tbuckley/cabot-search huggingface dataset:
Evaluation of prognostic factors in upper tract urothelial carcinoma (UTUC).
Authors: Hamid Emamekhoo, Dharmesh Gopalakrishnan, Puneet Dhillon, Haider Al taii, Paul Elson, Jesse McKenney, Cristina Magi-Galluzzi, Holly Lynn Harper, Homi Zargar, Brian I. Rini, Andrew J. Stephenson, Michael C. Gong, Amr Farouk Fergany, Georges-Pascal Haber, Steven C. Campbell, Jihad Kaouk, Ryan Kent Berglund, Robert Stein, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

372 Background: UTUC is relatively rare (5-10% of UC). Limited data on prognostic factors is available. Methods: A retrospective study of UTUC patients (pts) who had surgery (1995-2014) at Cleveland Clinic (n = 454) was conducted. Univariable (UVA) and multivariable (MVA) analysis (proportional hazards) with a stepwise selection algorithm (p = .10 and .05, as criteria for entry and retention in the model) was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: 192 pts with invasive high grade UTUC were identified; median age at resection was 72; 69% men. 72% of pts had laparoscopic and 17% open nephrouretectomy, 23% had +ve margins (including bladder/ureter cuff), 22% had multifocal tumor. Median tumor size 3.5 cm (0.2-12); 70% had tumors &lt; 5 cm; 65% pT3, 8% pT4 stage; among pts with lymph node (LN) dissection, 25% had +ve LN. All but 3 pts (2 sarcomatoid, 1 small cell) had primarily UC; 28% mixed UC histology; 40% CIS, 54% confirmed lymphovascular invasion (LVI); 10 neoadjuvant, 14 confirmed adjuvant therapy). Among 116 pts with RFS data available 59% had disease recurrence; 8% died with no known recurrence. Estimated median RFS was 13.1 months (m) (95%CI 8.6-18.6). In UVA, age, positive margins, tumor size, smoking history, pT stage, LVI, primary site impacted RFS. In MVA, margin status (p = .04), age (p = .04), pT stage (p = .05) were independently associated with RFS. Among 175 pts with OS data available, 38% died with estimated median OS 44.6 m (95%CI 24.1-107.4); median follow-up was 13.8 m (0.1-185.7) in pts alive at last follow up. In UVA, LVI, tumor size, age, pT stage, tumor location, ECOG PS impacted OS. In MVA, tumor size (p = .002), CIS (p = .004), tumor location (p = .04), LVI (p = .04) independently predicted OS. Using these factors, 3 prognostic groups were identified for each outcome (see table). Conclusions: Clinic-pathological parameters can be prognostic in UTUC; further validation is needed. [Table: see text]
Meeting report: Pre-exposure Human Immunodeficiency Virus Prophylaxis in the EU/EEA: Challenges and Opportunities, Stockholm April 2016
Authors: Teymur Noori, Anastasia Pharris
Journal: Eurosurveillance (2016)

The ECDC held an expert meeting in Stockholm on 27-28 April 2016 to discuss practical considerations for pre-exposure prophylaxis (PrEP) implementation in Europe. The meeting focused on four key areas: (i) eligibility criteria for PrEP in Europe; (ii) appropriate models of service delivery; (iii) cost-effectiveness of PrEP, and (iv) routine monitoring of people on PrEP. .
Medical Costs and Medical Markets
Authors: Joseph P. Newhouse
Journal: New England Journal of Medicine (1979)

In a recent issue of the Wall Street Journal, economist Keith Leffler wrote a provocative essay on physician manpower and national health insurance from which one can distill three principal conclusions1:"Nearly all facts about the market for physicians suggest a market closely regulated by the classic forces of economics." Secretary Califano's worries about an oversupply of physicians2 are therefore groundless: supply adjusts to demand.Past governmental interference in the medical marketplace has been responsible for high and rising costs; proposals for full-coverage national health insurance would raise costs of physician services further.The government could lower the . . .
RetroSternal — Looking Back at Thymectomy for Myasthenia Gravis
Authors: Allan H. Ropper
Journal: New England Journal of Medicine (2016)

The benefit of thymectomy in patients with myasthenia gravis was discovered 80 years ago, when Alfred Blalock removed a cystic tumor of the thymus in a young woman and witnessed a remission of her myasthenic weakness.1 Blalock’s group, in an office conversation, proposed that “it might be helpful to remove the thymus whether there was tumor or not.”2 Thymic enlargement had been associated with myasthenia even before Blalock’s report, but the reasons for remission are still not known beyond the likelihood that epitopes in thymic tissue stimulate antibodies against the neuromuscular junction. On the basis of a persuasive but anecdotal . . .
Abstract 1811: ERβ sensitizes NSCLC cells to chemotherapeutic agents by regulating DNA damage response
Authors: Igor Bado, Fotis Nikolos, Jan-Åke Gustafsson, Christoforos Thomas
Journal: Cancer Research (2016)

Abstract The expression of wild-type estrogen receptor β (ERβ1) correlates with increased survival in patients with Non-Small Cell Lung Cancer (NSCLC). However, the molecular mechanism that accounts for this association is unknown. ERβ1 was previously shown to sensitize breast cancer cells to chemotherapeutic agents. The role of the receptor in regulating sensitivity of NSCLC cells to chemotherapy, a common treatment option for advanced disease, has not been studied. Here we show that upregulation of ERβ1 decreases the survival of NSCLC cells in response to treatment with doxorubicin. This effect was observed in p53-defective but not wild-type p53-expressing cells. ERβ1 enhanced G2/M cell cycle arrest in NSCLC cells by activating the checkpoint kinase 1 (Chk1) and altering downstream signaling. The expression of the p63 target gene cyclin G2 that regulates the G2/M checkpoint was induced by ERβ1 proposing an ERβ1-p63 transcriptional cooperation. Our findings suggest the involvement of ERβ1 in the regulation of DNA damage response in NSCLC cells and support the potential predictive value of the receptor in clinical management of the disease. Citation Format: Igor Bado, Fotis Nikolos, Jan-Åke Gustafsson, Christoforos Thomas. ERβ sensitizes NSCLC cells to chemotherapeutic agents by regulating DNA damage response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1811.
Abstract LB-226: The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma
Authors: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi
Journal: Cancer Research (2016)

Abstract Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD&amp;gt;3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB. Conclusions: Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies. nCRPRSDPDRR(%)CBR(%)TB/CTB1732842976TB921333367CTB811512587.5 Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.
P271 Using age-adjusted D-dimers for ruling out PEs in an ambulatory care setting: Abstract P271 Table 1
Authors: FA Khan, K Ryanna, E Bailie, Y Vali
Journal: Thorax (2015)

<h3>Introduction</h3> Patients attending the ambulatory pulmonary embolism (PE) clinic at the Glenfield Hospital are risk stratified into low, intermediate and high risk based on the BTS scoring.<sup>1</sup> Those with a low or intermediate pre-test probability go on to have a microlatex D-dimer assay and if this is greater than 0.5 ug/mL, imaging in the form of CTPA or VQ scan is carried out. It has been suggested recently that using age adjusted D-dimers (patient’s age X 10) ug/L in patients above the age of fifty may improve the negative predictive value in ruling out a PE, whilst not affecting sensitivity.<sup>2</sup> <h3>Methods</h3> Data was collected for 2139 consecutive patients who presented to the ambulatory PE clinic between June 2010 and Dec 2014. For each of these patients, age, BTS clinical probability, D-dimer results and final diagnosis was recorded. For each patient above the age of 50, an age adjusted D-dimer was calculated by multiplying the age by 10. The patient’s actual D-dimer was then compared against the age adjusted D-dimer to determine how many scans could have been avoided, and how many PE’s may have been missed. <h3>Results</h3> Above and including the age of 50, there were 660 patients in the low risk, 242 patients in the intermediate risk and 104 in the high-risk categories. Using an age adjusted D-dimer approach would have resulted in 123 scans being rightfully avoided (84 in the low risk and 39 in the intermediate risk), but 6 PE’s would have been missed (2 in the low risk and 4 in the intermediate risk). No patients with a D-dimer of &lt;0.5 ug/mL who were discharged without any radiological investigations have returned with a missed diagnosis of PE. <h3>Conclusion</h3> The optimum D-dimer value must be chosen in the context of missed PEs versus scanning fewer people and thus avoiding unnecessary radiation and using resources more efficiently. An age-adjusted D-dimer in patients above the age of 50 would result in PEs being missed, and a conventional cut off value of 0.5 ug/mL is most appropriate for patients in an ambulatory care setting. <h3>References</h3> 1 British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. <i>Thorax</i> 2003;<b>58</b>:470–484 2 Douma RA, le Gal G, Sohne M, <i>et al</i>. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. <i>BMJ</i> 2010;<b>340</b>:c1475
Abstract 203: Single cell imaging of kinase inhibitor-induced effects in breast cancer cell lines
Authors: Caitlin Mills, David Andrews, Peter Sorger
Journal: Cancer Research (2016)

Abstract There is need for improved targeted therapies for the treatment of breast cancer. Kinase inhibitors are candidates to be used in this context. With the goal of uncovering specific vulnerabilities in differing cell lines, we treated five breast cancer cell lines representing triple negative (BT20, MDAMB231, and Hs578T), hormone receptor positive (MCF7), and Her2 amplified (SKBR3) disease and the non-malignant MCF10A line with a panel of 105 kinase inhibitors covering a broad range of targets. Cells were treated with doses between 0.1 and 10 μM for 24 hours, at which time they were stained with DRAQ5 (DNA) and TMRE (mitochondrial membrane potential). Live-cell images were acquired using a high throughput, confocal Opera microscope. Cell segmentation, based on the DRAQ5 staining, and feature extraction (intensity, morphology, and texture) were performed with Acapella software. Over 300 features were extracted for ∼1.5 million cells. Analytical methods have been applied to identify those treatments that induced significant changes to the cells. Over half of the kinase inhibitors queried had a significant effect within 24 hours in all cell lines at 10 μM. Cell cycle inhibitors had the most common effects across cell lines. Cell line specific effects were also uncovered, for example, MDAMB231 cells were the most sensitive to MAPK inhibitors. These, early time point, results have been compared with the effects of the same inhibitors on cell growth to better understand the mechanisms leading to cell line and pathway specific effects. Citation Format: Caitlin Mills, David Andrews, Peter Sorger. Single cell imaging of kinase inhibitor-induced effects in breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 203.
Outcomes of medical and surgical inpatients newly diagnosed with advanced cancers
Authors: R. L. Burkes, W. Y. Cheung
Journal: Journal of Clinical Oncology (2008)

17530 Background: The prognosis of patients (pts) with advanced cancers that are newly diagnosed during hospital admission is unclear. A better understanding of their outcomes can streamline management and facilitate referrals to specialists. Our aims were to evaluate the likelihood of hospital discharge and receipt of outpatient palliative systemic therapy (ST) in this group of pts and examine clinical factors associated with treatment. Methods: Pts who were admitted to a medical or surgical ward from 2004 to 2007 and assessed by the medical oncology inpatient consultation service for de novo stage IV lung or gastrointestinal (GI) cancers were reviewed. Logistic regression analyses were performed to determine pt demographics, disease characteristics and baseline admission laboratory investigations that predicted for subsequent assessment in an outpatient medical oncology clinic (OMOC) and treatment with ST. Results: Of the 139 eligible pts, 80 (58%) were male, 58 (42%) had lung cancer and 86 (62%) were admitted to a medical ward. The median age was 66.6 years (range 19 to 93). Dyspnea and abdominal discomfort were the most common hospital presenting complaints from lung and GI cancer pts, respectively. Median time from admission to first medical oncology consultation and median duration of hospital stay was 1.4 and 2.9 weeks, respectively. In 52 (37%) cases, pts successfully proceeded to hospital discharge. Within this cohort, median interval from discharge to OMOC assessment was 3.2 weeks. In multivariate analysis, pts with low hemoglobin and high AST levels were less likely to be seen in the OMOC for ST (OR 0.13 p=0.02 and OR 0.03 p=0.01, respectively). Other demographical features and disease parameters failed to predict for prognosis (all p>0.05). Conclusions: More than one-third of inpatients diagnosed with advanced cancers are discharged from hospital and given outpatient palliative ST, but time from discharge to first outpatient assessment is long. Conversely, close to two-thirds of inpatients never receive outpatient ST for their advanced diseases suggesting that admission to hospital at the time of initial diagnosis is a poor prognostic factor. In the subset of individuals with evidence of anemia and liver dysfunction on admission, early palliative care referral may be beneficial. No significant financial relationships to disclose.
Abstract 2115: MEK/ERK and MCL-1 inhibition synergistically reverse apoptosis resistance in colon cancer cells with BRAF(V600E)-mediated MCL-1-upregulation
Authors: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope
Journal: Cancer Research (2016)

