tbuckley/cabot-search huggingface dataset:
Does the receptor expression pattern in ductal carcinoma in situ predict recurrence?
Authors: L. S. Viana, F. H. Souza, J. S. Nunes, N. C. Correia, J. V. Hohmann, S. V. Serrano
Journal: Journal of Clinical Oncology (2008)

22189 Background: Ductal carcinoma in situ (DCIS) of breast is a heterogeneous disease, and the treatment strategy is based on tumor size and pathologic features. We evaluated the value of estrogen, progesterone and Her-2/neu receptors expression in DCIS for predicting recurrence. Methods: This retrospective study included 50 patients with DCIS treated at Barretos Cancer Hospital between January 2000 and December 2002. DCIS with microinvasion was not included. Results: Fifty patients were included and the median age and tumor size was 56.5 years and 17 mm, respectively. Thirty five patients (70%) had wide excision with final margins of > or = 10 mm or a re-excision without residual DCIS and only two patients had margin < 1mm. Twenty four DCIS were comedo-type DCIS and 15 were classified as high-grade DCIS. The ER, PR, HER-2 receptors were assessed in 27 patients and we found positive expression of ER, PR, and HER-2 in 85.2%, 74.0% and 26.9%, respectively. Median follow-up was 65.3 months. Four patients developed recurrence (two were non-invasive local recurrence, one was invasive local recurrence and one patient developed bone and liver metastasis) and one patient developed contralateral invasive breast cancers. Ten ER-positive patients received tamoxifen for 5 years and 43/50 (86%) were treated with adjuvant radiotherapy (boost was reported in 14 patients). Disease-free-survival (DFS) and overall survival (OS) were similar between groups of ER-positive (with or without tamoxifen) or ER-negative receptor (p>0.05); PR-positive or PR-negative receptor (p>0.05); and HER-positive and HER- negative receptor (DFS: 51.0 versus 65.0 months, p>0.05; OS: 62.0 versus 66.0 months, respectively, p>0.05). Conclusions: Receptor expression did not predict DCIS recurrence neither clinical benefit to tamoxifen therapy in this small population of DCIS. HER-2- overexpressing DCIS was not associated with a higher risk of recurrence. No significant financial relationships to disclose.
Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens.
Authors: C K Osborne, L Kitten, C L Arteaga
Journal: Journal of Clinical Oncology (1989)

In a prior National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant study, the addition of the antiestrogen tamoxifen to chemotherapy with melphalan and fluorouracil adversely affected survival in several patient subsets, suggesting an antagonistic drug interaction. To investigate this possibility, we studied the interaction of tamoxifen and other antiestrogens with several cytotoxic drugs in cultured human breast cancer cell lines. Clinically relevant concentrations of tamoxifen and melphalan reduced colony survival of estrogen receptor (ER)-positive breast cancer cells when used alone in a colony-forming assay. However, pretreatment of cells with tamoxifen followed by exposure to melphalan resulted in antagonism, with more colonies surviving treatment with the combination than with melphalan alone. Identical effects were seen using several other triphenylethelene antiestrogens. An antagonistic interaction was observed even with a brief preincubation with tamoxifen that had no effect on cell proliferation, indicating that antagonism was not due to tamoxifen's known cell kinetic effects. Tamoxifen even antagonized melphalan cytotoxicity in ER-negative breast cancer cells and in cultured liver cells. An additive drug interaction occurred when melphalan was combined with pharmacologic concentrations of estradiol or medroxyprogesterone acetate, but antagonism was also observed with dexamethasone. Tamoxifen also antagonized the cytotoxicity of fluorouracil in these cells. However, an additive interaction occurred when the antiestrogen was combined with doxorubicin or 4-hydroxy-cyclophosphamide, an alkylating agent that is transported into the cell by a different carrier-mediated mechanism than melphalan. To avoid potential antagonism in the clinic, combinations of tamoxifen with melphalan and/or fluorouracil should be avoided.
Specialised commissioning for severe asthma: oxymoron or opportunity?
Authors: Binita Kane, Sophie Cramb, Val Hudson, Louise Fleming, Clare Murray, John D Blakey
Journal: Thorax (2015)

