tbuckley/cabot-search huggingface dataset:
SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor
Authors: Li-Sheng Zheng, Jun-Ping Yang, Yun Cao, Li-Xia Peng, Rui Sun, Ping Xie, Meng-Yao Wang, Dong-Fang Meng, Dong-Hua Luo, Xiong Zou, Ming-Yuan Chen, Hai-Qiang Mai, Ling Guo, Xiang Guo, Jian-Yong Shao, Bi-Jun Huang, Wei Zhang, Chao-Nan Qian
Journal: Cancer Research (2016)

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis-free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial-mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease-inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579-89. ©2016 AACR.
A randomized study on the value of Fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high risk myelodysplastic syndromes and elderly AML. A report from the Dutch-Belgian hemato-oncology cooperative group (HOVON)
Authors: GJ Ossenkoppele, B van der Holt, P Sonneveld, E Vellenga, L Verdonck, D Biesma, P Westveer, G Peters, P Noordhuis, P Muus, W Graveland, M Schaafsma, D Selleslag, Michel Delforge, B Lowenberg, Gregor Verhoef
Journal: Blood (2001)
LP19 : Early introduction of subcutaneous (S.C.) hepatitis B immunoglobulin (HBIg) provides effective prophylaxis for hepatitis B virus (HBV) reinfection after liver transplantation (TX)
Authors: D. Samuel, P. De Simone, M. Salizoni, A.D. Pinna, U. Cillo, F. Zamboni, D. Mutimer
Journal: Journal of Hepatology (2015)
Ten years too long: strontium ranelate, cardiac events, and the European Medicines Agency
Authors: Mark J Bolland, Andrew Grey
Journal: BMJ (2016)

Delays in acting on cardiovascular safety concerns of the osteoporosis drug strontium ranelate have placed patients at risk, argue Mark Bolland and Andrew Grey Strontium ranelate was registered in Europe in 2004 for postmenopausal osteoporosis. Sales reached about €200m (£170m; $220m) a year by 2010,1 with 3.4 million patient years of use by February 2013.2 In April 2013 the European Medicines Agency (EMA) reported that strontium increased the risk of myocardial infarction.2 Surprisingly, this was driven by the results of TROPOS, a phase III trial completed in November 2003, almost 10 years earlier. No further large clinical trials of strontium had been conducted, and cardiac safety concerns were not mentioned in previous trial publications or publicly available regulatory documents (fig 1⇓).3 Fig 1 Timeline of key trials and regulatory events for strontium ranelate. PRAC=Pharmacovigilance Risk Assessment Committee. CHMP=Committee for Medicinal Products for Human Use. To understand how it could take 10 years for an important adverse effect to be reported, we requested the clinical safety reports (CSRs, box 1) of the two phase III trials, SOTI and TROPOS. Our request was declined by the EMA on the grounds of commercial sensitivity, but we successfully appealed. The CSRs, together with data derived from safety assessments carried out by the EMA in 2006-07, confirm that the agency identified cardiac safety concerns in 2007 but did not report them, raising concerns about the regulatory process. #### Box 1: EMA definitions, documents, and committees
What do patients rank as more important in quality-of-life (QL) and patient-reported outcome (PRO) evaluation: Symptoms (Sx) or summative assessments? Results of a 3,860-patient survey in lung, breast, and prostate cancers with implications for drug development.
Authors: H. Raftopoulos, R. J. Gralla, P. J. Hollen, B. J. Davis, J. A. Petersen, J. L. Horigan
Journal: Journal of Clinical Oncology (2010)

