tbuckley/cabot-search huggingface dataset:
Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction
Authors: Elizabeth A. Magnuson, Haiyan Li, Kaijun Wang, Katherine Vilain, Ali Shafiq, Marc P. Bonaca, Deepak L. Bhatt, Marc Cohen, Philippe Gabriel Steg, Robert F. Storey, Eugene Braunwald, Marc S. Sabatine, David J. Cohen
Journal: Journal of the American College of Cardiology (2017)
What Becomes of the Brokenhearted
Authors: Mary J. Breen
Journal: JAMA Cardiology (2017)

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Breast cancer and diabetes.
Authors: Philippe Autier, Alice Koechlin, Chris Robertson, Maria Bota, Mathieu Boniol, Derek Leroith, Geremia Bolli, Julio Rosenstock, Peter Boyle
Journal: Journal of Clinical Oncology (2013)

e12507 Background: Diabetes and Breast Cancer are common conditions in women and there have been various links proposed between the two conditions. Methods: To clarify the potential association between diabetes, related factors, treatments and breast cancer risk, a series of meta-analyses were carried out following PRISMA guidelines. Results: For breast cancer at all ages, the risks obtained from prospective studies were: diabetes (SRR=1.27, 95% CI (1.16, 1.39); physical activity (SRR=0.88 (0.85, 0.92)); glycaemic load (SRR=1.05, (1.00, 1.10)); glycaemic index (SRR=1.05, (1.00, 1.09)); fasting glucose (SRR=1.14, (0.94, 1.37)); serum insulin (SRR=1.11, (0.75, 1.85)); c-peptide (SRR=1.00, (0.69, 1.46)) and adiponectin (SRR=1.16, (0.93, 1.46. An increase of 5 units in BMI was associated with post-menopausal breast cancer (SRR=1.12, 95% CI (1.08, 1.16)) but not at pre-menopausal ages (SRR=0.83, 95% CI (0.72, 0.95)). Serum insulin and c-peptide were associated with breast cancer at post-menopausal ages but not at pre-menopausal. For IGF-1, Hodge’s Standardised Mean Difference (HSMD) was calculated and there was no significant association with breast cancer (HSMD=0.026, 95% CI (-0.031, 0.084). The SRR for breast cancer among users of insulin glargine was 1.08 (0.98, 1.20) and was 0.92 (0.32, 2.65) when restricted to randomized trials. Among new users, the SRR for breast cancer was 1.09 (0.98, 1.21) and there was no trend of increasing breast cancer risk with increasing duration of use of glargine (β=0.04)(p=0.52). Risk of breast cancer in a prospective cohort declined with increasing follow-up, from 1.99 (1.31, 2.03) with two years of follow-up, to 1.60 (1.10, 2.32) with 3 years, 1.50 (1.10, 2.10) with four years and 1.18 (0.84, 1.66) with five years of follow-up. There is no reduction in risk of breast cancer associated with metformin use (SRR=0.96, 95% CI (0.85, 1.08)) even for the longest duration of use (SRR=0.94, 95% CI (0.81, 1.09)). Conclusions: An association between these two common diseases could have important implications for public health with common risk factors driving further increases in both diseases yet holding the tantalizing possibility for prevention of both. Overweight/Obesity and Physcal activity appear to be common links with the two diseases.
Poly-ICLC as an adjuvant for NY-ESO-1 protein vaccination with or without Montanide ISA-51 VG in patients with melanoma.
Authors: Rachel Lubong Sabado, Anna C. Pavlick, Sacha Gnjatic, Farah Hasan, Meredith Spadaccia, Bike Su Oner, Hanqing Dong, Rose Marie Holman, Isabelita Vengco, Caroline Muren, Crystal Escano, Ethel Yepes, Claire Stein, Achim A Jungbluth, Linda S. Pan, Ralph Rudolph Venhaus, Andres M. Salazar, Patrick Alexander Ott, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2015)

