tbuckley/cabot-search huggingface dataset:
Correlation of polymorphic variants into the susceptibility of CDKN2 locus with melanoma outcome.
Authors: G. Palmieri, M. Casula, M. Budroni, A. Cossu, F. Tanda, P. A. Ascierto, S. Canzanella, G. Palomba, M. Colombino, A. Muggiano
Journal: Journal of Clinical Oncology (2010)

8543 Background: Impairment of p16CDKN2A protein expression has been demonstrated to contribute to melanoma progression as well as to correlate with a shorter overall survival. Toward the characterization of a genetic profile with prognostic value within the CDKN2 locus (which harbors the CDKN2A gene, encoding p16CDKN2A and p14CDKN2A proteins, and the CDKN2B gene, encoding p15CDKN2B protein), we here analyzed single nucleotide polymorphisms (SNPs) in order to determine whether a SNP genotype may have prognostic role in melanoma. Methods: Nine SNPs spanning the CDKN2 locus were investigated jointly by logistic regression among 383 healthy controls and 396 patients with melanoma originating from South Italy. Among patients, 325/396 (82%) presented localized disease and the remaining 71 (18%) had regional nodal involvement. After obtaining individuals' written consent, genomic DNA from cases and controls was screened using an automated sequencing approach. Statistical tests were computed by Stata Software. Results: The coexistence of T/T genotype in three SNPs (rs2811710, rs2518720, and rs2811708) spanning the coding exon 1a, the first intron, and the regulatory flanking DNA at the 5′-end of p16CDKN2A was strongly associated with melanoma (p < 0.0001; OR, 5.63; 95%CI, 2.96-10.7). No other combination of genotypes presented a frequency significantly higher in melanoma patients than in controls. After a median follow-up of 68 months (range, 13-212), patients carrying the identified genotype presented a lower overall survival in comparison with those presenting different combination of genotypes at the CDKN2 locus. Using the Cox model for a multivariate analysis, the disease stage (p < 0.001; HR, 2.05; 95%CI, 1.43-2.98) and the presence of the T/T genotype in rs2811710-rs2518720-rs2811708 SNPs (p = 0.047; HR, 1.54; 95%CI, 1.17-1.91) remained the parameters with a significant impact on prognosis. Conclusions: If confirmed in other populations, such a polymorphic pattern might become a useful marker for both melanoma risk and outcome. Our findings further support the general idea that a better understanding of the relationship between underlying biological factors may lead to improvements in disease management. No significant financial relationships to disclose.
Expression of MUC-1 Epitopes on Normal Bone Marrow: Implications for the Detection of Micrometastatic Tumor Cells
Authors: Wolfram Brugger, Hans-Jörg Bühring, Frank Grünebach, Wichard Vogel, Sepp Kaul, Robert Müller, Tim H. Brümmendorf, Benedikt L. Ziegler, Irene Rappold, Peter Brossart, Stefan Scheding, Lothar Kanz
Journal: Journal of Clinical Oncology (1999)

