tbuckley/cabot-search huggingface dataset:
Overexpression of a critical target of rapamycin, translation regulatory protein 4E-BP1, is largely restricted to locally advanced breast and prostate cancers and is lost with tumor invasiveness
Authors: Robert J. Schneider, Ksenia Kharpasheva, Silvia Formenti, Steven Braunstein, Eileen Connolly
Journal: Cancer Research (2004)

5020   We characterized the molecular and biochemical changes in the regulation of mRNA translation associated with tumor restriction to locally advanced disease or progression to metastasis. A key event involved in tumor progression, the ability of tumor cells to maintain protein synthesis, has not been investigated in restriction of tumors to locally advanced disease. We show that restriction of mRNA translation, probably resulting from hypoxia, limits tumor cell growth to local disease, and is deregulated with progression to metastatic disease. Locally advanced breast and prostate cancers are associated with remarkable overexpression of rapamycin target, translation regulatory protein 4E-BP1, which is activated by hypoxia and promotes translation of angiogenic mRNAs. With progression of breast and prostate tumors to metastasis, 4E-BP1 over-expression is largely lost. Tumor progression to invasive disease is also associated with upregulation (3-5 fold) of the translation initiation factor eIF4G. Studies used pre-treatment tumor biopsies from locally advanced breast cancers (LABC), invasive ductal and lobular breast cancers, and locally advanced or invasive prostate cancers. We determined the changes in the translational apparatus that confer adaptation of tumor cells to hypoxia and promote angiogenesis. Using immunohistochemical staining of tissue arrays and conventional sections with specific antibodies, a single key alteration of the translational apparatus was found in the mTOR/rapamycin arm of the translation pathway involving strong overexpression of the 4E-BP1 gene. 4E-BP1 was overexpressed (approximately 20 fold) compared to normal breast epithelium in 92% of LABC tumors (n=35) and 85% of locally advanced prostate tumors (n=100, up to Gleason 6). With advancement of prostate cancer to more than Gleason 7, 4E-BP1 levels declined to below that of normal matched prostate tissue (n=100). Accordingly, in invasive breast ductal carcinomas (n=40) and invasive lobular carcinomas (n=47), 4E-BP1 was only overexpressed by 3 fold in 50% of tumors and at normal levels in the remainder. The translation initiation factor eIF4G is the most limiting factor which is essential for mRNA translation, and is needed in larger amounts for efficient translation of angiogenic mRNAs such as VEGF and anti-apoptotic mRNAs such as Bcl2 which initiate translation by internal ribosome entry. eIF4G was overexpressed by more than 5 fold in 60% of LABC tumors (similar to the number that proceed to invasive disease), and greater than 80% of invasive ductal and lobular breast carcinomas. Thus, 4E-BP1 may be a tumor suppressor that participates in restricting progression to locally advanced disease, and locally advanced breast and prostate cancers may be better targets for rapamycin treatment than metastatic disease.
Men seeking counselling in a Breast Cancer Evaluation Clinic: fifteen years experience of a multidisciplinary program.
Authors: Ana Catarina Freitas, Ana Opiniao, Hugo Nunes, Ana Clara, Sandra Bento, Ana Luis, Jorge Silva, Cecilia Moura, Bruno Filipe, Sofia Fragoso, Patricia Machado, Sidonia Santos, Paula Rodrigues, Joana Parreira, Fatima Vaz
Journal: Journal of Clinical Oncology (2016)