In the UK, almost 15% of the annual healthcare budget is set aside by the National Health Service (NHS) for specialised services . This significant resource (£14 billion last year) is directed towards a clearly defined pool of uncommon and complex conditions, and specifically supports small numbers of ‘centres of excellence’ with large catchment areas. In respiratory medicine, specialised commissioning has funded services for cystic fibrosis and pulmonary hypertension for some years. However, variations in commissioning arrangements for other complex conditions have led to variable service provision. In 2013, NHS England (NHSE) produced service specifications for an additional set of respiratory conditions, including severe asthma1 (figure 1), and these have fuelled a good deal of debate.



Figure 1 
Under specialised commissioning, patients fitting the criteria would be referred to their most geographically convenient regional specialist unit from either primary, secondary or tertiary care. The specialist units, based at an unspecified number of pre-existing centres, would act as concentrated centres of excellence located around the UK, with all other severe asthma services decommissioned in their existing form. To be commissioned as a specialist unit, centres must have access to all facilities outlined in the specification4 required to deliver full multidisciplinary team assessments over 2-day case visits and must be led by at least two consultant respiratory physicians with a special interest in severe asthma.



We all recognise asthma to be a major source of physical and psychological morbidity and of indirect and healthcare expenditure. Indeed, preventative inhaler therapy is the largest drug cost faced by the NHS. It came as little surprise to us that the recent National Review of Asthma Deaths revealed failings across the whole spectrum of asthma care,2 with this report and other publications (such as the NHS Atlas of Variation3) also highlighting disparities in outcomes …
Single-center experience with ipilimumab in patients with pretreated advanced melanoma.
Authors: Sofie Wilgenhof, Amelie Clementine Seghers, Stephanie Du Four, Danielle Lienard, Isabelle Salmon, Veronique Del Marmol, Bart Neyns
Journal: Journal of Clinical Oncology (2012)

e19026 Background: Ipilimumab (IPI) is a CTLA-4 blocking mAb with established activity in patients (pts) with advanced melanoma. Methods: Observational study on the outcome of advanced melanoma pts treated with IPI in an expanded access program (EAP) at a single-center. Results: Fifty pts initiated IPI (3 mg/kg q3wks x4, allowing for reinduction after a PFS of &gt;24 wks). Baseline characteristics: 28M/22F, m50y, Stage: 1x IV-M1a, 2x -M1b, 47x -M1c; 44 pts skin-, 2x mucosal-, and 4x unknown primary melanoma; WHO-PS 0/1/2: 17-, 25-, 8 pts; LDH &gt;ULN 33 pts; CRP &gt;ULN 29 pts; ALC&lt;1000/mm³ 15 pts; all pts were pretreated with dacarbazine and 16 pts for brain metastases. Thirty-one pts completed IPI-induction; 8/11 pts offered reinduction completed the planned 4 administrations (treatment ongoing in 1pt). Most immune-related adverse events (irAE) were generally mild/reversible; CTCAE gr3 irAE: diarrhea/colitis (3), hepatitis (1), hypophysitis (1), pancreatitis (1) and Guillain-Barré syndrome (1); no grade 4/5 irAE. BORR by mWHO-criteria: 1 CR, 3 PR and 4 SD (disease control rate [DCR]: 16%). BORR by immune-related response criteria (irRC): additional 2 PR and 3 SD (DCR: 26%). In 5/10 evaluable pts a similar or lower total tumor burden was obtained following reinduction. Two pts who experienced gr3 irAE during induction did not experience the same irAE at reinduction. After a median follow-up of 18 mths (range 7.5-19.3), 32 pts have died. Six- and 12-mths OS were 53% (95% CI 40-67) and 45% (95%CI 31-59) respectively. Disease control with IPI has been maintained in 8 pts (of which 4 received reinduction) after a median follow-up of 17 mths (range 12-17). Elevated CRP (&gt;5x the upper limit of normal [ULN]) was the only independent baseline co-variable (HR 0,10; 95% CI 0,04-0,25; p 0.001). An ALC of &lt;800/mm³ at week 7 and disease-control by irRC post-induction significantly correlated with OS. Conclusions: This single-center experience with IPI in an EAP for pts with advanced pretreated melanoma is comparable with that of prospective studies. Reinduction therapy seems important for long-term disease control in responding pts. Baseline CRP and ALC at week 7 deserve further evaluation as a prognostic and/or predictive (surrogate) markers.
Abstract 17569: T Wave Abnormality in Lead aVR and Cardiovascular Mortality - Insights Into the Forgotten Lead from NHANES-III
Authors: Peeyush Grover, Nilesh Patel, George R Marzouka, Vikas Singh, Ankit Rathod, Tushar Tuliani, Abhishek Deshmukh, Apurva O Badheka, Mauro Moscucci, Mauricio G Cohen
Journal: Circulation (2012)

