tbuckley/cabot-search huggingface dataset:
Outcome of 123 patients (pts) with peritoneal carcinomatosis (PC)—Limited metastases from colorectal cancer (CRC) and appendiceal adenocarcinoma (ADC): The British Columbia Cancer Agency (BCCA) experience.
Authors: F. Aubin, S. Gill, C. Speers, H. F. Kennecke
Journal: Journal of Clinical Oncology (2010)

3547 Background: Pts with PC-limited metastases from CRC or appendiceal ADC are uncommon and seem to have less favourable outcomes. There is limited data to describe the efficacy of modern chemotherapy (CT) in this setting. The aim of this study is to evaluate the outcome of pts with PC-only metastases from CRC or appendiceal primaries referred to the BCCA. Methods: Pts with a diagnosis of colon (C), rectal (R), ileocecal (IC) or appendiceal (A) ADC with PC without distant metastases diagnosed between 1994 and 2007 were identified from the BCCA CRC Outcomes Unit. Data were obtained from chart review. Analysis was by log-rank comparison and Cox-regression. Results: Among 123 eligible pts, median age was 68 and median overall survival (OS) 10.2 months (mo). 55% of pts received CT. 5 pts were treated with complete surgical cytoreduction (CSC), 23 with incomplete debulking and 95 had no or only palliative surgery. In univariate analysis, age < 70 (n = 57) was associated with a longer OS (11.8 vs. 7.8 mo, p = 0.004). Appendiceal site was associated with the best prognosis (38.2 vs. 9.2 R, vs. 9.7 C vs. 8.1 mo IC, p = 0.006). CT was associated with improved OS (12.1 vs. 6.8 mo p = 0.03). No difference observed in OS between pts treated with 5FU (n = 23) and FOLFOX (n = 18) or FOLFIRI (n = 25) (16.7 vs. 11.8 vs. 11.8 mo). The addition of bevacizumab (bev) (n = 12) to CT was associated with significant improved median OS (21.4 vs. 9.3 mo, p = 0.02). CSC was associated with a trend for improved OS compared to palliative surgery/no surgery and incomplete debulking (21.4 vs. 9.8 vs. 7.8 mo, p = 0.052). By Cox regression, age, site, and bev retained independent significance. Conclusions: For pts with PC-limited metastases, age < 70 and appendiceal site were associated with a better prognosis. No benefit was associated with incomplete debulking while selected pts with CSC appeared to have longer survival. Pts treated with CT plus bev had an OS of 21.4 mo, similar to that observed with cytoreductive surgery and comparable to the expected outcome of pts with typical metastatic CRC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche
Improved clinical and cell cycle response with an mTOR inhibitor, daily oral RAD001 (everolimus) plus letrozole versus placebo plus letrozole in a randomized phase II neoadjuvant trial in ER+ breast cancer
Authors: J. Baselga, P. A. van Dam, R. Greil, H. Gardner, R. Bandaru, B. Molloy, J. Steinseifer, P. Phillips, J. M. Dixon, H. S. Rugo
Journal: Journal of Clinical Oncology (2008)