e14034 Background: Poly-ICLC (Hiltonol, Oncovir Inc) is a synthetic dsRNA complex which directly activates DCs and also triggers NK cells to kill tumor cells. Compared to LPS and R848, Poly-ICLC is the most potent TLR adjuvant due to its induction of cytokines such as IL-12 in the absence of IL-10, and maintenance of high levels of CD80 and CD86 in DCs. This study evaluated the therapeutic potential of TLR3 activation by adding Poly-ICLC to an NY-ESO-1 protein vaccine with and without Montanide in surgically resected stage IIB-IV melanoma patients. Methods: In Phase I of the study, patients received subcutaneous injections of 100μg NY-ESO-1 protein and 1.1mL Montanide emulsified in escalating doses of Poly-ICLC: 0.35mg (cohort 1; N = 3), 0.70mg (cohort 2; N = 3), or 1.4mg (cohort 3; N = 3). Vaccinations were repeated every 3 weeks for a total of 4 cycles. In Phase II of the study, patients were randomized to subcutaneous vaccination of 100μg NY-ESO-1 protein with 1.4 mg Poly-ICLC, the dose established in the Phase I of the study, (Arm A; N = 12) or with 100μg NY-ESO-1 protein, 1.4mg Poly-ICLC and 1.1ml Montanide (Arm B; N = 12). Vaccinations were repeated every 3 weeks for a total of 4 cycles. Blood samples were collected at baseline, one week after each cycle of vaccination, and at follow-up visit for the assessment of NY-ESO-1-specific humoral and cellular immune responses. Results: The vaccine combination was generally well tolerated, with no grade 3 or 4 adverse events or study-related deaths. Most patients experienced mild grade 1 or 2 (CTCAE criteria v4) adverse reactions. The most common reactions were influenza-like symptoms and injection site reactions. Five patients did not complete the study due to disease recurrence or personal choice (unrelated medical issue). Analysis of T cell responses shows induction of NY-ESO-1-specific humoral and cellular immune responses. Conclusions: This study demonstrates the safety and immunogenicity of Poly-ICLC as an adjuvant for NY-ESO-1 protein vaccination. Clinical trial information: NCT01079741.
Phase I/II dose-escalation and expansion study of afuresertib + carboplatin and paclitaxel in recurrent ovarian cancer.
Authors: Sarah Patricia Blagden, Hani Gabra, Anne L. Hamilton, Shirley S. Wong, Agnieszka Michael, Linda R. Mileshkin, Marcia Hall, Jeffrey Goh, Alla Sergeevua Lisyanskaya, Michelle DeSilvio, Dany Habr, Shelby Gainer, Prashanth Gopalakrishna, Tarek Meniawy
Journal: Journal of Clinical Oncology (2016)

2551 Background: Patients (pts) with ovarian cancer (OC) often develop resistance to standard medical treatment (Rx) with platinum-taxane chemotherapy. Preclinical studies have shown that intra-nuclear activation of AKT by DNA-dependent protein kinase inhibits cisplatin-mediated DNA damage in OC cell lines, which is reversible through AKT inhibition. The following study investigates whether the oral pan-AKT inhibitor afuresertib can restore sensitivity to platinum Rx and reverse acquired resistance to standard Rx in recurrent OC. Methods: In phase I, the maximum tolerated dose (MTD) was investigated; pts with recurrent OC were treated with afuresertib (orally qd) at doses escalating from 50 to 150 mg combined with paclitaxel (IV 175 mg/m2) and carboplatin (AUC 5) q3w for ≤ 6 cycles followed by afuresertib maintenance until progression/toxicity. Phase II investigated efficacy and safety of afuresertib at MTD plus paclitaxel and carboplatin followed by afuresertib maintenance. Pts were split into two cohorts: platinum resistant (PTR) or platinum refractory pts. Results: Phase I enrolled 29 pts; dose-limiting toxicities (DLTs) were reported in 1 pt from the 125 mg cohort (G3 rash [n = 1]) and 2 pts from the 150 mg cohort (G3 rash in both pts with concurrent G2 febrile neutropenia and G2 lip swelling in 1 pt). The MTD of afuresertib was established as 125 mg. Phase II enrolled 30 heavily pre-treated pts (median time since diagnosis = 2.1 y; median prior Rx lines = 3); 28 were PTR and 2 were platinum refractory. Tolerability of Rx was consistent with findings in phase I; G3/4 AEs included diarrhea (20%), fatigue (10%), rash (10%), vomiting (7%), and nausea (3%). Overall response rate (ORR) per RECIST v1.1 for pts in the platinum-resistant cohort was 32.1% (95% CI: 15.9–52.4) and median PFS was 7.1 months (95% CI: 6.3–9.0). ORR per GCIG CA125 in evaluable pts was 52.0% (n = 25; 95% CI: 31.3–72.2). Ad hoc analyses showed ORR to correlate with duration of sensitivity to prior platinum Rx and platinum-free intervals. Conclusions: An MTD of 125 mg afuresertib was established for the Rx of pts in combination with paclitaxel and carboplatin. Combination Rx was well tolerated and showed promising activity in pts with PTR OC. Clinical trial information: NCT01653912.
Charlie Gard’s parents end legal fight to keep son alive
Authors: Abi Rimmer
Journal: BMJ (2017)