Background: Lead aVR is often ignored in clinical practice. We investigated whether T wave changes in aVR are predictive of cardiovascular mortality (CM) in a cross sectional US population. Methodo...
Amplification and overexpression of the PSMB5 gene contributes to bortezomib resistance in retreatment of patients with multiple myeloma
Authors: G. Altavilla, C. Arrigo, G. Marabello, G. Galletti, M. Santarpia, M. Sauta, V. Pitini
Journal: Journal of Clinical Oncology (2009)

e19500 Background: The proteasome inhibitor Bortezomib is a novel anticancer drug that targets primarily the beta5 subunit (PSMB5) of the 26 S proteasome which has also demonstrated efficacy in re-treatment of almost half of relapsed Multiple Myeloma (MM) pts. Recent studies have identified qualitative and quantitative alterations at the level of PSMB5 subunit, which is located at 14q11, and cells that carry these alterations displayed a marked resistance to proteasome inhibition. We investigated the relevance of amplification and PSMB5 overexpression in the clinical outcome of pts with MM during retreatment with bortezomib. Methods: Between January and June 2008 pts with secretory MM on relapse were elegible for bortezomib re-treatment (1.3 or 1.0 mg/mq on days 1,4,8 and 11 of a 21 day cycle) if they had at least a partial remission to a bortezomib based on most recent treatment and a free interval of at least 6 months since the last dose. Bone marrow samples for morphologic analysis, mRNA expression levels of PSMB5, classical cytogenetics, FISH and in situ hybridization using a fluorescein-labeled probe to detect the amplification of PSMB5 gene, were obtained from 26 pts (16 male, 10 female mean age 64 years) before and during re-treatment with Bortezomib. Results: At the time of analyses all pts who received at least two cycles were evaluable. We identified 12 pts refractory to retreatment and five of these pts (3 males, 2 females, mean age 65 years) had a detectable amplification and overexpression of PSMB5 which interestingly appears rapidly following exposure to bortezomib and wanes with time off-therapy, even if it curiously reappeared rapidly after re-exposure to bortezomib. Conclusions: Amplification and overexpression of PSMB5 contributes to bortezomib resistance in clinical practice. These findings do highlight the susceptibility of proteasome units to genetic modifications under constant selective pressure which occur with continued treatment, furthermore, the drug resistance remains dormant but it rapidly revives upon re-exposure to bortezomib. No significant financial relationships to disclose.
Biomaterial‐Stabilized Soft Tissue Healing for Healing of Critical‐Sized Bone Defects: the Masquelet Technique
Authors: Magdalena Tarchala, Edward J. Harvey, Jake Barralet
Journal: Advanced Healthcare Materials (2016)