530 Background: Activation of the mTOR pathway is a key adaptive change driving endocrine resistance. RAD001, an oral mTOR inhibitor, and letrozole synergistically inhibit proliferation in breast cancer cells. Methods: 270 postmenopausal women with > T2 ER+ tumors were randomized to receive 4 mo of letrozole 2.5mg QD + RAD001 10mg QD or letrozole 2.5mg plus placebo. The primary endpoint was overall clinical response. Mandatory needle biopsies were collected immediately prior to initial treatment, and at day 15 after treatment initiation. Samples were assessed at baseline for Her2 by FISH and mutation of exons 9 and 20 of PIK3CA and exons 5–8 of TP53, and at baseline and day 15 for Ki67, phospho-Akt S473, phospho-S6, PTEN, CyclinD1, ER, PR, p53, and total Akt and S6 by immunohistochemistry. A total of 207 patients (77%) were primary marker evaluable and clinical outcome evaluable; 186 patients had an evaluable second biopsy. Results: The clinical response rate with RAD001 + letrozole was significantly superior to letrozole alone at the preplanned Alpha of 0.1 (68 vs 59%, p=0.062). This was confirmed by ultrasound (OR 58% vs 47 %, p=0.035). Pharmacodynamic changes in each treatment arm were observed. Marked downregulation in progesterone receptor and cyclin D1 were seen in response to letrozole. Phospho- S6 levels showed dramatic down-regulation only in response to RAD001. Cell cycle response, as defined by either % reduction in Ki67 at day 15 or by proportion of patients with Ki67≤2 at day 15, was also significantly higher in the RAD001 + letrozole arm (57% vs 30% for Ki67≤2 at day 15, p<0.01). The rate of grade 3/4 adverse events (Aes) was 22.6% in the RAD001 + letrozole arm vs 3.8% in the placebo + letrozole arm. Most frequent grade 3/4 Aes with RAD001 + letrozole were hyperglycemia (n=7), stomatitis (3), interstitial lung disease/pneumonitis (3) and infections (3). Conclusions: RAD001 significantly increases the efficacy of letrozole in newly diagnosed ER+ breast cancer, with regard to both clinical and cell cycle response. The increased cell cycle response rate in the RAD001 arm was found in all subsets of tumors, including PTEN-positive, PIK3CA wild-type tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis
Tumor progression in osteosarcoma (OS): Role of the chemokine receptor CXCR4 and of its ligand stromal-cell derived factor 1 (SDF-1)
Authors: E. Perissinotto, V. Fonsato, G. Cavalloni, F. Leone, S. Mitola, G. Grignani, N. Surrenti, F. Bussolino, W. Piacibello, M. Aglietta
Journal: Journal of Clinical Oncology (2004)

9021 Background. Despite intensive chemotherapy and surgery treatment, lung and bone metastases develop in about 30% of OS patients. Mechanisms for this preferential metastatic behaviour are largely unknown. The CXCR4/SDF-1 system was shown to play a role in the homing of neoplastic cells in breast cancer as well as in rabdhomyosarcoma. This hypothesis was tested in vitro and in vivo in a mouse model. Methods. Human OS cell lines MG-63, SJSA, U2-OS and HOS were studied in standard colture conditions. Cell lines were evaluated for: CXCR4 expression by FACS analysis (mAb anti-CXCR4, BD Pharmingen); SDF-1 levels in conditioned medium (antibody sandwich ELISA, R&D Systems); modulation of CXCR4 expression on OS cells by exposure to recombinant human SDF-1 (rhSDF-1). The adhesion and migration of SJSA cells were tested on a monolayer of bone marrow stromal cells in response to rhSDF-1. We evaluated lung metastasis development in mouse model (Balb-c nu/nu) with and without monoclonal antibody anti-CXCR4 (T134) treatment. Results. CXCR4 was detected in about 40% of SJSA cell lines. On the contrary SDF-1 expression was lowest in SJSA cells compared to other OS cell lines. Moreover, SDF-1 down-regulated receptor expression on CXCR4 positive cell lines from 86% positivity to 8%. A migration assay showed cell locomotion was SDF-1 dependent. SJSA cells had the highest migration in response to SDF-1. Also cell adhesion was CXCR4/SDF-1 system dependent. In vitro, neutralization of CXCR4/SDF-1 interactions significantly impairs migration and adhesion of OS cells. In vivo: lung metastasis development, after SJSA cells injection, was prevented by T134 (5 μM) administration. Conclusions. These data suggest a possible mechanism to explain and to prevent the preferential metastatic development into bone marrow and lung tissue, where SDF-1 concentration are highest, and suggest how inhibiting CXCR4/SDF-1 axis prevents dissemination of OS cells. No significant financial relationships to disclose.
Prenatal, perinatal, and childhood vitamin D exposure and their association with childhood allergic rhinitis and allergic sensitization
Authors: Supinda Bunyavanich, Sheryl L. Rifas-Shiman, Thomas A. Platts-Mills, Lisa Workman, Joanne E. Sordillo, Carlos A. Camargo, Matthew W. Gillman, Diane R. Gold, Augusto A. Litonjua
Journal: Journal of Allergy and Clinical Immunology (2016)
Opioids for chronic non-cancer pain
Journal: BMJ (2014)

