tbuckley/cabot-search huggingface dataset:
Anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure.
Authors: Vivianne C. Tjan-Heijnen, Irene Van Hellemond, Ingeborg Vriens, Petronella Peer, Astrid Swinkels, Carolien H. Smorenburg, Maurice Van Der Sangen, Judith R. Kroep, Hiltje de Graaf, Aafke H. Honkoop, Frans Erdkamp, Franchette van den Berkmortel, Maaike De Boer, Wilfred de Roos, Sabine C. Linn, Alexander Imholz, Caroline Seynaeve
Journal: Journal of Clinical Oncology (2017)

523 Background: The DATA study compared 6 and 3 years of anastrozole therapy in postmenopausal women with hormone-receptor positive early breast cancer previously treated with 2-3 years tamoxifen (oral presentation SABCS 2016 #S01-03). The study included postmenopausal women, allowing those with chemotherapy-induced ovarian function failure (CIOFF). However, these may be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definite postmenopausal women and examined the influence of OFR on survival. Methods: We selected patients from the DATA study aged 45-57 years at randomization who had received (neo-)adjuvant chemotherapy. They were classified by menopausal status at randomization (definite postmenopausal before chemotherapy or by ovariectomy, versus CIOFF). The latter were monitored by estradiol measurements for OFR during anastrozole. Endpoints: Disease-free Survival (DFS), Distant Recurrence-free Survival (DRFS), and Overall Survival (OS), corrected for tumor size, nodal status, grade, and hormone-receptor status. We used the landmark method to calculate residual 5-year survival rates. Results: In total, 261 patients were definite postmenopausal and 395 had CIOFF, of whom 39 experienced OFR while 290 did not (66 were excluded from the landmark analysis because follow-up estradiol levels were lacking). When comparing the CIOFF with the definite postmenopausal women, the 5-year survival rates were not significantly different. Within the group with CIOFF, experiencing OFR was associated with a trend for worse outcome (DFS-event HR 1.33 (95% CI 0.61-2.90), P=0.48; DRFS-event HR 2.11 (95% CI 0.89-5.02), P=0.09; and OS-event HR 2.24 (95% CI 0.92-5.45), P=0.07). Patients who experienced OFR in the first year had a residual 5-year rate for DFS of 73.1% compared with 87.4% in those who did not. For DRFS these rates were 76.9% vs. 92.1%, and for OS 80.8% vs. 94.4% respectively. Conclusions: These results suggest that women with CIOFF undergoing anastrozole treatment may be at increased risk of disease recurrence if experiencing OFR despite close monitoring of estradiol levels and adjusting endocrine treatment. Clinical trial information: NCT00301457.
Standard anthracycline-based vs. docetaxel-capecitabine in early breast cancer: Results from the chemotherapy randomization (R-C) of EORTC 10041/ BIG 3-04 MINDACT phase III trial.
Authors: Fatima Cardoso, Martine J. Piccart-Gebhart, Emiel J. Rutgers, Saskia Litière, Laura Van't Veer, Giuseppe Viale, Jean-Yves Pierga, Franchette W.P.J. van den Berkmortel, Etienne Brain, Patricia Gomez, Theodora Goulioti, Susan Knox, Elisabeth Luporsi, Ulrike Nitz, Isabel T Rubio, Lisette Stork, Peter Vuylsteke, KONSTANTINOS TRYFONIDIS, Jan Bogaerts, Suzette Delaloge
Journal: Journal of Clinical Oncology (2017)