1584 Background: Hereditary breast and ovary syndrome affects both genders. Ours is a referral group for public and private health structures: male breast cancer (BC) is a referral criteria and men from BRCA2 families are tested due to high prostate and gastric cancer risk. Since 2014 men from BRCA1families began to be tested, and other hereditary prostate cancer families (HPC) were identified. This study aims to characterize the male population counselled in 15 years of activity. Methods: Descriptive analysis of male patients (pts) counselled from January 2000 to December 2015. Mutation carriers (MC) are included in prospective surveillance programs and follow up since post-test counselling to the last visit is included. Results: From the4320 families registered (includes 323 BRCA1/2; 28 HPC; 7 Li-Fraumeni, 5 CHEK2), 362 records were reviewed. Most (236pts) belong to families with hereditary cancer (Group1: 195 BRCA2; 32 BRCA1; 3 CHEK2; 5 p53; 1 Rb1) and the others (126 pts, Group 2): 107 were self-referred or referred by their doctors after a cancer diagnosis (BC- 60% and prostate cancer (PC) - 15,5%)); 19 sought counselling because of a high-risk perception due to cancer in their family. Median age was 54 years (16-86yrs) (47,5y, 19-79y for G1 and 63,5yrs, 17-86y for G2). Pts previously diagnosed with cancer were 33 in G1 with 39 diagnoses (BC: 18; PC: 14; melanoma: 1; other: 7); and 107 pts in G2 with 129 diagnoses (BC: 77; PC: 20; gastric: 1; melanoma: 8; bladder: 1; other: 22). We identified 117 MC (100 BRCA2, 14 BRCA1, 1CHEK2, 2 p53), median age 50yrs (23-78yrs), 96 under prospective surveillance. With a median follow up (MFU) of 36,9mo (0-131,1mo) 16 new cancer cases were diagnosed in 13 pts: BC - 2; PC - 5; gastric – 3 (only 1 early); colon/rectum - 2; pancreatic - 1; kidney - 1; bladder - 1; thyroid - 1. For these 13 pts MFU is 74,4mo (1,2-131,1mo); all are alive except 2 gastric pts. Conclusions: Management of risk in mutation male carriers is complex, due to the heterogeneity of neoplasia involved and lack of evidence. Genetics Clinics need to adapt to the needs of a growing male population, either identified MC or high-risk pts posing complex questions regarding multigene testing, surveillance and progeny counselling.
Jéjunostomie percutanée endoscopique
Authors: MG Lapalus, M Courbière, G Gautier, F Pilleul, T Ponchon, J Dumortier
Journal: Endoscopy (2005)

La gastrostomie percutanée endoscopique est la méthode de choix pour l'alimentation entérale artificielle. Elle est parfois impossible à réaliser (gastrectomie) ou compliquée d'effets secondaires sévères (reflux, pneumopathie d'inhalation, …). Le but de cette étude était d'évaluer la faisabilité de la mise en place d'une jéjunostomie percutanée endoscopique, sous guidage radioscopique.
Perceptions of genetic testing among patients undergoing genetic counseling.
Authors: Katherine Clifton, Nadine M. Tung, Jill Krejdovsky, Phil Connors, Kim DeLeonardis, Kristin Sedgwick, Lindsey Stobie
Journal: Journal of Clinical Oncology (2016)

e13107 Background: The utility of genetic testing for germline mutations in high-penetrance cancer susceptibility genes is well established. However, the clinical utility of mutations in more moderate-penetrance genes is less clear. The aim of this study was to examine factors that motivate patients to choose panel testing over traditional BRCA1/2 testing and if the perception of utility is consistent between patients and genetic counselors. Methods: Adults presenting for genetic counseling at an academic center were invited to complete a survey to identify psychological, medical and social factors which influence patient decision-making. Additional variables included age, personal and family history of cancer, and previous knowledge of BRCA1/2 and panel testing. Genetic counselors completed a survey indicating how strongly they felt the individual would benefit from panel testing, rated on a scale from 1 (little benefit) to 5 (strong benefit). Results: Forty-one women completed surveys, 36 (87.8%) with a matched genetic counselor survey. The majority of participants were white (95.1%), 51-70 years old (68.3%) with a family history of cancer (95.1%). More than half (53.7%) had a personal history of cancer. Thirty-three women (80.5%) chose panel testing, while 8 (19.5%) chose BRCA1/2 testing alone. Of participants, 46.3% cited “learning more about my own cancer risk,” and 43.9% cited “providing information for my family” as the most important factor when choosing genetic testing. These findings were similar among women choosing BRCA1/2 alone and those choosing panel testing. Of the 33 patients who chose panel testing, genetic counselors felt that only 15 (45.4%) would strongly benefit from multi-gene testing (as rated ≥ 4). Conclusions: We found that patients who chose genetic testing strongly value learning more information about their own cancer risk, as well as their families’ risks, whether they opt for panel testing or BRCA1/2 testing alone. The majority of patients ultimately chose panel testing despite genetic counselors’ belief that panel testing would have limited benefit for many patients. These findings emphasize the need for further research exploring patient expectations and understanding of panel testing.
CXCR-4 activation mediates resistance to mTOR-directed therapy via regulation of VEGF expression
Authors: Colin Weekes, Manuel Hidalgo
Journal: Clinical Cancer Research (2007)