PREVIEWOpioids are powerful medications with a history that includes use for pain relief and, at times, addiction. This history of therapy versus drug abuse continues to cloud their prescription today, despite reports of effective treatment for the chronic pain that certain diseases can bring. Here, Drs Antoin and Beasley review the use of opioid agents in medicine, highlight the importance of proper patient selection and education in their use, and convey how opioids can be a viable option today for successful therapy for chronic noncancer pain.
Metabolism of the Pancreatic Carcinogens N -Nitroso-bis(2-oxopropyl)amine and N -Nitroso-bis(2-hydroxypropyl)amine in the Syrian Hamster 2
Authors: Ralph Gingell, Lawrence Wallcave, Donald Nagel, Robert Kupper, Parviz Pour
Journal: JNCI Journal of the National Cancer Institute (1976)

Metabolisms of the potent pancreatic carcinogens N-nitroso-bis(2-oxopropyl)amine (BOP) and N-nitroso-bis(2-hydroxypropyl) amine (BHP) were studied in male Syrian hamsters. BHP and a new metabolite, N-nitroso-(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), were detected in the urine of hamsters administered BOP and BHP. The rates of HPOP formation from BOP and BHP were determined by the measurement of blood and urine levels at various times after each compound was administered: HPOP was formed readily from BOP, but slowly from BHP. This may explain the different organotropic spectra and carcinogenic potencies of BOP and BHP.
In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity
Authors: Stephan Halle, Kirsten Anja Keyser, Felix Rolf Stahl, Andreas Busche, Anja Marquardt, Xiang Zheng, Melanie Galla, Vigo Heissmeyer, Katrin Heller, Jasmin Boelter, Karen Wagner, Yvonne Bischoff, Rieke Martens, Asolina Braun, Kathrin Werth, Alexey Uvarovskii, Harald Kempf, Michael Meyer-Hermann, Ramon Arens, Melanie Kremer, Gerd Sutter, Martin Messerle, Reinhold Förster
Journal: Immunity (2016)

According to in vitro assays, T cells are thought to kill rapidly and efficiently, but the efficacy and dynamics of cytotoxic T lymphocyte (CTL)-mediated killing of virus-infected cells in vivo remains elusive. We used two-photon microscopy to quantify CTL-mediated killing in mice infected with herpesviruses or poxviruses. On average, one CTL killed 2–16 virus-infected cells per day as determined by real-time imaging and by mathematical modeling. In contrast, upon virus-induced MHC class I downmodulation, CTLs failed to destroy their targets. During killing, CTLs remained migratory and formed motile kinapses rather than static synapses with targets. Viruses encoding the calcium sensor GCaMP6s revealed strong heterogeneity in individual CTL functional capacity. Furthermore, the probability of death of infected cells increased for those contacted by more than two CTLs, indicative of CTL cooperation. Thus, direct visualization of CTLs during killing of virus-infected cells reveals crucial parameters of CD8+ T cell immunity.
Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T cell anergy and promotes survival in tumor-bearing mice
Authors: Stefanie Linch, Melissa J Kasiewicz, Michael McNamara, Ian Hilgart-Martiszus, Mohammad Farhad, William Redmond
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and only benefit a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to further
Abstract 16139: Differences in Endo and Epicardial Substrate of Post-Infarction Ventricular Tachycardias Identified by Magnetic Resonance-Based Signal Intensity Mapping
Authors: Pablo avila, angel Arenal, Esther Perez-David, Javier Fernandez-Portales, Veronica Crisostomo, Gerard Loughlin, Claudia Baez, Maria J Ledesma-Carbayo, Javier Bermejo, Francisco Fernandez-Aviles
Journal: Circulation (2013)