PURPOSE: The expression of the carcinoma-associated mucin MUC-1 is thought to be restricted to epithelial cells and is used for micrometastatic tumor cell detection in patients with solid tumors, including those with breast cancer. Little is known, however, about the expression of MUC-1 epitopes in normal hematopoietic cells. MATERIALS AND METHODS: MUC-1 expression was analyzed by flow cytometry and immunocytology on bone marrow (BM) mononuclear cells and purified CD34 + cells from healthy volunteers, using different anti-MUC-1–specific monoclonal antibodies. In addition, Western blotting of MUC-1 proteins was performed. RESULTS: Surprisingly, 2% to 10% of normal human BM mononuclear cells expressed MUC-1, as defined by the anti–MUC-1 antibodies BM-2 (2E11), BM-7, 12H12, MAM-6, and HMFG-1. In contrast, two antibodies recognizing the BM-8 and the HMFG-2 epitopes of MUC-1 were not detected. MUC-1 + cells from normal BM consisted primarily of erythroblasts and normoblasts. In agreement with this, normal CD34 + cells cultured in vitro to differentiate into the erythroid lineage showed a strong MUC-1 expression on day 7 proerythroblasts. Western blotting of these cells confirmed that the reactive species is the known high molecular weight MUC-1 protein. CONCLUSION: Our data demonstrate that some MUC-1 epitopes are expressed on normal BM cells and particularly on cells of the erythroid lineage. Hence the application of anti–MUC-1 antibodies for disseminated tumor cell detection in BM or peripheral blood progenitor cells may provide false-positive results, and only carefully evaluated anti–MUC-1 antibodies (eg, HMFG-2) might be selected. Furthermore, MUC-1–targeted immunotherapy in cancer patients might be hampered by the suppression of erythropoiesis.
Impact Of Patient/Donor Cytokine Genotypes On The Development Of Acute Graft Versus Host Disease (aGVHD) After Peripheral Blood Stem Cell Transplantation From An Identical Sibling
Authors: Azza M Kamel, Gamal TA Ebid, Abdullah Gamil, Abd El-Fattah Raafat, Hossam K Mahmoud, Mohammed Abd El-Mooti
Journal: Blood (2013)
ONC-2014-001: An open-label phase II study of regorafenib in patients with metastatic solid tumors who have progressed after standard therapy - RESOUND
Authors: S. Bozzarelli, L. Rimassa, L. Giordano, I. Garassino, A. Marrari, M.C. Tronconi, R.M. De Sanctis, R. Cavina, M. Baretti, N. Personeni, T. Pressiani, A. Santoro
Journal: Annals of Oncology (2015)
Adjuvant docetaxel plus cisplatin in stage I/II non-small cell lung cancer (NSCLC): Preliminary results of a randomized phase II pilot trial of the Central European Cooperative Oncology Group (CECOG)
Authors: S. Tomek, A. End, W. Klepetko, E. Csiszer, A. Csekeö, G. Kovacs, E. Gingrich, B. Balint, E. Francovszky, C. C. Zielinski
Journal: Journal of Clinical Oncology (2004)

7297 Background: Adjuvant chemotherapy treatment for early stage NSCLC patients is not yet standard practice. The aim of the present trial is to compare the activity, safety, and quality of life effects of adjuvant docetaxel plus cisplatin versus observation only. Methods: Patients with completely resected stage I-II NSCLC, no prior chemotherapy and/or radiotherapy, and a WHO performance status of ≤2, were randomized to docetaxel plus cisplatin, 75 mg/m2 each, both on day 1, every 21 days for 6 cycles (arm A) versus observation only (arm B). Time-to-event endpoints were calculated using the Kaplan-Meier method and compared between arms using the log-rank test. The incidence of grade 3 and 4 toxicity was compared using Pearson's chi-squared test. The primary objective is disease-free survival; secondary objectives are overall survival, treatment-related toxicity, and quality of life. Planned recruitment is 80 patients. Results: From December 2001 to December 2003, 30 patients were randomized to each arm. There were 22 males and 8 females in each arm. Arm A: 17 patients had stage I and 13 patients stage II disease; arm B: 18 patients had stage I and 12 stage II disease. Mean age (range) arm A was 58.1 years (44 – 77) and arm B was 56.9 (46 – 72). An interim analysis of toxicities in the treatment arm after inclusion of 40 patients (20 arm A; 20 arm B) revealed that 64% (13 of 20) experienced leucopenia grade 3 or 4; 43% (9 of 20) peripheral neurotoxicity 2 or 3; and 50% (10 of 20) experienced fatigue grade 2 or 3. Furthermore a significant decrease in patients' quality of life was noted during the 5th and 6th chemotherapy cycles. Based on this analysis, a protocol amendment reduced the total number of cycles to 4, with a further 2 cycles administered at investigators' discretion. Current relapse rates and time to progression will be reported at the meeting. Conclusions: The administration of 4 cycles of docetaxel plus cisplatin is feasible in the adjuvant setting for patients with stage I/II NSCLC. No significant financial relationships to disclose.
Abstract 12943: Malignant Melanoma Presenting as a Cardiac Tumor
Authors: Rachit Shah, Gautham Kalahasty, Patricia Nicolato, John Grizzard, J V Nixon
Journal: Circulation (2014)