Abstract Background. Oncogenic BRAFV600E mutations in colorectal cancer (CRC) are associated with poor prognosis and treatment resistance. BRAF mutations activate MAP kinase signaling and may confer apoptosis resistance by upregulating anti-apoptotic BCL-2/BCL-XL/MCL-1 proteins. Results. Ectopic expression of mutant BRAFV600E was shown to potently activate MEK/ ERK that mediated the phosphorylation (T163) and upregulation of MCL-1, but not BCL-2 or BCL-XL. MEK/ERK-mediated phosphorylation of MCL-1 (T163) increased its protein stability, shown by an MCL-1 phospho-mimic mutant. In human colon cancers, mutant vs wild-type BRAF was associated with increased MCL-1 expression by IHC. MEK/ERK inhibition by cobimetinib induced pro-apoptotic BIM in BRAF mutant CRC cell lines (HT-29, RKO), and suppressed phospho-MCL-1/MCL-1 proteins as did ERK siRNA. Suppression of MCL-1 by shRNA or using a small molecule MCL-1 inhibitor (A-1210477) synergistically enhanced cobimetinib-induced apoptosis (Table) that was associated with BAK/BAX activation. A-1210477 antagonized MCL-1 by disrupting its interaction with BAK and BIM proteins, shown by immunoprecipitation. Conclusion. BRAF/MEK/ERK induces upregulation of MCL-1 via phosphorylation/stabilization to confer apoptosis resistance that can be overcome by combined ERK and MCL-1 inhibition, suggesting a novel therapeutic strategy against BRAF mutant CRCs. Drug-induced apoptosis (annexin V) in CRC cell linesDrugsHT-29 % apoptosisRKO % apoptosisDMSO16.842.11A-1210477 (2.5 μM)29.5222.88Cobimetinib(5 μM)28.0421.05Combination53.2250.93 Citation Format: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope. MEK/ERK and MCL-1 inhibition synergistically reverse apoptosis resistance in colon cancer cells with BRAF(V600E)-mediated MCL-1-upregulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2115.
An open-label trial of SMK treatment of advanced metastatic cancer.
Authors: Steve Hoffman, Howard Bruckner, Giuseppe Del Priore, Daniel Gurell, Ruslan Mull, Damian Stega, Gail Goodwin, Mike Demurjian, Jeanetta Malanowska-Stega
Journal: Journal of Clinical Oncology (2013)