B35  An explant pancreas adenocarcinoma xenograft model was used to determine potential mediators of resistance to mTOR-directed therapy. A panel of 16 individual patient tumors where treated with temsirolimus for 28 days identifying 7 xenografts as resistant and 9 as sensitive to temsirolimus. Baseline real-time mRNA analysis of these tumors demonstrated that high levels of SDF-1α expression, not CXCR4, correlated with resistance to temsirolimus (correlation coefficient 0.586, p-value 0.017). Treatment of mTOR resistant xenograft Panc159 with the combination of CXCR4 inhibitor (AMD3465) and temsirolimus synergistically inhibited Panc159 growth kinetics compared to treatment with either single agent. This response was associated with an inhibition of p70 phosphorylation as well as cyclin D and cMyc expression. Furthermore, the activation of CXCR4 by exogenous SDF-1α converted the temsirolimus sensitive tumor Panc410 to a resistant xenograft. The inhibition of CXCR4 signal transduction by AMD3465 negated the effect of exogenous SDF-1α on Panc410 growth kinetics in the presence of temsirolimus. Exposure of the xenograft Panc410 to SDF-1α in the presence of temsirolimus specifically induced a 3 fold induction in cyclin D and cMyc expression. Next, modulation in VEGF expression was analyzed as angiogenesis has been demonstrated to be an important determinant of response to mTOR-directed therapy. Treatment of the mTOR resistant xenograft Panc159 with temsirolimus resulted in an induction of VEGF expression. The addition of AMD3465 to temsirolimus abrogated VEGF mRNA and protein expression. Conversely, induction of an mTOR resistant phenotype in Panc410 xenografts was associated with the specific induction of VEGF mRNA and protein expression. Together these data provide initial evidence that CXCR4 activation by SDF-1α is a mediator of resistance to mTOR-directed therapy via regulation of VEGF production.
8-Chloro-Adenosine Inhibits Molecular Poor-Risk Acute Myeloid Leukemia (AML) and Leukemic Stem Cells (LSC) Growth and Synergizes with the BCL-2 Inhibitor Venetoclax (ABT-199)
Authors: Ralf Buettner, Ching-Cheng Chen, Bijender Kumar, Corey Morales, Lisa S Chen, Krister Wennerberg, Ryan Thompson, Tea Pemovska, Ling Li, Bin Zhang, Claudia Kowolik, Mika Kontro, Calum Leitch, David Horne, Joycelynne Palmer, Varsha Gandhi, Guido Marcucci, Vinod Pullarkat, Steven T. Rosen
Journal: Blood (2016)
Translation from SCD Mouse to Man: Chronic Administration of Tucaresol Reduces RBC Sickling and Improves Hematological Parameters, but Does Not Impact Inflammatory Markers in SCD Model Mice
Authors: Kelly Marie Knee, Reema Jasuja, Amey Barakat, John J. Kelly, Joseph C. Nneji, Pratap Singh, Jay M. Janz
Journal: Blood (2016)
Association of aggressive resection with survival and progression-free survival in adult low-grade glioma: A systematic review and meta-analysis with numbers needed to treat.
Authors: Timothy J Brown, Daniela Annenelie Bota, Elizabeth A. Maher, Dawit Gebremichael Aregawi, Linda M. Liau, Paul D. Brown, Jan C. Buckner, Michael Weller, Martin J. Van Den Bent, Mitchel S. Berger, Michael J. Glantz
Journal: Journal of Clinical Oncology (2017)