Critical‐sized bone defects present a significant burden to the medical community due to their challenging treatment. However, a successful limb‐salvaging technique, the Masquelet Technique (MT), has significantly improved the prognosis of many segmental bone defects in helping to restore form and function. Although the Masquelet Technique has proven to be clinically effective, the physiology of the healing it induces is not well understood. Multiple modifiable factors have been implicated by various surgical and research teams, but no single factor has been proven to be critical to the success of the Masquelet Technique. In this review the most recent clinical and experimental evidence that supports and helps to decipher the traditional Masquelet, as well as the modifiable factors and their effect on the success of the technique are discussed. In addition, future developments for the integration of the traditional Masquelet Technique with the use of alternative biomaterials to increase the effectiveness and expand the clinical applicability of the Masquelet Technique are reviewed.
Reactivation of Hepatitis B Virus (Hbv) in Hbv-Resolved Patients with Adult T-Cell Leukemia/Lymphoma
Authors: Haruhito Totani, Shigeru Kusumoto, Takashi Ishida, Asahi Ito, Masaki Ri, Hirokazu Komatsu, Ryuzo Ueda, Yasuhito Tanaka, Akio Niimi, Shinsuke Iida
Journal: Annals of Oncology (2014)
Cyclic Nucleotides in the Regulation of Expression of Differentiated Functions in Neuroblastoma Cells12
Authors: Kedar N. Prasad, S. K. Sahu, P. K. Sinha
Journal: JNCI Journal of the National Cancer Institute (1976)

Adenosine 3',5'-cyclic monophosphate (cAMP) may be one of the important factors in regulating the expression of many differentiated functions in neuroblastoma cells, but some of these functions can be induced by agents that do not increase the intracellular level of cAMP. An elevation of the intracellular level of guanosine 3',5'-cyclic monophosphate (cGMP) neither induced differentiation nor antagonized the effects of cAMP. Neuroblastoma cells increased the level of cAMP-binding proteins during differentiation, whereas glial cells and L-cells did not. This might have accounted in part for an increase in the intracellular level of cAMP even in the presence of high phosphodiesterase activity in neuroblastoma cells, since the protein-bound with the same proteins, but cAMP had about 10 times higher affinity than did cGMP. cAMP promoted the organization of microtubules and microfilaments necessary for the expression of differentiated phenotypes. The extension of neurites required the synthesis of new protein, but it did not need the synthesis of new RNA. cAMP induced differentiation in neuroblastoma cells by increasing the expression of some genetic information while suppressing the expression of others; e.g., the activities of neural enzymes increased, whereas the synthesis of histone and the phosphorylation of H1-histone markedly decreased in differentiated cells. A hypothesis was offered: An increase in cAMP phosphodiesterase activity as a result of mutation in the regulatory gene for phosphodiesterase in a single, or group of, dividing nerve cell(s) is the primary lesion that leads to malignancy. Based on the concept that selective cytocytoxic drugs should be used with agents that cause differentiation, a new therapeutic approach was suggested for the treatment of neuroblastoma. This involved administration of sodium butyrate followed by L-DOPA or prostaglandin E1 in the presence of cAMP phosphodiesterase inhibitor followed by the less immunosuppressive vincristine and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide.
Comparative Analysis of Autografting in Chronic Myelogenous Leukemia: Effects of Priming Regimen and Marrow or Blood Origin of Stem Cells
Authors: Catherine M. Verfaillie, Ravi Bhatia, Michael Steinbuch, Todd DeFor, Betsy Hirsch, Jeffrey S. Miller, Daniel Weisdorf, Philip B. McGlave
Journal: Blood (1998)
CHAPTER 5: Frequent and Sustained Hemodialysis
Authors: Kailash Jindal, Christopher T. Chan, Clement Deziel, David Hirsch, Steven D. Soroka, Marcello Tonelli, Bruce F. Culleton
Journal: Journal of the American Society of Nephrology (2006)

There is an emerging body of evidence which suggests that frequent hemodialysis may provide significant clinical advantages for patients with end-stage renal disease (ESRD) over conventional hemodialysis (CvHD). The aim of this chapter is to provide a rational, evidence-based approach for the
Measuring the latent reservoir in vivo
Authors: Marta Massanella, Douglas D. Richman
Journal: Journal of Clinical Investigation (2016)