Introduction:  Melanoma is a neoplasm with a high propensity to metastasize to the heart. This report describes a case of widespread malignant melanoma with unknown primary diagnosed initially via screening echocardiography (TTE) during a health fair.   Case report:  A 54 year old Caucasian male patient (pt) with a history of rheumatoid arthritis underwent a screening TTE at a local health fair. At the health fair, he was told about a concerning finding seen on the TTE and instructed to follow-up with his primary care physician. Subsequently he underwent a repeat TTE which was suggestive of a large mass in the right atrium (7.4 x 4.5 cm) protruding through tricuspid valve (TV) into right ventricle. It was also suggestive of an incidental finding of a large liver mass (6 cm) with possible additional tumor invasion into the hepatic vein and the inferior vena cava. The pt was admitted to the hospital for further evaluation of this cardiac mass. Cardiac MRI showed a large lobulated right atrial mass with heterogeneous postcontrast enhancement, causing mass effect and prolapse, with concern for invasion of the TV and extension through the right atrial wall into the pericardium. Abdominal MRI showed multiple large liver masses. Thereafter, the pt underwent a liver biopsy consistent with metastatic melanoma. One month later, he developed worsening dyspnea on exertion and bilateral lower extremity edema. Subsequently, the pt was taken to the operating room and he underwent extensive resection of the right atrial mass with atrial reconstruction. Patient showed symptomatic improvement following the surgery.   Discussion:  Malignant melanoma carries a high tendency for cardiac involvement, although cardiac metastasis as the initial presentation is a rare clinical finding.
Mechanical Forces Reshape Differentiation Cues That Guide Cardiomyogenesis
Authors: Cassandra L. Happe, Adam J. Engler
Journal: Circulation Research (2016)

Soluble morphogen gradients have long been studied in the context of heart specification and patterning. However, recent data have begun to challenge the notion that long-standing in vivo observations are driven solely by these gradients alone. Evidence from multiple biological models, from stem cells to ex vivo biophysical assays, now supports a role for mechanical forces in not only modulating cell behavior but also inducing it de novo in a process termed mechanotransduction. Structural proteins that connect the cell to its niche, for example, integrins and cadherins, and that couple to other growth factor receptors, either directly or indirectly, seem to mediate these changes, although specific mechanistic details are still being elucidated. In this review, we summarize how the wingless (Wnt), transforming growth factor-β, and bone morphogenetic protein signaling pathways affect cardiomyogenesis and then highlight the interplay between each pathway and mechanical forces. In addition, we will outline the role of integrins and cadherins during cardiac development. For each, we will describe how the interplay could change multiple processes during cardiomyogenesis, including the specification of undifferentiated cells, the establishment of heart patterns to accomplish tube and chamber formation, or the maturation of myocytes in the fully formed heart.
Abstract #DDT01-2: Development of an RNAi therapeutic targeting KSP and VEGF for the treatment of liver cancers
Authors: Iva Toudjarska, Tim Buck, Josh Brodsky, Adam Judge, K. McClintock, Tim Racie, Anke Geick, Birgit Bramlage, Pamela Tan, Philipp Hadwiger, Gang Wang, Klaus Charisse, Lloyd Jeffs, Ian McLachlan, Jared Gollob, Muthiah Manoharan, Victor Kotelianski, David Bumcrot, Dinah Sah
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Malignancies of the liver, including hepatocelluar carcinoma and metastatic tumors of different origin, represent a high unmet medical need. Current therapeutic strategies frequently comprise inhibiting more than one molecular pathway contributing to tumor growth and maintenance. We are developing ALN-VSP, an RNAi therapeutic for liver malignancies comprised of lipid particle-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5, Kif11). For each target, potent and specific siRNA duplexes have been identified following extensive screening in cell culture. Single dose screens were conducted initially; then, a subset of siRNAs was evaluated for dose-response and lead siRNAs selected based on potency in vitro . Moreover, silencing of KSP in vitro leads to cell death in multiple tumor cell lines, while silencing of VEGF leads to inhibition of VEGF secretion into cell culture medium. To achieve hepatic delivery, lipid particle formulations have been evaluated and shown to achieve silencing of hepatic gene expression with multiple siRNAs directed against distinct targets, including VEGF and KSP. To evaluate the potential of this approach for treating liver cancer, pre-clinical mouse orthotopic liver tumor model studies have been conducted with ALN-VSP. These tumor models comprised direct injection of human hepatoma cells (Hep3B) into the liver of scid/beige mice, which resulted in tumor growth as well as alpha-fetoprotein secretion. In these studies, ALN-VSP demonstrated dose-dependent mRNA suppression, mRNA cleavage consistent with an RNAi mechanism, monoaster formation consistent with KSP inhibition, inhibition of tumor growth and reduction of circulating AFP, and prolongation of survival. In addition, extension of lifespan with ALN-VSP was superior to the approved multi-kinase inhibitor, Sorafenib, in preliminary studies using this animal model. These studies indicate the potential therapeutic benefit of the RNAi therapeutic ALN-VSP targeting VEGF and KSP for the treatment of liver cancer. An IND application for ALN-VSP was submitted in 2008 and received FDA clearance in January. The Phase I clinical trial of ALN-VSP in patients will be initiated in the first half of 2009. 