9093 Background: Patient (pt) involvement in establishing content validity (CV) is critical for QL and PRO instrument development. Instruments usually contain both multidimensional summative items and single Sx items. As endpoints in drug development, the FDA has emphasized Sx assessment in PRO guidance and has questioned the CV of many instruments as not having sufficient pt input. This survey was conducted to 1) provide in depth CV in several major cancers, and 2) provide an opportunity to assess whether pts agree with the FDA in prioritizing Sx over summative items in PRO/QL evaluation. Methods: Lung, breast, or prostate cancer pts registered with the web-based NexCura resource were surveyed. Pts ranked 20 to 21 issues, including general, physical, functional, psychosocial and summative items, on a 5-point scale. 3,860 pts completed the anonymous web survey. Multiple demographic factors were also assessed to allow subgroup analysis. Results: The Table shows the 5 highest ranked items as rated in the single top category (“very important”); ranking did not change if the 2 top categories were used. The highest rated items are the same in all 3 cancers; none of the top ranked items are disease specific, and clearly pts rate summative items above typical cancer Sx. Conclusions: This study represents the largest survey of pt expressed concerns. While both Sx and summative items are important, pts consistently prioritize summative items. Interestingly, among these 3 different major cancer types pts ranked most items in a similar order. Patients' rank preference should be taken into account when determining what constitutes benefit in evaluating QL and PROs. Patient ranking of the highest rated items as “Very Important” (percent of patients and rank order) Lung cancer (n = 660) Breast cancer (n = 1,072) Prostate cancer (n = 2,128) Quality of life 80% (1) 82% (1) 76% (1) Maintaining independence 71% (2) 75% (2) 74% (2) Ability to perform normal activities 64% (4) 62% (5) 66% (3) Ability to sleep 63% (5) 69% (3) 51% (6) Fatigue 58% (7) 61% (6) 40% (7) No significant financial relationships to disclose.
Pathologic response rate in HER2-positive locally advanced breast cancers treated with neoadjuvant trastuzumab and concurrent paclitaxel/radiotherapy.
Authors: Sylvia Adams, Tsivia Hochman, Nelly Huppert, Shubhada Dhage, Cristina Checka, Baljit Singh, James L. Speyer, Robert Schneider, Judith D. Goldberg, Silvia Formenti
Journal: Journal of Clinical Oncology (2012)

e11064 Background: We demonstrated in three prospective trials that taxane-based concurrent chemo-radiation achieves high pathological response rates that correlate with decreased recurrence rates and improved survival in locally advanced breast cancers (LABC, Adams et al, BCRT 2010). We now report the results among HER-2 positive LABC patients treated with trastuzumab and concurrent paclitaxel and radiotherapy, preoperatively. Methods: Patients with HER-2 positive LABC (stages IIB-IIIC) were prospectively treated as part of an IRB-approved neoadjuvant trastuzumab-paclitaxel-radiotherapy protocol. Paclitaxel was administered at a dose of 30 mg/m 2 twice a week and trastuzumab was given weekly at a dose of 2 mg/kg (after initial loading with 4 mg/kg) for a total of 10 weeks. Radiotherapy was delivered to the breast and regional lymph nodes during weeks 2-7, daily, at 1.8 Gy per fraction to a total dose of 45 Gy. A 14 Gy boost (2 Gy per fraction) was added to the area of the originally palpable tumor site. Tumor response was assessed at definitive cancer surgery; defined as pathological complete response (pCR) in the absence of invasive cancer in breast and lymph nodes; pathological partial response (pPR) as the persistence of &lt; 10 microscopic foci of invasive carcinoma in breast or lymph nodes. All other patients were classified as having achieved no pathologic response. Results: Twenty-one patients with HER-2 positive LABC were treated. The median age of the patients was 50 years (range 28-76). The most common toxicity was acute dermatitis; no grade IV toxicity was detected. Pathological response (pCR and pPR) after neoadjuvant trastuzumab/paclitaxel/radiation was achieved in 12 patients (57%, 95% CI: 37% - 76%). Responses were observed in 8/12 patients with hormone receptor (HR)-negative (7 pCR, 1 pPR) and in 4/9 patients with HR-positive cancers (3 pCR, 1 pPR). Conclusions: In HER-2 positive LABC, neoadjuvant trastuzumab during paclitaxel and concurrent radiotherapy resulted in a 57% pathological response rate, independently of HR status.
Repeated cannulation attempts or late precut: which is more risky for post-ERCP pancreatitis?
Authors: A. Yildirim, Abdurrahman Kadayifci
Journal: Endoscopy (2016)

We read with great interest the recent article by Mariani et al. relating to the effect of early precut sphincterotomy on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) [1]. In this clinical trial, patients who had difficult biliary cannulation were randomized to early precut (Group A) or repeated papillary cannulation attempts followed, in cases of failure, by late precut (Group B). The authors found that PEP developed in 5.4 % (10/185) of Group A and in 12.1 % (23/190) of Group B patients. The difference was significant (P = 0.02), and the authors concluded that early precut sphincterotomy for difficult biliary access has less risk of PEP than persistent cannulation attempts and delayed precut.
The role of skin and gut microbiota in the development of atopic eczema
Authors: T. Marrs, C. Flohr
Journal: British Journal of Dermatology (2016)