Background: a substantial number of post-infarction ventricular tachycardias (VT) are located in the epicardium. The characterization of substrate differences between endo and epicardial VT would d...
Update: Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure — United States, 2016
Authors: Titilope Oduyebo, Emily E. Petersen, Sonja A. Rasmussen, Paul S. Mead, Dana Meaney-Delman, Christina M. Renquist, Sascha R. Ellington, Marc Fischer, J. Erin Staples, Ann M. Powers, Julie Villanueva, Romeo R. Galang, Ada Dieke, Jorge L. Muñoz, Margaret A. Honein, Denise J. Jamieson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

CDC has updated its interim guidelines for U.S. health care providers caring for pregnant women during a Zika virus outbreak (1). Updated guidelines include a new recommendation to offer serologic testing to asymptomatic pregnant women (women who do not report clinical illness consistent with Zika virus disease) who have traveled to areas with ongoing Zika virus transmission. Testing can be offered 2-12 weeks after pregnant women return from travel. This update also expands guidance to women who reside in areas with ongoing Zika virus transmission, and includes recommendations for screening, testing, and management of pregnant women and recommendations for counseling women of reproductive age (15-44 years). Pregnant women who reside in areas with ongoing Zika virus transmission have an ongoing risk for infection throughout their pregnancy. For pregnant women with clinical illness consistent with Zika virus disease,* testing is recommended during the first week of illness. For asymptomatic pregnant women residing in areas with ongoing Zika virus transmission, testing is recommended at the initiation of prenatal care with follow-up testing mid-second trimester. Local health officials should determine when to implement testing of asymptomatic pregnant women based on information about levels of Zika virus transmission and laboratory capacity. Health care providers should discuss reproductive life plans, including pregnancy intention and timing, with women of reproductive age in the context of the potential risks associated with Zika virus infection.
Abstract 14994: How Low Should You Go in Secondary Prevention Treatment of LDL Cholesterol: Observational Insights from the Intermountain Heart Collaborative Study
Authors: Joseph B Muhlestein, Heidi T May, Donald L Lappé, Tami L Bair, Viet T Le, Jeffrey L Anderson
Journal: Circulation (2014)

Introduction: Epidemiologic studies have identified high LDL cholesterol levels as an independent risk factor for cardiovascular (CV) disease, and randomized trials with statin therapy have demonstrated added clinical benefit when LDL levels are reduced to at least 70 mg/dL. However, whether targeting significantly lower secondary prevention LDL levels is beneficial, or perhaps actually may be unsafe, is not known. Methods: Patients undergoing coronary angiography who were documented to have significant (≥50% stenosis) coronary artery disease (CAD), discharged on statin therapy with an LDL level &lt;100 mg/dL and had ≤3y clinical follow-up were studied. Patients were stratified, according to on-statin LDL levels, into ultra low (&lt;40 mg/dL [n=221]), very low (40-69 mg/dL [n=1,684]) and low (70-99 mg/dL [n=3,317]) categories and followed for the long-term endpoints of all-cause death, cardiac death, non-cardiac death, MI, stroke, coronary revascularization (CR) and MACE (death, MI, stroke, CR). Hazard ratios (HRs) comparing the three LDL groups were calculated by Cox regression, adjusting for 17 baseline variables. Results: A total of 5,222 patients (age = 66±12 yrs, men = 72%, hypertension = 69%, diabetes = 30%, smokers = 29%, ACS presentation = 69%) were studied. Follow-up for the ultra low, very low and low LDL categories was 6.1±4.3, 6.4±3.9 and 7.3±4.1 yrs respectively. Event rates and adjusted HRs are shown in the Table. Conclusions: In a large secondary prevention population with significant CAD on statin therapy, treating LDL cholesterol levels to &lt;70 mg/dL compared to 70-99 mg/dL was not associated with superior long-term CV outcomes. From a non-CV standpoint, LDL levels down to 40 mg/dL appeared to be safe, but ultra low LDL levels (&lt;40 mg/dL) were associated with a significantly increased risk of non-CV death. Based on this information, very aggressive secondary prevention treatment of LDL cholesterol to levels below 40 mg/dL may require further study.
Relationship of systemic immune dysregulation in advanced tumors to vascular growth factor overproduction
Authors: M. S. Block, S. N. Markovic
Journal: Journal of Clinical Oncology (2009)