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr DDT01-2.
Patterns of Outcome Following Recurrence After Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma
Authors: J. Apostolidis, J. M. Foran, P.W.M. Johnson, A. Norton, J. Amess, J. Matthews, M. Bradburn, T.A. Lister, A. Z.S. Rohatiner
Journal: Journal of Clinical Oncology (1999)

To assess the patterns of recurrence, management, and survival following recurrence after myeloablative therapy with autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma (FL).Between June 1985 and October 1995, 99 patients with FL received cyclophosphamide and total-body irradiation with ABMT as consolidation of second or subsequent remission.Median length of follow-up was 5 1/2 years, and 33 patients developed recurrent lymphoma a median of 14 months after ABMT. In 26 patients, the recurrence was overt; in seven, it was detected on surveillance investigation. Twenty-six patients presented with recurrence at previous sites of disease. Twenty-two patients (67%) had FL at the time of recurrence; in 11 (33%), there was evidence of transformation to diffuse large B-cell lymphoma. Eight patients were managed expectantly; five were alive 21 to 53 months later. Twenty-five patients have required treatment to date; eight remained alive 6 months to 10 years later, and five were in remission. The Kaplan-Meier estimate of patients alive 5 years after recurrence is 45% (95% confidence interval, 27% to 62%). In univariate and multivariate analyses, survival after recurrence and overall survival after diagnosis were similar to those of a historical control group who received conventional treatment, before the introduction of myeloablative therapy (adjusted hazard ratio [HR], 1.56, P = .3, and HR, 1.34, P = .4, respectively).The survival pattern of patients with FL following recurrence after myeloablative therapy and ABMT suggests that this treatment does not compromise outcome in patients in whom it fails, reflecting the survival pattern of the disease when treated conventionally.
Leptin and its potential interest in assisted reproduction cycles
Authors: A. Catteau, H. Caillon, P. Barrière, M.G. Denis, D. Masson, T. Fréour
Journal: Human Reproduction Update (2015)

Leptin, an adipose hormone, has been shown to control energy homeostasis and food intake, and exert many actions on female reproductive function. Consequently, this adipokine is a pivotal factor in studies conducted on animal models and humans to decipher the mechanisms behind the infertility often observed in obese women. A systematic PubMed search was conducted on all articles, published up to January 2015 and related to leptin and its actions on energy balance and reproduction, using the following key words: leptin, reproduction, infertility, IVF and controlled ovarian stimulation. The available literature was reviewed in order to provide an overview of the current knowledge on the physiological roles of leptin, its involvement in female reproductive function and its potential interest as a prognostic marker in IVF cycles. Animal and human studies show that leptin communicates nutritional status to the central nervous system and emerging evidence has demonstrated that leptin is involved in the control of reproductive functions by acting both directly on the ovaries and indirectly on the central nervous system. With respect to the clinical use of leptin as a biomarker in IVF cycles, a systematic review of the literature suggested its potential interest as a predictor of IVF outcome, as high serum and/or follicular fluid leptin concentrations have correlated negatively with cycle outcome. However, these preliminary results remain to be confirmed. Leptin regulates energy balance and female reproductive function, mainly through its action on hypothalamic-pituitary-ovarian function, whose molecular and cellular aspects are progressively being deciphered. Preliminary studies evaluating leptin as a biomarker in human IVF seem promising but need further confirmation.
An unusual case of respiratory arrest
Authors: V Chew, J Azam, S Shah
Journal: Thorax (2015)

A 38-year-old non-smoker was found by paramedics holding on to a salbutamol inhaler. Examination showed generalised reduced air entry but no wheeze. She was initially treated as having an acute exacerbation of asthma with nebulisers and intravenous steroid. On arrival at A&E, the patient deteriorated further and went into respiratory arrest. She was intubated and ventilated. A chest X-ray …
Are general internal medical (GIM) trainees confident in the use of acute non-invasive ventilation (NIV)?
Authors: Sega Pathmanthan, Rebecca Dickinson
Journal: European Respiratory Journal (2014)

Background: 

NICE[i] guidelines suggest that COPD patients requiring acute NIV should be assessed and managed by appropriately trained staff.

With the increasing number of referrals to the respiratory team to review and commence NIV acutely, we conducted a survey of GIM trainees to evaluate their training and confidence in managing acute NIV.