Current efforts toward achieving a cure for HIV are focused on developing strategies to eliminate latently infected CD4+ T cells, which represent the major barrier to virus eradication. Sensitive, precise, and practical assays that can reliably characterize and measure this HIV reservoir and can reliably measure the impact of a candidate treatment strategy are essential. PCR-based procedures for detecting integrated HIV DNA will overestimate the size of the reservoir by detecting replication-incompetent proviruses; however, viral outgrowth assays underestimate the size of the reservoir. Here, we describe the attributes and limitations of current procedures for measuring the HIV reservoir. Characterizing their relative merits will require rigorous evaluation of their performance characteristics (sensitivity, specificity, reproducibility, etc.) and their relationship to the results of clinical studies.
Absence of the CHEK2*1100delC mutation in non-BRCA1/2 families with multiple cancer types in a high-risk clinic population of Caucasian ancestry
Authors: M. A. Gorin, M. D. Iniesta, J. A. Douglas, K. J. Milliron, S. D. Merajver
Journal: Journal of Clinical Oncology (2009)

11040 Background: Checkpoint kinase 2(CHEK2) is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. The contribution of CHEK2 mutations to familial cancer has been widely studied in breast cancer. Most notably, the CHEK2*1100delC mutation has been characterized to confer a 2-fold increased risk for breast cancer in carriers. This finding comes from studies performed on Northern and Eastern European populations. Few studies, however, have been conducted in North American. In contrast to the work done in Europe, these studies suggest a lower frequency of CHEK2*1100delC mutations in breast cancer families. The aim of this study was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2. Methods: DNA sequencing was used to genotype 115 individuals for CHEK2*1100delC. Families were characterized by the presence of several cases of breast and/or ovarian cancer and multiple members with other cancers in a single lineage. Given the broad variety of cancers associated with CHEK2 mutations and its function in DNA repair, we hypothesized that these families would be enriched for harboring the CHEK2*1100delC in the germline. Results: No CHEK2*1100delC mutations were detected in 115 individuals, including 39 women diagnosed with breast cancer at an early age, 7 women with bilateral cancer, 2 men with breast cancer and 6 women with ovarian cancer, all of whom were negative for mutations in BRCA1/2.The CHEK2 Breast Cancer Consortium previously reported a frequency of 2.3% for the CHEK2*1100delC mutation among breast cancer cases from families with at least 2 cases of breast cancer (or breast and ovarian cancer) in a first- or second-degree relationship. Based on that, we had approximately 92% power to detect at least one mutation among our study cohort. Conclusions: Our data are consistent with previous reports that suggest a lower frequency of CHEK2*1100delC mutations in North American hereditary breast cancer families without BRCA1/2 mutations and enriched for multiple cancer types. The low frequency of the CHEK2*1100delC in the North American population limits its clinical relevance as a cancer predisposing gene. No significant financial relationships to disclose.
It will take more than an existing exercise programme to prevent injury
Authors: James O'Brien, Alex Donaldson, Caroline F Finch
Journal: British Journal of Sports Medicine (2015)

<h3>Background:</h3> Ground hardness is considered one of the possible risk factors associated with rugby injuries. <h3>Objectives:</h3> To examine the contribution of ground hardness, rainfall and evapotranspiration to the incidence of injury, and to investigate seasonal injury bias throughout one full season of rugby union. <h3>Methods:</h3> A prospective epidemiological study of rugby injuries was performed on 271 players from rugby union teams involved in the premier grade rugby competition in Dunedin, New Zealand. Ground hardness was measured before each match over 20 rounds with an industrial penetrometer, and local weather information was collected through the National Institute of Weather and Atmospheric Research and the Otago Regional Council. Poisson mixed models were used to describe injury incidence as a function of ground hardness throughout the season. <h3>Results:</h3> The overall injury incidence during the season was 52 injuries per 1000 match player-hours (95% CI 42 to 65). Although injury incidence decreased gradually by round with a rate ratio of 0.98 (95% CI 0.96 to 0.99) (p = 0.036), and the hardness of match grounds decreased significantly over the season (0.16 MPa/round, 95% CI 0.12 to 0.21, p&lt;0.001), a non-significant association was demonstrated between injury incidence and ground hardness. Injury incidence was not associated with a combination of ground hardness, rainfall and evapotranspiration on the day of the match or cumulative rainfall and evapotranspiration before each match. <h3>Conclusions:</h3> Seasonal change in ground hardness and an early-season bias of injuries was demonstrated. Although the contribution of ground hardness to injury incidence was not statistically significant, match round and injury incidence were highly correlated, confirming a seasonal bias, which may confound the relationship of injury to ground condition.