Nobutaka Koibuchi, Yu Hasegawa, Ken Uekawa, Tetsuji Katayama, Daisuke Sueta, Hiroaki Kusaka, Ma Ming Jie, Takashi Nakagawa, Lin Bowen, Hisao Ogawa, Shokei Kim-Mitsuyama
Journal: Circulation (2013)
Choi response criteria for prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib
Authors: A. van der Veldt, M. R. Meijerink, A. J. van den Eertwegh, J. B. Haanen, E. Boven
Journal: Journal of Clinical Oncology (2009)

5044 Background: Sunitinib (SU) has been approved for the treatment of metastatic renal cell cancer (mRCC). Since SU can induce extensive necrosis, RECIST may be inappropriate for tumor response evaluation. We evaluated whether the new Choi criteria (J Clin Oncol. 2007;25:1753–1759) are of additional value to predict outcome in mRCC patients (pts) treated with SU. Methods: 56 mRCC pts treated with SU were included. Imaging data consisted of thoracic and abdominal helical CT scans at baseline, after a median of 2 months and were repeated during treatment. For Choi criteria the longest diameter was ≥15 mm. Density of these lesions was determined in Hounsfield units. According to Choi criteria partial response (PR) was defined as ≥10% decrease in size or ≥15% decrease in density, while progressive disease (PD) was defined as ≥10% increase in size without meeting PR criteria by density. Progression-free survival (PFS) and overall survival (OS) were calculated according to Kaplan-Meier. Log rank test was used to test the statistical difference between survival curves. Results: For RECIST and Choi criteria, respectively, 230 and 156 tumor lesions were eligible. At first evaluation, according to RECIST 7 pts had PR, 39 stable disease (SD), and 10 PD, while according to Choi criteria 33 pts had PR, 8 SD and 15 PD. The median tumor density decreased significantly (Wilcoxon Signed Ranks test, p ≤ 0.001). At first evaluation in patients with PR, Choi criteria had a significantly better predictive value for PFS and OS (p &lt; 0.001 and p &lt; 0.001, respectively) than RECIST (p = 0.384 and p = 0.392, respectively). When best response during treatment was analyzed according to RECIST, the predictive value of RECIST increased for both PFS and OS (p = 0.004 and p = 0.002, respectively). For clinical benefit (PR+SD), the predictive value of RECIST and Choi criteria for PFS and OS were comparable (both p &lt; 0.001). Conclusions: Choi criteria can be easily applied on contrast-enhanced CT scans. RECIST and Choi criteria have similar predictive value for outcome in pts with clinical benefit. Choi criteria, however, are more useful to early define a large pt population with favourable clinical outcome. [Table: see text]
Noninvasive monitoring of cellular versus acellular tumor DNA from immunoglobulin genes for DLBCL.
Authors: David Matthew Kurtz, Michael R Green, Scott Victor Bratman, Chih-Long Liu, Cynthia Glover, Colm Keane, Katie Kong, Malek Faham, David Bernard Miklos, Ranjana H. Advani, Ronald Levy, Mark S. Hertzberg, Maher K Gandhi, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2014)

8504 Background: In patients with diffuse large B cell lymphoma (DLBCL), tumor specific immunoglobulin genes can be detected in both the cellular and acellular compartments of blood (Green et al ASH 2013; Armand et al BJH 2013; Roschewski et al ASH 2013). Detection of these genes by high-throughput sequencing (Ig-HTS) has promise for monitoring minimal residual disease (MRD). We compared the performance of Ig-HTS in the cellular and acellular compartments of blood and related them to other measures of disease. Methods: We profiled 50 patients with DLBCL at time of diagnosis, therapy, remission, and relapse. Forty-two patients were treated at Stanford University with curative intent. Eight patients were from an Australian Phase 2 study (ALLG NHL21) for patients with poor risk treated with R-CHOP. Involved tissue was used to define clonotypic tumor heavy and light chains by Ig-HTS. Identified sequences were tracked in the cellular and acellular compartments of blood (Faham M et al Blood 2012). Results: We identified clonotypic sequences in 100% of fresh tissue but only 59% of FFPE (72% overall). Heavy chains were more frequent than light chains (86% vs 47%). For 36 cases with clonotypic sequences, we followed MRD with 216 tests on 98 blood samples. Within the cellular compartment of blood, we identified disease in 70% of patients at diagnosis, but only 20% at relapse. In the acellular compartment, we identified disease in 78% at diagnosis and 83% at relapse. In those achieving complete response, MRD became undetectable by cycle 2 and remained so while in CR. Only 1 of 46 assays revealed MRD in the cellular compartment while in CR; this in a patient with double-hit DLBCL and high relapse risk. Using radiographic assessment as gold standard, cellular Ig-HTS had 52% sensitivity and 97% specificity and acellular Ig-HTS had 67% Sn and 100% Sp. MRD level correlated with LDH (R=0.76, p<0.0001) and metabolic tumor volume (MTV) (R=0.58, p<0.01). Conclusions: Ig-HTS can detect tumor specific DNA in the blood of patients with DLBCL. Performance is superior in cell-free DNA from the acellular compartment of blood compared to the cellular compartment. Given its high specificity, Ig-HTS has potential clinical utility during surveillance after achieving CR.
Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva
Authors: Brooke E. Howitt, Heather H. Sun, Margaretha G. M. Roemer, Alyssa Kelley, Bjoern Chapuy, Emeline Aviki, Christine Pak, Courtney Connelly, Evisa Gjini, Yunling Shi, Larissa Lee, Akila Viswanathan, Neil Horowitz, Donna Neuberg, Christopher P. Crum, Neal L. Lindeman, Frank Kuo, Azra H. Ligon, Gordon J. Freeman, F. Stephen Hodi, Margaret A. Shipp, Scott J. Rodig
Journal: JAMA Oncology (2016)

Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1.To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression.We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs.Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC.Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women's Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy.Recurrent copy number gain of the genes encoding the PD-1 ligands provides a genetic basis for PD-L1 expression in a subset of cervical and vulvar SCCs and identifies a class of patients that are rational candidates for therapies targeting PD-1.
Abstract 1139: Necrostatin-1 is a Novel Protector of Myocardial Infarction
Authors: Balvin H Chua, Jinping Gao, Hong Wang, Ronald C Hamdy, Chu C Chua
Journal: Circulation (2006)

To date, it has been difficult to investigate the potential mechanisms of necrosis, which is generally believed to be a passive cellular response to external damage. Recently, a new non-apoptotic p...
Abstract 15170: Telomere Length and Incident Carotid Atherosclerosis
Authors: Shufeng Chen, Mary J Roman, Fawn Yeh, Jue Lin, Tet Matsuguchi, Elizabeth Blackburn, Richard B Devereux, Elisa T Lee, Barbara V Howard, Jinying Zhao
Journal: Circulation (2013)

Background: Telomere length shortens progressively during each round of cell division and declines significantly with age, and thus has emerged as a valuable biomarker for cellular aging and age-re...
Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL
Authors: Kerry J. Savage, Graham W. Slack, Anja Mottok, Laurie H. Sehn, Diego Villa, Roopesh Kansara, Robert Kridel, Christian Steidl, Daisuke Ennishi, King L. Tan, Susana Ben-Neriah, Nathalie A. Johnson, Joseph M. Connors, Pedro Farinha, David W. Scott, Randy D. Gascoyne
Journal: Blood (2016)
Richard Smith Ankle Arthroplasty
Authors: John Kirkup
Journal: Journal of the Royal Society of Medicine (1985)

The indications for ankle joint replacement and the advantages of a 'ball-and-socket' type of prosthesis are examined. The results of 24 Richard Smith ankle replacements of which 18 were followed for an average of 7 years are analysed and the case for abandoning this prosthesis is discussed.
HER3 as a potential prognostic biomarker in pancreatic cancer.
Authors: Andrea Wang-Gillam, Victoria Rimkunas, Adnan Abu-Yousif, Timothy M. Nywening, Feng Gao, David G DeNardo, David Linehan, Akos Gabor Czibere, Alexey Lugovskoy
Journal: Journal of Clinical Oncology (2015)

295 Background: HER 3 is revealing itself to be increasingly important in HER family signaling. Understanding the role of HER 3 in pancreatic cancer may shed light on targeted therapy development. Methods: A large human pancreatic cancer tumor tissue microarray (TMA) was established at our institution from 165 patients with pancreatic cancer who underwent surgical resection. The TMA contains two cores from each patient. Clinical information of these patients has been prospectively maintained in a clinical database. Immunohistochemistry (IHC) was performed on the TMA using a monoclonal antibody against HER 3. An independent pathologist blinded to the patient data applied the H score to grade the expression level of HER 3. The association between expression levels of HER 3 and survival were evaluated by the Kaplan-Meyer product limit method and log-rank test, while the optimal cut-off for each marker was determined using the Martingale residuals from Cox proportional hazard models. Results: Out of 165 patients, 136 patients’ tumors were identified to have adequate tumor content for IHC analysis. The group with higher HER 3 levels at the cell membrane (n=50)(H score ≥150) had a superior overall survival compared to the low HER 3 membrane expression group (n=86) (22.5 months vs. 17 months; p=0.036). Interestingly, the group with higher expression levels at both the cell membrane and in the cytosol (n=37) (H score ≥190) had a more striking survival difference compared to the lower group (n=99) (26 months vs. 15 months; p= 0.035). Conclusions: Patients with high HER 3 expression either at the cell membrane only or at both the membrane and in the cytosol have longer survival, perhaps indicating a lower heregulin and inactive HER 3 signaling. Additional biomarker analyses are ongoing. The functional role of HER 3 in pancreatic cancer is being further explored to assist clinical evaluation of HER 3 targeting in pancreatic cancer.
Nephrogenic Diabetes Insipidus
Journal: BMJ (1963)

The incidence of hereditary nephrogenic diabetes insipidus (NDI) is estimated to be approximately 9 in 1 million male live births for the most common X-linked variety representing about 90% of patients. It is characterized by a loss of arginine-vasopressin (AVP)-mediated antidiuresis. It belongs to a large group of protein-misfolding diseases. In congenital NDI that results from mutations in the AVPR2 gene that encodes the V2 receptor, most missense mutations are misfolded, trapped in the endoplasmic reticulum and unable to reach the basolateral membrane to engage the circulating antidiuretic hormone AVP. In about 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance and is secondary to mutations in the aquaporin-2 gene (AQP2). Mutant AQP2 proteins are also misrouted. Mutants that encode other renal membrane proteins that are responsible for Gitelman syndrome, Bartter syndrome and cystinuria are also retained in the endoplasmic reticulum. The purpose of this review is to first describe in molecular terms the regulated transepithelial water permeability of the collecting ducts then to describe two types of hereditary nephrogenic diabetes insipidus: a pure type characterized by loss of water only, and a complex type characterized by loss of water and ions. Patients with hereditary NDI bearing mutations in AVPR2, the gene coding for the arginine vasopressin 2 receptor, or in AQP2, the gene coding for the vasopressin-sensitive water channel, have a pure NDI phenotype with loss of water, but normal conservation of sodium, potassium, chloride, and calcium. Patients bearing inactivating mutations in one of the five genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium.