tbuckley/cabot-search huggingface dataset:
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Authors: Anna Linda Zignego, Laura Gragnani, Marcella Visentini, Milvia Casato
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Reply: We thank Artemova et al. for their observations. They emphasize the interest in the reversibility of hepatitis C virus–mixed cryoglobulinemia (HCV‐MC) after direct‐acting antiviral (DAA)–based therapy, reporting their experience on 9 HCV‐MC patients, 5 with symptomatic MC (MCS) and 4 with only serum cryoglobulins. Despite virologic response, a persistence of the syndrome or serum cryoglobulins was observed in 2/5 and in 3/4 cases, respectively. Persistence of laboratory and/or clinical MC stigmata after viral eradication is not uncommon. Our study on 44 DAA‐treated MCS patients showed a progressive increase of complete clinical response rate,1 and a wider analysis including over 150 DAA‐treated MC/MCS patients confirmed these results (in preparation). The persistence of MC is not an exclusive effect of interferon‐free treatment, although it is conceivable that it is favored by the absence of immunomodulatory/ antiproliferative effects. We showed that after interferon‐based treatment for mild/moderate MCS, 43% of sustained virological response patients maintained some, generally milder stigmata and 57% of patients completely recovered.2 This suggests the importance of the evaluation of symptom improvement in addition to full disappearance. The persistence of cryoglobulins could be, in some cases, attributed to short follow‐ups and correlated with a Kupffer cell impairment in clearing immune complexes, especially in cirrhosis.3 The overcoming of pathogenetic no‐return points may represent another cause. The evolution of lymphoproliferative disorder to malignancy was suggested to play a major role in persistent MCS.4 The possibility of occult HCV infection after DAAs was also suggested,5 but no data on MC exist. Another cause of persisting symptoms is the presence of irreversible damage (e.g., neurological, axonal). Finally, a role may be played by the rebound effect of removal of previous therapies during DAA treatment, e.g., because of the fear of drug–drug interactions. In our experience, this was especially observed in cases of exacerbation (usually transient) during and after therapy. Therefore, it appears logical to maintain, when possible, previous therapies, especially in more severe cases, and to reduce them gradually as the symptoms improve or to combine antiviral and rituximab therapy. In conclusion, available data suggest that the degree of reversibility of MC is inversely correlated with the degree of lymphoproliferative disorder evolution and/or of organ damage, indicating the need to eradicate HCV infection as early as possible.
Alterations in genes regulating cell cycle and apoptosis in high-grade urothelial carcinoma.
Authors: H. Al-Ahmadie, G. Iyer, O. Lin, A. Gopalan, S. Fine, S. Tickoo, V. E. Reuter, D. F. Bajorin, M. I. Milowsky, D. B. Solit
Journal: Journal of Clinical Oncology (2011)

237 Background: Dysregulations of cell cycle and inhibition of apoptosis are crucial factors in tumorigenesis of multiple malignancies, including urothelial carcinoma (UC). Deletions of TP53 and CDKN2A and amplification of MDM2 have been observed in UC, but their exact frequency and functional consequence is less known. We sought to determine the frequency of copy number alteration (CNA) and mutations of genes that regulate cell cycle or apoptosis in a panel of 96 cases of high-grade UC (HGUC) of bladder. Methods: 96 frozen cases of HGUC were studied, including 11 bladder small cell carcinomas. DNA was isolated and analyzed for CNA by comparative genomic hybridization (CGH) using a one million oligonucleotide probe array from Agilent. The targeted genes included TP53, MDM2, CCND1, CCNE1, CDKN2A/B, E2F3 and Rb1. Traditional Sanger sequencing for mutations within TP53, Rb1, and CDKN2A was also performed. Results: The frequency of CNA and mutations are listed in the table. Overall, 54 of 96 cases (56%) showed CNA (45) or mutation (13). Deletion of CDKN2A/B and amplification of E2F3 were the most common alterations in cell cycle regulatory genes (13 cases each, 14%), followed by amplification of CCND1 (11 cases, 11%). There was no co-amplification of CCND1 and CCNE1 in any sample. Rb1 deletion was present in five cases. CNA in E2F3 and Rb1 were mutually exclusive in 14 of 16 cases (88%) and were both present in two cases only. Mutations in TP53 were noted in 13 cases and deletions in nine. Amplification of MDM2 was noted in four cases, none of which overlapped with TP53 deletions or mutations. Overexpression of E2F3 was significantly more common in small cell carcinoma (5/11) compared to conventional UC (8/85, p = 0.006). Conclusions: Regulators of cell cycle and apoptosis are amplified, deleted or mutated in more than half of cases (56%) of high-grade urothelial carcinoma. The overwhelming majority of these abnormalities are nonoverlapping. Amplification of E2F3 seems to be overrepresented in small cell carcinoma of bladder. [Table: see text] No significant financial relationships to disclose.
Repeat use of chemotherapy in metastatic breast cancer.
Authors: A. Im, A. Brufsky, J. G. Reeder, M. Q. Rosenzweig, S. Y. Jung
Journal: Journal of Clinical Oncology (2011)

1088 Background: Novel strategies for the use of chemotherapy in metastatic breast cancer (MBC) are needed. Patients are treated with sequential cytotoxic agents, using different drug classes to avoid cross resistance. Both anthracyclines and taxanes have shown activity when reused in MBC after initial use in the adjuvant setting. Our aim was to determine response with repeat use of chemotherapy during treatment for MBC. Methods: Patients were identified from a database of women with MBC from the University of Pittsburgh Cancer Institute Breast Cancer Program followed from 1999 through 2009. Subjects were women with MBC who had at least one repeat use of a drug or class of drugs during treatment for metastatic disease only. A retrospective analysis was performed to determine response rates (RR) with initial and repeat uses, time interval between initial and repeat use, and time to progression (TTP) and overall survival (OS) after repeat use. Results: Of 754 women with MBC, 103 had at least one repeat use of a chemotherapeutic agent, with 121 instances of repeat use during treatment for MBC. The most frequently reused agents were docetaxel (D), nab-paclitaxel (Abraxane [A]), vinorelbine tartrate (Navelbine [N]), gemcitabine (G), capecitabine (C), and combination docetaxel/carboplatin/trastuzumab (DCT). Overall, there was a RR of 13.3% and stable disease (SD) in 33.3% for repeat use of any chemotherapy. Median interval between first and second use was 436 days. Median TTP was 91 days, and median OS was 213 days after repeat use. There was no association between time interval and response. Conclusions: Chemotherapy resistance may be variable over time or between different metastatic deposits. Our study describes the response after repeat use of chemotherapeutic agents or class of agents during treatment for MBC, and suggests that this may be an effective strategy. RR with first use RR with repeat use SD with repeat use Median time interval (days) Median TTP after repeat use (days) OS after repeat use(days) All repeat uses (N=121) 49.2% 13.3% 33.3% 436 91 213 D (N=14) 23.5% 0 57.1% 304 135 189 G (N=10) 44.4% 10% 20% 361 52.5 165 N (N=24) 44% 4.3% 47.8% 444 72.5 340 C (N=12) 44.4% 25% 8.3% 170 77 99 A (N=6) 83.3% 33.3% 33.3% 339 107 212 A after any taxane (N=34) 52.9% 14.7% 29.4% 434 91 184 DCT (N=10) 70% 40% 30% 572.5 71 236
Immediate action of imatinib mesylate on calcium signaling in gastrointestinal stromal tumors (GIST).
Authors: E. Berglund, M. Lu, P. Akcakaya, J. Zedenius, I. Nilsson, J. Ahlen, W. Lui, C. Larsson, R. Branstrom
Journal: Journal of Clinical Oncology (2011)

e20503 Background: In the majority of gastrointestinal stromal tumors (GISTs) mutation in tyrosine kinase receptors, c-KIT or PDGFRA, is thought to be the primary event. Both of these receptors are targets of tyrosine kinase inhibitors (TKIs) like imatinib mesylate. Downstream of the receptors the cellular signaling machinery is still obscure. In many cell types, including interstitial cells of Cajal, intracellular calcium (Cai) is accepted as an essential part of cell signaling and cellular function, including apoptosis. In this study we have evaluated Cai handling using electrophysiology and cell imaging in primary gastric GISTs. Methods: GIST cell cultures were prepared from primary untreated GISTs taken directly from surgery. Samples were also taken for pathology examination, verifying GIST diagnosis, and analyzed for mutations, showing a c-KIT exon 11 mutation in all included material. Measurements of Cai by Fura-2/AM fluorescence, patch-clamp techniques and molecular biology techniques were used in this study. Results: Cai measurements traced a persistent increase in Cai after stimulation with thapsigargin and a decrease upon stimulation with high levels of K+. After a short 10 uM imatinib mesylate exposure the thapsigargin effect was completely abolished. The source of Cai is most likely an influx through the plasma membrane. Furthermore, RT-PCR and Western-blot experiments confirmed the existence of store operated calcium channels including transient receptor potential canonical type (TRPC) ion channels and its associated proteins. Conclusions: This study shows that Imatinib mesylate, the most widely used TKI, has immediate and potent action on Cai handling in primary untreated GIST cells. Cai handling in GIST is complex and is likely to involve release from intracellular stores and additional influx through TRPC channels, as monitored by patch-clamp and the expression of TRPC channels and its regulatory proteins. We propose that alterations in Cai handling can, at least partly, explain the apoptotic effect of TKIs in GISTs.
Incidental breast lesions detected on diagnostic CT scans: A 3-year prospective study.
Authors: A. R. Ismail
Journal: Journal of Clinical Oncology (2011)

69 Background: With increasing usage of diagnostic cross sectional radiology tests, patients are presenting to rapid access one-stop breast clinic with incidental breast lesions. Methods: A prospective study over a 3-year period, collecting details of all patients shown to have breast abnormalities detected by computed tomography (CT) scans done for various reasons. These patients were assessed by clinical breast examination coupled with mammography, ultrasonography and tissue biopsy if indicated. Results: An increasing trend has been seen in the total number of thoracic CT scans with 1,939 scans in 2005 and 5,215 scans in 2010 (169% increase). 26 patients were included in this study with CT scans showing incidental breast lesions in the last three years. They were all women with age range of 50-92 (median 82.5) years. The clinical indications of CT scans included evaluation of the abnormal chest radiograph (8, 31%), preoperative evaluation of non-breast malignancy (3, 11%), infectious diseases (3, 11%), weight loss (7, 27%) and miscellaneous (5, 20%). These 13 breast cancer patients constitute 1.36% of 956 breast cancers diagnosed over this three-year period. 8 out of 13 breast cancer patients in this group (62%) had metastases at the time of diagnosis. Conclusions: A significant number of breast lesions incidentally found on CT scans are shown to be breast cancers (50%). These patients need rapid access to one-stop breast clinic for full evaluation. [Table: see text]
A Prospective Study of Imatinib 400 mg vs 800 mg Frontline in High Risk Ph+ Chronic Myeloid Leukemia (CML) Patients.
Authors: Michele Baccarani, Fausto Castagnetti, Kimmo Porkka, Johan L. Nielsen, Henrik Hjorth-Hansen, Ibrahim Haznedaroglu, Arnon Nagler, Giovanna Rege-Cambrin, Giorgina Specchia, Marilina Amabile, Nicoletta Testoni, Francesca Palandri, Fabrizio Pane, Giuliana Alimena, Giovanni Martinelli, Gianantonio Rosti, Bengt Simonsson
Journal: Blood (2007)
A population-based analysis of prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.
Authors: Alan D. Smith, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2012)

163 Background: Available clinical prognostic scoring systems for advanced hepatocellular carcinoma (HCC) were developed in the era of conventional chemotherapy. In 2008, the molecularly targeted agent sorafenib became the new standard of care for advanced HCC due to its survival benefit. The utility of these prognostic models in the setting of sorafenib is unclear. Our aims were to assess for new prognostic factors in patients treated with sorafenib and compare these with known prognostic systems. Methods: All patients diagnosed with advanced HCC from 2008 to 2010 in British Columbia, Canada and treated with sorafenib at any 1 of 5 regional cancer centers were eligible. Based on the established Okuda, CLIP, Barcelona, and French staging systems, we collected baseline demographic and disease characteristics of patients prior to receipt of sorafenib. Multivariate logistic regression models were constructed to examine for associations between these clinical factors and overall survival. Results: Of 183 patients identified, 152 were evaluable: median age was 63 years, 78% were men, average number of sorafenib treatment was 5.3 cycles, and median overall survival was 9.6 months. The prevalence of hepatitis B, hepatitis C, and alcohol-related liver disease were 32%, 15%, and 11%, respectively. Univariate analyses showed that poor performance status, presence of clinical ascites, as well as elevated serum AST, GGT, ALP, bilirubin and platelet levels were each associated with worse overall survival (all p&lt;0.05). In multivariate analyses, however, none of these clinical factors continued to be independently predictive of outcome (all p&gt;0.05). Conclusions: Traditional clinical prognostic factors developed in the era of conventional chemotherapy do not appear to have the same prognostic utility in this contemporary Western cohort of advanced HCC patients treated with sorafenib. This observation underscores the need to identify molecular biomarkers that provide better prognostic information.
Long-Term Disease-Free Survival in Patients with Relapsed/Refractory Follicular Lymphoma After Autologous Stem Cell Trasplantation
Authors: Pablo A Garcia, Guillermina Remaggi, Diego A de Goycoechea, Sebastian Yantorno, Maria Marta Rivas, Ana Basquiera, Maria Virginia Prates, Soledad Molnar, Maria L Rizzi, Gustavo Jarchum, Gustavo Milone, Jorge H Milone, Gustavo Daniel Kusminsky, Miguel Arturo Pavlovsky, Juliana Martinez Rolon, Juan Garcia
Journal: Blood (2012)
Use of gene expression patterns post neoadjuvant chemotherapy to identify a role for the MAPK phosphatase DUSP4 in therapeutic resistance and a stem-like phenotype in basal-like breast cancer (BLBC).
Authors: J. M. Balko, R. S. Cook, T. W. Miller, N. E. Bhola, M. Sanders, N. M. Granja-Ingram, V. Sanchez, I. M. Meszoely, J. Salter, M. Dowsett, K. Stemke-Hale, A. M. Gonzalez-Angulo, G. B. Mills, C. L. Arteaga
Journal: Journal of Clinical Oncology (2011)

10509 Background: Neoadjuvant chemotherapy (NAC) leads to a pathological complete response in ~20% of patients with breast cancer. The remaining patients have residual disease and are more likely to develop metastasis. In post-NAC tumors, Ki67 levels, a marker of cell proliferation, have been shown to inform odds of recurrence and death. We hypothesized that post-NAC residual cancers with a high Ki67 harbor molecular alterations that are associated with drug resistance. Methods: We utilized Nanostring digital RNA quantification to measure the expression levels of 350 cancer-related genes in 49 post-NAC breast cancers. Gene expression data were tested for associations with post-NAC Ki67. The cohort was enriched for triple-negative breast cancer (24/49 tumors). The candidate gene DUSP4 was explored in in vitro models of breast cancer. Results: The post-NAC Ki67 (range 2.4 - 99%; median: 31.6%) was statistically different among the molecular subtypes of breast cancers enrolled, being highest in BLBC (p<0.0001). Gene expression signatures of KRAS activation were enriched in BLBC. Low levels of the MAPK phosphatase DUSP4 correlated with a high Ki67 in BLBCs (r=-0.54, p=8x10-4) and with Ras/MAPK pathway activation in human breast tumors and cell lines. Genome-wide studies identified preferential methylation of the DUSP4 promoter in BLBC. Among BLBC cell lines, low DUSP4 expression predicted for sensitivity to MEK inhibitors and resistance to docetaxel. Inhibition of MEK with AZD6244 or overexpression of DUSP4 in DUSP4-low BLBC cell lines improved sensitivity to docetaxel and inhibited mammosphere formation. RNAi-mediated knockdown of DUSP4 in BLBC cells enhanced ETS-1 phosphorylation, mammosphere formation, and MAPK-dependent secretion of the cancer stem cell-promoting cytokines IL6 and IL8. Conclusions: Low levels of DUSP4 correlate with high tumor cell proliferation after NAC. Downregulation of DUSP4 may underlie activation of the MAPK pathway in the absence of KRAS mutations in BLBC while conferring resistance to chemotherapy and a stem cell-like phenotype that is therapeutically targetable with MAPK inhibitors.
Estimating HIV incidence and number of undiagnosed individuals living with HIV in the European Union/European Economic Area, 2015
Authors: Anastasia Pharris, Chantal Quinten, Teymur Noori, Andrew J Amato-Gauci, Ard van Sighem
Journal: Eurosurveillance (2016)

Since 2011, human immunodeficiency virus (HIV) incidence appears unchanged in the European Union/European Economic Area with between 29,000 and 33,000 new cases reported annually up to 2015. Despite evidence that HIV diagnosis is occurring earlier post-infection, the estimated number of people living with HIV (PLHIV) who were unaware of being infected in 2015 was 122,000, or 15% of all PLHIV (n=810,000). This is concerning as such individuals cannot benefit from highly effective treatment and may unknowingly sustain transmission.
Dose-escalated radiotherapy with helical tomotherapy to spine oligometastasis from intrahepatic malignancies.
Authors: Jinsil Seong, Younsun Choi, Jun Won Kim
Journal: Journal of Clinical Oncology (2012)

325 Background: Traditional palliative radiotherapy of 30 Gy in 10 fractions to spine metastases often results in poor local control. This study evaluated the role of high dose helical tomotherapy (HT) to improve local control of spine oligometastasis from intrahepatic malignancies Methods: From 2006 to 2010, 11 hepatocellular carcinoma (HCC) patients and 3 intrahepatic cholangiocellular carcinoma patients were treated with HT for oligometastsis to spine. The gross tumor volume (GTV) was the tumor evident from MRI images fused with simulation CT images. Planning target volume (PTV) encompassed involved vertebral body or 1cm margin to GTV. The spinal cord contour represented a small area within the intradural space. To the adjacent spinal cord volume, 20 Gy dose constraint was used. Mega-voltage computed tomography (MVCT) images were used to maintain setup error within 1 mm. We assessed local control rate after HT for spine metastasis in this retrospective study. Pain response was scored by using a numerical rating scale (from 0 to 10). Results: Spine metastatic lesions were treated with median dose of 40 Gy (range 31-51 Gy) and median 5 Gy per fraction (range 3-6 Gy) to GTV and median dose of 29 Gy (range 22.5-42.5 Gy) and median 3.75 Gy per fraction( range 2.5-5 Gy) to PTV. Median biologically equivalent dose (BED, α/β=10 Gy) was 55.2 Gy (range 45.6-76.8) to GTV. Infield failure rate was 35.7% and outfield failure rate was 78.6%. Ten patients initially accompanied pain with spine metastasis (median NPIS 7.5), and all patients showed pain relief after tomotherapy. Complete relief was shown in 20% of patients and partial relief in 80 % of patients, with median NPIS reduction of 5. The patients treated with BED (α/β=10 Gy) over 56 Gy had no local failure. Median local recurrence free survival (LRFS) was 3 months. In the univariate analysis, BED (α/β=10 Gy) over 56 Gy was a prognostic factor associated with improved LRFS (p=0.008). Conclusions: HT was capable of delivering higher BED to metastatic lesions in close proximity of the spinal cord. Spine metastases from intrahepatic tumors were sensitive to high dose radiation, and BED (α/β=10Gy) higher than 56 Gy could improve local control.
The role of E-cadherin expression in response and outcome in patients with leiomyosarcoma treated with chemotherapy.
Authors: V. Ravi, J. Yang, D. M. Araujo, M. S. Park, R. S. Benjamin, W. Zhang, J. C. Trent, S. Patel
Journal: Journal of Clinical Oncology (2011)

10096 Background: Leiomyosarcoma (LMS) is a mesenchymal neoplasm showing smooth muscle differentiation commonly occurring in the uterus, blood vessels and GI tract. We have previously demonstrated mesenchymal-to-epithelial reverting transition in LMS and the correlation between tumor E-cadherin expression and improved overall survival (OS). In this study we investigate the relationship between E-cadherin expression and response to doxorubicin- and gemcitabine-based chemotherapy regimens. Methods: We analyzed the presence of E-cadherin expression in 31 LMS samples from our institutional tumor bank using reverse-phase protein lysate array and immunohistochemical staining of tissue microarray. Clinical data including demographics and treatment history were collected. Primary outcome measure was progression free survival (PFS); secondary outcome measures included response rate and overall survival (OS). Results: Twenty-six patients who received doxorubicin- or gemcitabine-based chemotherapy were identified. Sixteen (62%) patients had E-cadherin positive tumors (M:F = 4:12; median age 52), and ten (38%) patients had E-cadherin negative tumors (M:F = 2:8; median age 50). No statistically significant relationship between tumor site (uterine vs. non-uterine) and E-cadherin expression was found. Median PFS for patients treated with gemcitabine-based therapy was 14 months for the E-cadherin positive group and 9 months for the E-cadherin negative group, but no statistical significance was reached. Responses to gemcitabine-based therapy were similar between the two groups (40% partial response (PR) vs 40 % PR). Overall survival was 59 months (95% CI 55.8 – 186.0) for the E-cadherin positive group and 25 months (95% CI 23.7 – 69.9) for the E-cadherin negative group. Conclusions: E-cadherin expression in LMS correlates with improved OS but does not predict response to chemotherapy.
Later Onset Fabry Disease, Cardiac Damage Progress in Silence
Authors: Ting-Rong Hsu, Sheng-Che Hung, Fu-Pang Chang, Wen-Chung Yu, Shih-Hsien Sung, Chia-Lin Hsu, Ivan Dzhagalov, Chia-Feng Yang, Tzu-Hung Chu, Han-Jui Lee, Yung-Hsiu Lu, Sheng-Kai Chang, Hsuan-Chieh Liao, Hsiang-Yu Lin, Tsan-Chieh Liao, Pi-Chang Lee, Hsing-Yuan Li, An-Hang Yang, Hui-Chen Ho, Chuan-Chi Chiang, Ching-Yuang Lin, Robert J. Desnick, Dau-Ming Niu
Journal: Journal of the American College of Cardiology (2016)