Conventional culture‐based studies have suggested that a reduction in microbial exposure in early life predisposes to atopic eczema and allergies. However, molecular microbiological methods have shown that conventional culture fails to grow around 80% of the bacterial flora. More recent work reviewed in this paper has employed next generation sequencing to study the influence of the gut and skin microbiota, both with regard to the risk of developing atopic eczema but also the role of pathogenic and commensal bacteria in established disease. Birth cohorts investigating the gastrointestinal tract reported reduced faecal microbiota diversity among those who later developed atopic eczema, using gel electrophoresis, real‐time PCR or 16S ribosomal RNA gene pyrosequencing. However, the inverse association with reduced faecal bacterial diversity was not confirmed in cross‐sectional studies among patients with established atopic eczema. Only two studies investigated the cutaneous microbiota in a longitudinal study design and both were unable to provide evidence that Staphylococcus aureus colonisation precedes the development of atopic eczema. Next generation sequencing has confirmed the cross‐sectional association between atopic eczema and S. aureus colonisation. The two studies that used this approach have also shown that disease flares are associated with a significant fall in skin microbiota diversity and an increase in the relative abundance of both S. aureus and epidermidis. Interestingly, S. aureus elimination does not appear to be the main reason why atopic eczema improves after a flare and antimicrobial and anti‐inflammatory therapy enhances bacterial diversity. Further, well‐phenotyped birth cohorts that take key confounders, such as antibiotic exposure, into account are required.
Plasma angiogenic markers in patients with metastatic breast cancer treated with weekly docetaxel.
Authors: G. Papaxoinis, D. G. Pectasides, I. Korantzis, A. Koutras, P. A. Kosmidis, H. Linardou, G. Aravantinos, I. Varthalitis, K. T. Kalogeras, G. Fountzilas
Journal: Journal of Clinical Oncology (2010)

e21004 Background: The aim of the study was to evaluate angiogenic plasma markers in patients with metastatic breast cancer (MBC) treated with first-line weekly docetaxel (D), considered to be standard treatment at the time of the design of the study. Methods: Females with MBC were treated with weekly D 35 mg/m2 ± trastuzumab. Plasma levels of HER2 extracellular domain (HER2-ECD), nitric oxide (NO), interleukin-8, and VEGF-A were measured by ELISA before and after the treatment, as well as in 38 healthy female controls. Prognostic and predictive significance of the pre-treatment values and their relative change with treatment were tested by Cox-regression analysis. Results: Between February 2006 and January 2008, 159 patients were treated. 61 patients (38%) responded (CR = 5%, PR = 33%) and 52 (33%) had stable disease. 37 patients received trastuzumab. Median follow-up was 33 months (2.8-45.0), median PFS 8.8 months (95%CI: 7.2-10.3) and median survival 27.7 months (95%CI: 24.7-30.6). HER2-ECD was the only plasma marker that decreased significantly with treatment (p < 0.001), from 2.08 ng/mL (range 0.2- 13.12) to 1.4 ng/mL (range 0.1-12.72). Normal controls had significantly higher NO levels than that of MBC patients before treatment (282.5 vs 199 umol/L, respectively; p = 0.006), whereas HER2-ECD levels were marginally lower (1.76 vs 2.08 ng/mL, respectively; p = 0.054). High pretreatment HER2-ECD levels were of adverse prognostic significance for survival and PFS (p = 0.033 and p = 0.046, respectively) in patients not treated with trastuzumab. High pretreatment NO levels were also of adverse prognostic value (p < 0.001 for survival, p = 0.004 for PFS), as were high pre-treatment IL8 values (p = 0.048 for survival). Plasma VEGF-A did not appear to have prognostic value. High NO relative change was associated with better survival (p = 0.003), in contrast patients with high IL8 relative change were found to have a worse PFS (p = 0.017). Responders had a smaller relative change of IL8 (p = 0.038) than non- responders. Conclusions: HER2-ECD, NO and IL8 plasma levels appear to be of prognostic value for survival in patients with MBC treated with weekly docetaxel. Tumor angiogenic markers will also be examined by PCR in these patients. No significant financial relationships to disclose.
24. Sustained Expression with Partial Correction of Neutrophil Defects 5 Years After Intramuscular rAAV1 Gene Therapy for Alpha-1 Antitrypsin Deficiency
Authors: Christian Mueller, Jeffrey D. Chulay, Noel G. McElvaney, Gwladys Gernoux, Emer P. Reeves, Farshid N. Rouhani, Margaret Humphries, Alisha M. Gruntman, Martha Campbell-Thompson, James M. Wilson, Terence R. Flotte
Journal: Molecular Therapy (2016)