2025 Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p &lt; 0.0001, NNT 17], 0.39 [0.29-0.51, p &lt; 0.00001, NNT 6], and 0.50 [0.35-0.70, p &lt; 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p &lt; 0.0001 NNT 7], 0.50 [0.39-0.64, p &lt; 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.
Les diverticules du colon droit sont plus fréquents en cas d'hémorragie diverticulaire... mais ne justifient pas une hémicolectomie droite de principe!
Authors: F Heluwaert, DR Capony, B Bohn, C Chevallier, J Auroux, DR Bost, DR Moulin, I Borel, V Leroy, X Roblin
Journal: Endoscopy (2006)

Il est communément admis que les diverticules du colon droit sont peu fréquents (env 15%) en europe, mais qu'ils sont plus souvent hémorragiques, ce dernier postulat conduisant parfois à proposer une hémicolectomie droite en cas d'hémorragie supposée diverticulaire. Le but de notre travail a été d'évaluer si ces 2 données étaient fondées.
Effectiveness of Supported Self-Help in Recurrent Depression: A Randomized Controlled Trial in Primary Care
Authors: Karolien E.M. Biesheuvel-Leliefeld, Sandra M.A. Dijkstra-Kersten, Digna J.F. van Schaik, Harm W.J. van Marwijk, Filip Smit, Henriette E. van der Horst, Claudi L.H. Bockting
Journal: Psychotherapy and Psychosomatics (2017)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; The burden and economic consequences of depression are high, mostly due to its recurrent nature. Due to current budget and time restraints, a preventive, low- cost, accessible minimal intervention is much needed. In this study, we evaluated the effectiveness of a supported self-help preventive cognitive therapy (S-PCT) added to treatment as usual (TAU) in primary care, compared to TAU alone. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We conducted a randomized controlled trial among 248 patients with a history of depression, currently in full or partial remission or recovery. Participants were randomized to TAU augmented with S-PCT (&lt;i&gt;n&lt;/i&gt; = 124) or TAU alone (&lt;i&gt;n&lt;/i&gt; = 124). S-PCT consisted of an 8-week self-help intervention, supported by weekly telephone guidance by a counselor. The intervention included a self-help book that could be read at home. The primary outcome was the incidence of relapse or recurrence and was assessed over the telephone by the Structured Clinical Interview for DSM-IV axis 1 disorders. Participants were observed for 12 months. Secondary outcomes were depressive symptoms, quality of life (EQ-5D and SF-12), comorbid psychopathology, and self-efficacy. These secondary outcomes were assessed by digital questionnaires. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; In the S-PCT group, 44 participants (35.5%) experienced a relapse or recurrence, compared to 62 participants (50.0%) in the TAU group (incidence rate ratio = 0.71, 95% CI 0.52-0.97; risk difference = 14, 95% CI 2-24, number needed to treat = 7). Compared to the TAU group, the S-PCT group showed a significant reduction in depressive symptoms over 12 months (mean difference -2.18; 95% CI -3.09 to -1.27) and a significant increase in quality of life (EQ-5D) (mean difference 0.04; 95% CI 0.004-0.08). S-PCT had no effect on comorbid psychopathology, self-efficacy, and quality of life based on the SF-12. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; A supported self-help preventive cognitive therapy, guided by a counselor in primary care, proved to be effective in reducing the burden of recurrent depression.
Prospective evaluation of stress in patients with newly diagnosed glioblastoma and in a close partner (TOGETHER-study).
Authors: Katrin Lisa Conen, Regula Schüpbach, Barbara Handschin, Diana Zwahlen, Martin Voss, Günter Eisele, Katharina Rentsch, Ralf Beyrau, Deborah R Vogt, Mira Katan, Michael Weller, Joachim Peter Steinbach, Viviane Hess
Journal: Journal of Clinical Oncology (2017)