e22124 Background: Therapeutic anti-cancer vaccine strategies have been effective in a broad range of preclinical tumor models, but clinical trials of vaccines in metastatic cancer patients have failed to show clinical benefit. We have previously shown that patients with stage IV melanoma have systemic immunosuppression including elevated plasma levels of immunosuppressive cytokines and impaired DTH responses to recall antigens. Patients with stage IV melanoma also have elevated circulating levels of the vascular growth factors vascular endothelial growth factor A (VEGF A) and placental growth factor (PlGF). Based on these observations, we have hypothesized that vascular growth factors such as VEGF and PlGF mediate systemic immunosuppression. Methods: FVB mice with established ANV6 transplantable breast tumors were bled, and plasma samples were assayed for VEGF, PlGF, and interleukin (IL)-10. Splenocytes taken from tumor-bearing mice were stimulated via the T cell receptor (TCR), and interferon gamma (IFN) production was measured. Splenocytes from normal mice were stimulated in the presence or absence of VEGF; IFN production was measured. Results: Compared with age- and sex-matched controls, tumor-bearing mice had elevated plasma levels of VEGF, PlGF, and the immunosuppressive cytokine IL-10 (see table ). Furthermore, splenocytes from tumor-bearing mice produced less IFN upon TCR stimulation than did splenocytes from control mice. Finally, normal mouse splenocytes produced less IFN when stimulated in the presence of VEGF than in its absence (70.2 ± 37.2 vs. 260.0 ± 130.9 pg/ml). Conclusions: We have shown that mice with advanced tumors exhibit both elevated levels of vascular growth factors and systemic immune inhibition. We have also shown that VEGF leads to impairment of immune function in normal splenocytes. Taken together, these results suggest that excess vascular growth factors may mediate immunosuppression in animals with advanced tumors, which may in turn impair anti-tumor vaccine efficacy. [Table: see text] No significant financial relationships to disclose.
The Lymphatic System in Disease Processes and Cancer Progression
Authors: Timothy P. Padera, Eelco F.J. Meijer, Lance L. Munn
Journal: Annual Review of Biomedical Engineering (2016)

Advances in our understanding of the structure and function of the lymphatic system have made it possible to identify its role in a variety of disease processes. Because it is involved not only in fluid homeostasis but also in immune cell trafficking, the lymphatic system can mediate and ultimately alter immune responses. Our rapidly increasing knowledge of the molecular control of the lymphatic system will inevitably lead to new and effective therapies for patients with lymphatic dysfunction. In this review, we discuss the molecular and physiological control of lymphatic vessel function and explore how the lymphatic system contributes to many disease processes, including cancer and lymphedema.
Predicting survival after radical cystectomy: Validation of the SPARC score.
Authors: Brian Robin Hu, Manuel S Eisenberg, Stephen A. Boorjian, Igor Frank, Leo Dalag, Kamran Movassaghi, Prabin Thapa, Gus Miranda, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2015)