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We previously reported achieving plasma wild-type (M) AAT concentrations at 2.5-3.8% of the therapeutic level at 1 year after intramuscular (IM) administration of 6×1012vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients, with an associated regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. Here, we report sustained expression, at >2% of the therapeutic level, for 5 years after one-time treatment with rAAV1-AAT in an AAT-deficient patient from that study, with the partial correction of neutrophil defects previously reported in AAT-deficient patients. There was also evidence of an in-situ Treg response and an exhausted CD8+ T cell response to AAV1 capsid. These findings suggest that muscle-based AAT gene replacement is tolerogenic and that very stable levels of M AAT may exert beneficial effects at lower concentrations than previously anticipated.
Phase I/II study of carboplatin, vinorelbine and capecitabine in metastatic breast cance
Authors: M. J. Rabinowitz, A. Mangalik, F.-C. Lee, C. Cathcart, C. Verschraegen, I. Rabinowitz
Journal: Journal of Clinical Oncology (2004)

722 Background: Most patients with breast cancer receive antracyclines and taxanes in either the adjuvant or metastatic setting. Each of the three drugs in the combination of carboplatin (C), vinorelbine (V) and capectitabine (X) has activity in metastatic breast cancer. In addition they are non-cross resistant and generally have non-overlapping toxicities. The purpose of this study is to assess the response rate of CVX in women with metastatic breast cancer previously treated with anthracycline and taxane based chemotherapy. The phase I portion sought to determine the maximally tolerated dose (MTD) of capecitabine when given with CV. Methods: The initial dose of capecitabine was 1000mg/m2 divided BID. The MTD was 1750mg/m2, due to grade III/IV diarrhea and hand foot syndrome. The schedule used in the phase II portion was carboplatin 300mg/m2 day 1, vinorelbine 25mg/m2 day 1 & 8 and capecitabine 1500mg/m2 days 1–14 every 21 days. Results: 25 patients were evaluable for response and toxicity. The mean age was 54, the mean number of prior chemotherapy regimens was 2.3 and 60% were ER/PR positive. The mean number of cycles received was 6.6 (1–18), the overall response rate was 64% (95% CI: 45–83%), the complete response rate was 16% (95% CI: 6–30%), stable disease in 20% (95% CI: 9–35%) and mean progression free survival was 7.1 months (95% CI: 5.4 - 8.8). Two patients (8%) progressed on chemotherapy. The Kaplan-Meier estimated one year survival was 60% (95% CI: 28%–92%) with a mean survival of 16.3 months (95% CI: 11.6 - 21). Grade III/IV neutropenia, leukopenia, anemia, and thrombocytopenia occurred in 22%, 20%, 5% and 3% of cycles respectively. 56% of cycles required GCSF support. One patient died of respiratory failure (Grade V), possibly related to treatment. Conclusions: CVX is a highly active and well tolerated regimen in metastatic breast cancer. Future study is warranted with CVX . No significant financial relationships to disclose.
Germline, hematopoietic, mosaic, and somatic variation: interplay between inherited and acquired genetic alterations in disease assessment
Authors: Eric Q. Konnick, Colin C. Pritchard
Journal: Genome Medicine (2016)

Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Correct assessment of a genetic variant relies on the clinical context and knowledge of the underlying biology. We outline four scenarios encountered in genetic testing where careful consideration of the origin of genetic variation is required for variant interpretation.
A proposed new model for prognostic stratification of poor-risk patients with metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.
Authors: Daniele Santini, Matteo Santoni, Ugo De Giorgi, Stefano Iacobelli, Giuseppe Procopio, Gaetano Facchini, Luca Galli, Giuseppe di Lorenzo, Giuseppe Badalamenti, Francesco Maria Guida, Alessandra Felici, Paolo Marchetti, Roberto Iacovelli, Umberto Basso, Vincenzo Adamo, Flavia Longo, Francesco Massari, Joan Carles, Giuseppe Tonini, Michele Milella
Journal: Journal of Clinical Oncology (2014)