Methods: 

We designed a 10 question survey using a web-based survey programme (surveymonkey.com) with a computer generated link for easy access. A Likert scale (1-5) was used for confidence assessment. The link was sent to all GIM trainees (ST3 and above) within Yorkshire Deanery.

Results: 

Two hundred and fifty trainees were contacted with 94 fully completing the survey (35%) and 5 partial responses (2%).

Of the respondents, 73.6% were expected initiate patients NIV acutely. However, 29.2% of respondents have not had any formal training in acute NIV management. Confidence levels were low with 19.1% unconfident in commencing NIV, 50.6% unconfident in setting it up and 29.1% unconfident with the ongoing management.

Conclusion: 

This survey confirms that, whilst on call, most GIM trainees are expected to manage patients requiring acute NIV. However, despite current guidance, trainee confidence levels suggest that not all patients requiring acute NIV are being managed by appropriately trained medical staff. This reflects a potential gap in the training of postgraduate medical trainees.

\[i] National Institute for Health and Care Excellence (2010). [Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care\] \[CG101\]. London, National Institute of Clincal Excellence.
Thymidylate synthase (TS) gene copy number in NSCLC.
Authors: M. W. Wynes, R. Dziadziuszko, S. Singh, J. Ranger-Moore, B. Szostakiewicz, K. Dziadziuszko, J. Jassem, F. R. Hirsch
Journal: Journal of Clinical Oncology (2010)

e21063 Background: Studies suggest that high TS expression associates with poor prognosis and confers resistance to antifolates, particularly pemetrexed. TS is essential for de novo production of dTMP and for DNA synthesis. The aim of this study was to determine TS gene copy number in NSCLC, especially with regard to histology, and evaluate the prognostic impact of TS gene copy number. Methods: Using an experimental silver in situ hybridization assay (Ventana Medical Systems, Inc., Tucson, AZ), TS was evaluated on a tissue microarray containing triplicate samples from 189 patients (pts) who underwent surgery for NSCLC. Results were obtained for 124 pts (66%). This group included 83% males, 60% squamous cell carcinomas (SCC) and 25% adenocarcinomas (AC). The pathological stages were I: 39%, II: 25% and III: 30%, IV: 5% and unknown: 1%. A certified pathologist counted signals in 50 nuclei/core and determined the mean TS copies/nucleus/core. The average of the triplicate cores was compared to the highest core of same pt. The highest core was used for further analyses due to better relationship to parameters tested. Results: Median gene copy number in the population was 2.5 (1.4-9.6) while mean was 2.7 (± 1.0). Nine cases (7%) had ≥ 4 genes/nucleus and 1 had clusters. Gene copy number significantly differed (p = 0.04) by histology: AC median 2.2 (1.6-4.5) mean 2.5 (± 0.7); SCC 2.5 (1.4-9.6), 2.8 (± 1.2); NOS/other 2.9 (1.5-3.4), 2.7 (± 0.6). Using 2.5 as a cut-off, 32% of ADs, 50% of SCCs and 68%of NOS/others were positive. For TS ≥ 4, 7/9 pts were SCC and 2/9 AD. Kaplan-Meier analysis using median cut-off revealed no relationship between TS copy number and PFS (p = 0.45) or OS (p = 0.40). Similar results were obtained using adjusted Cox regression analysis and examining TS as a continuous variable; PFS (HR 0.96, p = 0.77) or OS (HR 0.94, p = 0.70). No relationship between TS and PFS (p = 0.56) or OS (p = 0.37) was found after stratification by histology (SCC vs. non-SCC). Conclusions: TS gene copy number is increased in primary tumors from NSCLC pts. Many SCC tumors had high TS gene copy number, but others did not. TS gene copy number is not associated with prognosis. Future studies should test whether TS gene copy number predicts clinical benefit from folate-targeted therapeutics, particularly pemetrexed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ventana Medical Systems Roche Ventana Medical Systems Ventana Medical Systems, Roche
Efficacy and Possible Biomarker of Gemcitabine and Erlotinib for Advanced Pancreatic Cancer
Authors: Hideaki Takahashi, Akiko Kuwahara, Hiroyuki Okuyama, Izumi Ohno, Satoshi Shimizu, Shuichi Mitsunaga, Akira Shinohara, Misaki Kobayashi, Takuji Okusaka, Masafumi Ikeda
Journal: Annals of Oncology (2014)