The parents of Charlie Gard have decided to end their legal fight over the treatment of their terminally ill baby son.

Charlie’s parents, Connie Yates and Chris Gard, have been fighting for the right to remove Charlie, who has infantile onset encephalomyopathic mitochondrial DNA depletion syndrome, from the care of Great Ormond Street Hospital for Children to take him to the United States for experimental treatment. But their barrister, Grant Armstrong, announced in court on 24 July that they wished to withdraw from legal proceedings.

In June, Charlie’s parents lost their appeal to the European Court of Human Rights to overturn a previous decision made by the High Court in April allowing Great Ormond Street Hospital to withdraw Charlie’s life support.1 The case returned to the High Court earlier this month after the hospital applied for a fresh hearing in light of claims about new evidence of a potential treatment for his condition.2

In a position statement issued at the High Court on 24 …
A phase I study of 1-methyl-D-tryptophan in combination with docetaxel in metastatic solid tumors.
Authors: Erica Jackson, Susan E. Minton, Roohi Ismail-Khan, Heather Han, Anthony Neuger, Scott Antonia, Daniel Sullivan, Hatem Hussein Soliman
Journal: Journal of Clinical Oncology (2012)

TPS2620 Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT), an oral inhibitor of the IDO pathway, showed favorable toxicity profile and biologic activity in prior studies. Remarkably, in prior animal models (MMTV-neu mice), 1-MT in combination with chemotherapy produced 30% greater tumor regressions. Based on this data, a phase I trial was initiated to study the synergism of 1-MT with docetaxel. The primary goal of this trial is to determine the MTD and toxicity for the combination of docetaxel and oral 1-MT. A secondary endpoint will be to determine the PK data and the overall response rate. Methods: This phase I study utilizes a 3+3 design comprised of five dose levels. Dose levels 1-4 will evaluate docetaxel 60mg/m 2 IV d1 q3wks plus 1-MT at 300mg, 600mg, 1000mg, and 2000mg PO BID d1-21 respectively. Dose level 5 is docetaxel 75mg/m2 IV d1 q3wks + 1-MT 2000mg PO BID d1-21. Eligibility for this study includes patients with measurable metastatic solid malignancy, no prior docetaxel for metastatic disease, age ≥18, life expectancy &gt;4 months, and adequate organ/marrow function. Patients will be excluded if they meet any of the following criteria: chemotherapy within the past 3 weeks, untreated brain metastases, active autoimmune disease, or GI disease causing malabsorption. In addition, any patients who have received prior immunotherapy such as ipilimumab are excluded. Treatment will continue until disease progression, unacceptable toxicity, or patient/physician discretion. Accrual to dose level 3 is complete and dose level 4 accrual is underway. The PK of 1-MT and docetaxel will also be characterized, using an HPLC assay. PK measurements for 1-MT are drawn on C1D1 after a single dose of 1-MT is given and then on C1D8 after the morning dose of 1-MT is given. (Drawn at 0,1,2,4,8,12,24, and 48 hours) Because IDO is hypothesized to cause regulatory T cell expansion, circulating Tregs will be quantified utilizing flow cytometry for CD4+CD25+ FoxP3+ cells. (NCT01191216)
Brief Report: De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases
Authors: Amandine Périer, Léa Savey, Anne‐Geneviève Marcelin, Philippe Serve, David Saadoun, Stéphane Barete
Journal: Arthritis & Rheumatology (2017)