e15588 Background: The stratification of poor risk mRCC patients in the era of targeted therapy represents an unmet medical need. We analyzed, individually, each prognostic factor included in modified Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng criteria to investigate their prognostic relevance in poor risk mRCC patients and proposed a model to stratify poor risk patients into 3 separate subgroups. Methods: Data were collected from 16 italian and 1 spanish centers. Overall survival (OS) was estimated using Kaplan-Meier method. Hemoglobin, Performance Status, Thrombocytosis, Neutrophilia, Number of metastatic sites, Time from diagnosis to treatment, LDH and Hypercalcemia, according to modified MSKCC and Heng criteria, were included in the Cox analysis. Results: 220 (142 Male; 190 clear cell) poor risk mRCC pts were enrolled according to, at least, three of MSKCC, or modified MSKCC or Heng criteria. 217 pts were treated with a first line therapy (55 pts with temsirolimus, 154 pts with tyrosin kinasi inhibithors (TKI), 8 pts with other agents); 95 pts with a second line (45 everolimus, 48 TKi, 2 other agents) and 28 pts with a third line ( 4 everolimus; 17 TKi, 7 other agents). Only Hemoglobin ( 11.24 vs 6.97 months; p = 0.0069), Performance Status (13.64 vs 5.88 months; p < 0.001), Neutrophilia (8.25 vs 5.16 months; p = 0.004) and Time from diagnosis to treatment (15.65 vs. 7.36 months; p = 0.009) were predictors of short survival, independently from the presence/absence of the other prognostic factors. We indentified three risk categories: the favourable-poor risk group (0-1 of previous confirmed four prognostic factors; 32 pts) in which mOS was 24.16 months; the intermediate-poor risk group ( 2 prognostic factors; 80 pts) in which mOS was 8.25 months and the poor-poor risk group (3- 4 prognostic factors; 98 pts) in which mOS was 5.16 months (p < 0.001). Conclusions: This is the first study that indentify three different prognostic poor risk subgroups RCC patients.
Radiofrequency ablation of gastric antral vascular ectasia of the gastric cardia
Authors: Arvind Trindade, Sumant Inamdar, David Magier
Journal: Endoscopy (2016)

A 63-year-old woman was referred for iron-deficiency anemia and melena that was requiring multiple blood transfusions. She had undergone multiple uninformative upper endoscopies and colonoscopies that had been performed by two different gastroenterologists. The patient had undergone a capsule endoscopy that had shown a questionable vascular ectasia in the distal ileum. She therefore underwent retrograde single-balloon enteroscopy; this showed melena from the terminal ileum to the middle jejunum. Given this finding, indicating a more proximal gastrointestinal bleed, an upper endoscopy was performed that showed a prominent erythematous ring of vascular ectasias in the gastric cardia just below the gastroesophageal junction; this was consistent with gastric antral vascular ectasia (GAVE) of the gastric cardia ([Fig. 1], [Video 1)].
Molecular cytogenetic characterization of chromosome 1 abnormalities in Burkitt's lymphoma
Authors: Eva Maria Murga Penas, Iwona Wlodarska, Marianne Klokow, Bettina Keller, Tijana Zivkovic, Kristina Hinz, Carsten Bokemeyer, Judith Dierlamm
Journal: Annals of Oncology (2006)
High Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Levels May Protect against Recurrent Fetal Loss.
Authors: Hendrika M Knol, Nic J.G.M. Veeger, Saskia Middeldorp, Karly Hamulyàk, Martin H Prins, Harry R Büller, Jan van der Meer
Journal: Blood (2008)
Randomised trial comparing Tacrolimus and cyclosporin in the prevention of renal allograft rejection. European study
Authors: JM Morales, J VanHooff, R Pichlmayr, Yves Vanrenterghem, JP Squifflet, B Buchholz, HH Neumayer, FW Eigler, BG Ericzon, Rwg Johnson, AD Mayer, R Taylor, F Muhlbacher, B Grabensee, W Land
Journal: Journal of the American Society of Nephrology (1996)
TMC435 IN COMBINATION WITH PEGINTERFERON ALPHA-2A/RIBAVIRIN IN TREATMENT-NAiVE PATIENTS INFECTED WITH HCV GENOTYPE 1: VIROLOGY ANALYSIS OF THE PILLAR STUDY
Authors: Oliver Lenz, Bart Fevery, Leen Vijgen, Jannick Verbeeck, Monika Peeters, Maria Beumont, Michael W Fried, Gaston Picchio
Journal: Hepatology (2011)