e22095 Background: SMK is a novel therapy that creates alteration in defenses to oxidative stress and increases free radical availability to the cancer cell. SMK is designed to penetrate the living cancer cells and introduce multiple mechanisms to kill the cell. Inducing transfer of electrons in the cancer cells allow catalyzed external free radicals to react and stress the cell. SMK is a combination of low dose agents used for non-cancer treatment. Methods: IRB approved study for metastatic cancer. No additional chemotherapy allowed. First 30 subjects meeting criteria were consented. SMK given orally and SQ, 5 days/wk, 6 weeks (1 cycle). Eligible subjects had cycles 2 and 3. Results: Average age 57.5 (30-81); 70% female; 30% Male. 90% Caucasian, 3.3% each- Asian, Hispanic, Native American. Cancer type: 43% breast, 20% lung, 10% pancreatic, 6.6% each: bile duct and prostate with bone metastasis, 3.3% each: colon, tongue, appendix and thyroid. 100% Breast cancer subjects had metastasis: 15% each: bone, lung, bone/lymph 8% each: lung, lymph, bone/brain/lung, bone/brain/spine, bone/liver, bone/brain, liver/bones/lymph. 10% treated for 1 cycle, 90% 2 -3 cycles. 13.3% maintained same ECOG rating. 76.6% had 1 pt, 6.6% had 2 pt, and 3.3% had 3 pt improvement. 13.3% had 1 pt decrease, 23.3% maintained the same, 63.3% had 1-3 pt improvement in health on EORTC (1-7) rating. 13.3% had a 1 pt decrease, 20% maintained the same, 66.7% had 1-4 pt improvement in quality of life on EORTC (1-7) rating. 56.6% gained 1-13lbs. 16.6% same weight, 26.6% lost 1-4 lbs. 73.3% had 1-8 pt. pain reduction (scale 1-10). 19.9% had minimal or moderate pain and maintained. 6.6% had minimal pain and had a 1 pt increase. 46.6% were on pain medication. 43% no longer needed pain medication after study. 100% Health and quality of life significantly improved: 16.6% show no uptake on a PT scan; 16.6% have significant reduction in quantity and/or size of the tumor; 26.8% have reduction in quantity/size of the tumor; 40% have a stable disease; 90% -Alive, median survival 257 days to date. 10% died, median survival 163 days.Total median survival 247 days (from first day of treatment). 100% had hyperpigmentation. No SMK related adverse events reported. Conclusions: SMK is a very promising treatment for metastatic cancer.
Abstract 4412: c-Myc-driven lymphomas require calcium-modulating cyclophilin ligand (CAML) for survival and proliferation
Authors: Jennifer C. Shing, Lonn D. Lindquist, Richard J. Bram
Journal: Cancer Research (2016)

Abstract Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions in a complex to mediate tail-anchored (TA) protein insertion into the ER membrane. CAML has also been implicated as a regulator of endocytic trafficking, modulator of intracellular calcium signaling, and essential factor for the survival and proliferation of specialized immune cells. To investigate the role of CAML in cell biology and cancer, we generated Eμ-Myc transgenic mice that carry a conditional deletion allele of CAML. From these mice, we derived B cell lymphoma cell lines driven by c-Myc and induced deletion of the CAML gene by treatment with tamoxifen to activate Cre-ERT2 in vitro. Homozygous loss of CAML in multiple independent B cell lymphoma lines activated apoptosis, while heterozygous deletion led to reduced cell proliferation. Apoptosis was inhibited by caspase inhibitor Q-VD-OPh or Bcl-2/xL overexpression; however, blocking apoptosis did not restore cell division. Loss of CAML did not activate the unfolded protein response, but did induce c-Jun and JNK phosphorylation. Structure-function studies indicated that lymphoma cell viability did not depend on interaction of CAML with TRC40, another component of TA protein insertion machinery. Conversely, expression of a minimal region of CAML that interacts with the TA insertion co-factor WRB was sufficient to rescue growth of CAML-deleted cells. In summary, our study demonstrates an essential pro-survival role for CAML in c-Myc-driven lymphomas. Future investigations will focus on the underlying mechanism of apoptosis in this system to advance our understanding of the biological functions of CAML, and consider CAML-dependent survival as a potential novel target for anticancer therapy. Citation Format: Jennifer C. Shing, Lonn D. Lindquist, Richard J. Bram. c-Myc-driven lymphomas require calcium-modulating cyclophilin ligand (CAML) for survival and proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4412.