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved in KS and other tumors, including multicentric Castleman's disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV-8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV-8 tumors induced by RTX.In this retrospective study, we investigated the clinical, virologic, and pathologic features of 5 HIV-negative male patients with HHV-8 tumors induced by RTX therapy.Patients were all immunocompromised by previous treatments, which consisted of steroids and/or immunosuppressive agents, and received RTX for insufficient response, disease progression, or transplant rejection. They developed HHV-8 tumors a median of 4 months after beginning treatment with RTX (range 3-13 months). Four patients had at least 1 risk factor for HHV-8, including a high Fitzpatrick skin phototype (of >3) (n = 3) and homosexuality (n = 1). Four patients developed KS (all 4 had skin lesions and 2 had visceral involvement), and 1 patient developed a solid primary effusion lymphoma. RTX was discontinued in all patients, and immunosuppressants were reduced when feasible. After a median follow-up of 20 months, 2 patients died. Remission of KS was complete in 1 patient and partial in 1 patient, and 1 patient had progression.Our findings indicate that patients who have a high skin phototype and are at risk of HHV-8 should be carefully screened for HHV-8 before RTX therapy. The safety of RTX, especially in nonlymphomatous disorders, should be carefully evaluated in patients at risk of HHV-8 tumors.
Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial
Authors: David A Margolis, Juan Gonzalez-Garcia, Hans-Jürgen Stellbrink, Joseph J Eron, Yazdan Yazdanpanah, Daniel Podzamczer, Thomas Lutz, Jonathan B Angel, Gary J Richmond, Bonaventura Clotet, Felix Gutierrez, Louis Sloan, Marty St Clair, Miranda Murray, Susan L Ford, Joseph Mrus, Parul Patel, Herta Crauwels, Sandy K Griffith, Kenneth C Sutton, David Dorey, Kimberly Y Smith, Peter E Williams, William R Spreen
Journal: The Lancet (2017)
Intravenous immunoglobulin as adjunct therapy for refractory pyoderma gangrenosum: systematic review of cases and case series
Authors: H. Song, N. Lahood, A. Mostaghimi
Journal: British Journal of Dermatology (2017)

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis. Treatment regimens for refractory cases are nonstandardized. Intravenous immunoglobulin (IVIG) is an emerging treatment with reported success, but the efficacy of IVIG for PG is unknown. In this systematic review of cases and case series, we assessed the efficacy of IVIG for the treatment of PG, as observed at our institution and reported in the literature. A retrospective chart review at two tertiary care hospitals between 2000 and 2015, and literature searches in PubMed/MEDLINE, EMBASE and Web of Science from all years were conducted. In total, there were 49 patients, including 43 patients from 26 articles and six institutional cases. There was complete or partial response in 43 (88%) patients and complete response in 26 (53%) patients. The mean time to initial response to treatment and treatment length were 3·5 (SD 3·3) weeks and 5·9 (SD 7·8) months, respectively. On average, 2·6 treatments had been trialled before IVIG initiation. IVIG was administered with systemic steroids in 43 (88%) cases. Mild adverse events, especially nausea and headache, were reported in 12 (24·5%) patients. Our systematic review suggests a potential role for IVIG as adjuvant therapy for refractory PG. Prospective clinical trials testing the efficacy of IVIG for refractory PG are needed to validate these findings.
Spectroscopy of blood samples for the diagnosis of endometrial cancer and classification of its different subtypes.
Authors: Maria Paraskevaidi, Camilo L. M. Morais, Olivia Raglan, Kassio M. G. Lima, Pierre L. Martin-Hirsch, Evangelos Paraskevaidis, Maria Kyrgiou, Francis L. Martin
Journal: Journal of Clinical Oncology (2017)