326 Background: The Survival Prediction After Radical Cystectomy (SPARC) score (Eisenberg et al, J Urol 2013) incorporates clinical and pathologic features to predict cancer specific survival (CSS) for urothelial carcinoma of the bladder. Validation of this model would improve its generalizability. Methods: Using the IRB-approved bladder cancer database at the University of Southern California (USC), we identified patients who underwent radical cystectomy (RC) for urothelial carcinoma of the bladder for curative intent from 1971-2009. Clinical factors (Charlson comorbidity index, ECOG performance status, hydronephrosis, adjuvant chemotherapy, smoking status) and pathologic factors (pathologic T stage, nodal status, multifocality, and lymphovascular invasion) included in the SPARC score were obtained. Patients were excluded if there were missing variables or if they underwent neoadjuvant chemotherapy. Associations between clinicopathologic factors and CSS were evaluated using Cox proportional hazards. Calibration plots were generated comparing actuarial CSS with SPARC predicted CSS by deciles. A c-index was generated to determine accuracy of the prediction. Kaplan Meier curves estimated CSS stratified by SPARC score and were compared with the log rank test. Results: A total of 2,045 patients underwent RC and 1,123 (55%) met inclusion criteria with a median follow-up of 4.7 years (IQR 2.0-8.9 years). Of the 1,123 patients, 332 (30%) died of bladder cancer. All the clinical and pathologic variables used in the SPARC scoring model were associated with CSS except for smoking status and tumor multifocality. Calibration plots demonstrated concordance between the SPARC-predicted and actuarial CSS with a c-index of 0.75. Kaplan Meier curves demonstrated significant differences in CSS based upon SPARC score, p&lt;0.001. Conclusions: The SPARC score represents a valid instrument for predicting bladder CSS after RC. The model can be utilized to better tailor adjuvant therapy and surveillance.
Association between nucleos(t)ide analog and tumor recurrence in hepatitis B virus–related hepatocellular carcinoma after radiofrequency ablation
Authors: Teng‐Yu Lee, Jaw‐Town Lin, Yi‐Siou Zeng, Yi‐Ju Chen, Ming‐Shiang Wu, Chun‐Ying Wu
Journal: Hepatology (2015)

Radiofrequency ablation (RFA) is the best choice for curative treatment of hepatocellular carcinoma (HCC) cases not suitable for surgical intervention, but efforts should be made to reduce the risk of tumor recurrence. We aimed to investigate the association between nucleos(t)ide analog (NA) therapy for hepatitis B virus (HBV) and the risk of HCC recurrence post‐RFA. Using the Taiwan National Health Insurance Research Database between July 1, 2004 and December 31, 2012, we screened 48,807 patients with newly diagnosed HBV‐related HCC. We identified 850 patients (200 patients who used NAs for more than 90 days and 650 who never used NA post‐RFA) who received RFA as a potentially curative treatment for HCC. Patients in the NA‐treated cohort were randomly matched 1:2 with patients in the untreated cohort by age, sex, cirrhosis, and the time period between RFA and initiation of NA therapy. Finally, 133 patients were recruited in the NA‐treated group and 266 in the untreated group for analysis. Cumulative incidences of and hazard ratios (HRs) for HCC recurrence were analyzed after adjusting for competing mortality. The HCC recurrence rate of the NA‐treated group was significantly lower than that of the untreated group (2‐year recurrence rate: 41.8%; 95% confidence interval [CI]: 32.9‐50.6 vs. 54.3%; 95% CI: 48.0‐60.6; modified log‐rank test: P &lt; 0.05). In modified Cox's regression analysis, NA therapy was independently associated with a decreased risk of HCC recurrence (HR, 0.69; 95% CI: 0.50‐0.95; P &lt; 0.05). Multivariate stratified analyses verified the association of NA therapy and decreased HCC recurrence in almost all patient subgroups. Conclusion: NA therapy was associated with a decreased risk of HCC recurrence among patients with HBV‐related HCC post‐RFA. (H epatology 2016;63:1517‐1527)