e13524 Background: Diagnosis and treatment of glioblastoma (GBM), the most common and aggressive malignant brain tumor in adults, impose profound chronic distress on patients and their partners. In order to assess how distress in patients and partners affects GBM outcome, we describe in a first step the level of distress – both biological and psychological – in patients and partners before and during standard radiochemotherapy -as measured by different assessment tools. Methods: Stress, measured by salivary cortisol levels (diurnal cortisol slope (DCS), cortisol awakening response (CAR)), copeptin serum level and distress thermometer (DT), perceived stress scale (PSS), anxiety/depression (HADS) and quality of life (FACT-G) was assessed prospectively in all patients with newly diagnosed GBM and their partners at 3 participating centers. The baseline measurements (T1), reported here, were taken immediately before start of standard first-line radiochemotherapy. Further follow-up is ongoing. The TOGETHER-Study with the primary aim to describe the impact of distress and exercise behavior on progression-free survival in GBM in patients and in a close partner was closed prematurely due to poor recruitment. Results: 12 patients and 11 partners were included. Pts were newly diagnosed with histologically confirmed GBM and immediately prior to starting radiochemotherapy with temozolomide. Age of pts in years (median = 62.5, range = 34-70), partners (median = 58, range = 47-79); sex (pts = all male/ partners = all female). Conclusions: Results from our small cohort lead to the hypothesis, that shortly after diagnosis and before start of radiochemotherapy partners of GBM patients seem to be more distressed than patients themselves -as assessed by DT and CAR. Clinical trial information: NCT02129335. [Table: see text]
Impact of postmastectomy radiation therapy on locoregional recurrence for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era.
Authors: Minoru Miyashita, Takanori Ishida, Akihiko Suzuki, Hiroshi Tada, Gou Watanabe, Narumi Harada-shoji, Akiko Sato-Tadano, Hisashi Hirakawa, Masakazu Amari, Kentaro Tamaki, Hironobu Sasano, Keiichi Jingu, Noriaki Ohuchi
Journal: Journal of Clinical Oncology (2016)

1046 Background: Clinical guidelines recommend strong consideration of postmastectomy radiation therapy (PMRT) for breast cancer patients with 1 to 3 positive axillary lymph nodes. However, given modern treatment strategies, controversy remains regarding whether PMRT is necessary for these patients. Our aim was to assess the significance of PMRT in the modern era for patients (2006-2012) with 1 to 3 positive lymph nodes by using propensity score matching. Methods: We identified 391 breast cancer patients with 1 to 3 positive lymph nodes who were treated with mastectomy and axillary lymph node (ALN) dissection between 1998 and 2012. Propensity score weighting was used to minimize the influence of confounding factors between the PMRT and no-PMRT groups. Results: The median follow-up time was 6.5 years. In the modern treatment era, no significant difference in locoregional recurrence (LRR)-free survival was noted between the PMRT and no-PMRT groups (P = 0.3921). The 8-year LRR-free survival rates of the PMRT and no-PMRT groups were 97.4% and 94.9%, respectively. After matching patients by propensity scores, the PMRT group, compared to the no-PMRT group, exhibited significantly better locoregional control (P = 0.0044) in the entire cohort. The 10-year LRR-free survival rates were 97.6% and 80.3% in the PMRT and no-PMRT groups, respectively. In contrast, no significant difference in the LRR-free survival was noted between the PMRT and no-PMRT groups in the modern treatment era (P = 0.5425). The 8-year LRR-free survival rates of patients treated in the modern era were approximately the same between the groups (97.6% and 94.9% in the PMRT and no-PMRT groups, respectively). Additionally, we evaluated factors correlated with LRR in the subgroup without PMRT. Only HER2 status was significantly correlated with LRR (HR: 3.24, 95% CI: 1.21-7.99, P= 0.0213) in multivariate analysis. Conclusions: We assessed the therapeutic significance of PMRT for breast cancer patients with 1 to 3 positive lymph nodes by using propensity score matching. PMRT had minimal impact on LRR for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era.