5596 Background: Symptoms of endometrial cancer often appear in early stages, thus a diagnosis, based on microscopic histological examination of endometrial tissue, can be given relatively on time. However, this procedure interferes subjective interpretation allowing human error, while screening of the asymptomatic population is not widely performed because of the high cost of the available tests (e.g. transvaginal ultrasound) and the relative invasiveness [biopsy or dilation and curettage (D+C)]. Consequently, there is a widespread need to develop inexpensive, non-invasive techniques that would accurately diagnose endometrial cancer, as well as classify the different subtypes. Spectrochemical methods generate a signature fingerprint of biological material in the form of spectra. Unlike immunological methods, which detect only one molecule at a time, the spectra obtained from a clinical sample represent all the molecular constituents within that sample, including proteins, lipids and carbohydrates; this provides a holistic picture of the sample. Previous studies have confirmed spectroscopy’s ability to diagnose gynecologic cancers in blood. Methods: Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy was used to analyse blood plasma and serum from 71 women with endometrial cancer and 18 age-matched healthy controls; classification algorithms were then applied to extract the underlying biological information. Results: Principal component analysis followed by support vector machine (PCA-SVM) diagnosed endometrial cancer with 100% accuracy in plasma and 95% in serum. Discrimination between the different subtypes [endometrioid adenocarcinoma (n = 43) vs carcinosarcoma (n = 14)] was achieved with 98.33% accuracy in both plasma and serum. The spectral regions responsible for discrimination were attributed to protein and lipid alterations. Conclusions: Our preliminary results suggest an accurate and objective diagnostic tool for endometrial cancer with blood testing, allowing therefore thoughts for a potential screening test in high risk populations. Future work will include higher number of normal cases and different subtypes and grades.
PRMT5 Transgenic Mice Develop Aggressive Lymphoblastic Lymphomas
Authors: Porsha L. Smith, Fengting Yan, John T. Patton, Lapo Alinari, Vrajesh Karkhanis, Leona Ayers, Natarajan Muthusamy, Anjali Mishra, Elshafa Ahmed, Said Sif, Rosa Lapalombella, Robert A Baiocchi
Journal: Blood (2016)
Basal-like Breast Cancer and the Clinical Implications of Biologic Diversity
Authors: Lisa Carey
Journal: Clinical Cancer Research (2007)

PL04-04   Basal-like breast cancer is a subtype identified by unsupervised cluster analysis of gene expression array data, and has characteristic gene and protein expression patterns, including high expression of basal cytokeratins and other genes within the basal cluster, high expression of proliferation genes, and low expression of HER2 and ER-related genes. Gene copy number aberrations and p53 mutations are common in this subtype. It has been consistently identified in multiple independent datasets, across platforms, and using both gene expression arrays and immunohistochemistry. Population-based studies suggest that between 15-20% of breast cancers are basal-like.  This breast cancer subtype has unique risk factors. Chief among these is an association with mutations in BRCA1. Although most basal-like breast cancers are sporadic, approximately 80% of breast cancers arising in women that carry germline BRCA1 mutations are basal-like. Emerging research suggests that some of the traditional risk factors for breast cancer are not relevant for the development of basal-like breast cancer while others, such as age at parity and breast feeding, may be more important or reversed in their effects on basal-like breast cancer risk.  These characteristics suggest that it is a distinct biologic entity, which has clinical implications. Basal-like breast cancer is associated with young age at diagnosis. While it can occur in any population subset, it is twice as frequent among premenopausal African-American breast cancer patients. It is associated with a poor prognosis in historical datasets. Because of its ER-, PR-, and HER2-negative qualities, it is not sensitive to the targeted agents currently used in the adjuvant setting, although subset analyses of large cooperative group metastatic trials suggest that it may be sensitive to antiangiogenesis strategies. Interestingly, this subtype is quite sensitive to cytotoxic chemotherapy. Some studies suggest that improvements in cytotoxic chemotherapy in particular benefit this subtype. High pathologic complete response (pCR) rates are seen with anthracycline- and taxane-based chemotherapy; the high risk of early relapse associated with this subtype appears to occur largely among those with residual disease. The association with BRCA1 mutations has generated interest in examining whether this subtype is particularly sensitive to DNA damaging agents or targeting dysfunctional BRCA1 DNA repair. Among the targeted agents that are in investigation for this subtype include EGFR inhibitors, src inhibitors, PARP inhibitors and VEGF inhibitors. A large CALGB neoadjuvant study will test both whether these tumors benefit from the addition of the DNA-damaging platinum drugs, but also test sensitivity to the anti-VEGF therapy. These investigations and others hold promise to exploit our greater understanding of the biology of this subtype to maximize chemotherapy effectiveness and to rationally develop targeted approaches.