516 Background: The MINDACT trial demonstrated that 46% of breast cancer patients (pts) at high clinical (C) but low genomic (G) risk based on MammaPrint (70-gene signature), might safely forego adjuvant CT (Cardoso NEJM 2016). A second 1:1 randomization (R-C) was optional in all pts for whom CT was decided, between standard anthracycline-based regimens (AT) and experimental docetaxel 75 mg/m² IV + oral capecitabine 825 mg/m² bid x 14 days (DC), q3wks for 6 cycles after surgery. Methods: MINDACT included 6693 pts, of whom 2895 received CT. C-low/G-low pts were allocated to no CT, C-high/G-high to CT and those with discordant G/C results were randomized to use either G or C risk to decide use of CT. Primary endpoint for R-C was disease-free survival (DFS). Secondary endpoints included OS and safety. Statistical hypothesis: HR-0.76 in favour of DC. Results: A total of 1301 pts (45%), of whom 787 (61%) were C-high/G-high, 351 (27%) C-high/G-low, 137 (11%) C-low/G-high, and 26 (2%) C-low/G-low, were randomized to AT or DC. Main reason for not inclusion in R-C was CT given outside the trial. Compliance rates for R-C were 97% overall. At 5-years median follow-up, DFS was not significantly different between AT (649 pts) and DC (652 pts) [HR = 0.83 (0.60- 1.15, p = 0.263], and OS was similar in both arms (HR 0.91, 95% CI, 0.54- 1.53). For the relevant C-high/G-high group, DFS was also not different (5-years DFS 86.1 vs 88.1%; HR 0.83, 95% CI, 0.58-1.21). Of note, number of events is still small (AT: 30; DC: 27). Commonest adverse events in DC were grade 2 hand/foot syndrome (28.5% vs 3.3%), grade 2 diarrhea (13.7% vs 5.8%) and grade 1 peripheral neuropathy (27.1% vs 11.2%). Grade 2 anemia (14.2% vs 5.1%) and grade 4 neutropenia (24.6% vs 20.5%) were higher in AT. Cardiac events occurred in 9 pts overall, including 1 cardiac failure (AT), while 53 pts developed secondary cancers (AT: 32; DC: 21; leukemia: 2 in AT vs. 1 in DC). Four deaths occurred (AT:1 and DC:3) while on therapy. Conclusions: Docetaxel-capecitabine did not improve DFS or OS, compared with standard anthracycline-based CT, including for the C-high/G-high group. Safety profile of both regimens was as expected. Clinical trial information: NCT00433589.
Abstract 9979: Health-Related Quality of Life in Children With Marfan Syndrome
Authors: Jill C Handisides, Danielle Hollenbeck-Pringle, Karen Uzark, Felicia L Trachtenberg, Victoria L Pemberton, Teresa W Atz, Timothy J Bradley, Sylvia De Nobele, Georgeann K Groh, Michelle S Hamstra, Rosalind Korsin, Jami C Levine, Meghan K Mac Neal, Larry W Markham, Tonia Morrison, Kathleen Mussatto, Aaron K Olson, Mary Ella M Pierpont, Mary J Roman, Reed E Pyeritz, Elizabeth A Radojewski, Michelle Robinson, Elizabeth A Sparks, Kathryn Waitzman, Mingfen Xu, Ronald V Lacro
Journal: Circulation (2015)

Background: Marfan syndrome (MFS) is an autosomal dominant disorder that affects the heart, aorta, eyes, skeleton, lungs, and other organs. Objective: To assess quality of life (QL) in a large multicenter cohort of children with MFS. Methods: The Pediatric Quality of Life Inventory (PedsQL) was administered to 256 subjects with MFS ages 5-18 years as an ancillary study to the Pediatric Heart Network’s Marfan Trial, which compared the effects of atenolol vs. losartan on aortic root growth. PedsQL scores were compared to population norms by one-sample t-tests. Scores &gt; 1 SD below the population sample mean represent at-risk status for impaired health-related QL. The impact of treatment arm (atenolol vs. losartan), severity of clinical features, and patient-reported symptoms on QL was assessed by general linear models. Results: The subjects had a mean age of 11.8±3.9 years and were 62% male, 84% white, and 88% non-Hispanic. Mean PedsQL scores for MFS subjects were significantly lower than population norms. Overall, scores were in the impaired range for physical QL and psychosocial QL in 34% and 27% of subjects, respectively. QL across multiple domains correlated negatively with frequency of patient-reported symptoms (r=0.32-0.40, p&lt;.0001). Subjects with a reported neurodevelopmental disorder (mainly learning disability, attention deficit disorder, and/or hyperactivity) had lower mean QL scores (5.5-7.4 lower, p&lt;.04). There were no significant differences in QL scores between treatment arms. We found no significant association between QL and aortic root z-score, extent of skeletal involvement, or presence of ectopia lentis. Conclusions: Children with MFS are at risk for impaired QL. Higher number of patient-reported symptoms had the greatest negative impact on QL, rather than treatment arm or severity of cardiac, skeletal, or ocular findings. Future interventions to address patient symptoms and neurodevelopmental disorders could improve QL for children with MFS.
Electronic self reporting of symptoms may improve survival in patients with metastatic cancer
Authors: Susan Mayor
Journal: BMJ (2017)

Enabling patients with metastatic cancer to report any severe or worsening symptoms electronically using tablet computers significantly improved their overall survival more than usual care, a randomised trial has reported.1

Symptoms are common in patients being treated for advanced cancers, but previous research has shown that these are not discussed with doctors on as many as half of the times they occur. Interest in integrating electronic patient reported outcomes into routine cancer care for symptom monitoring is growing, but evidence showing clinical benefit is limited.

Researchers randomly assigned 766 patients (median age 61) …
Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis
Authors: Lauren M Byrne, Filipe B Rodrigues, Kaj Blennow, Alexandra Durr, Blair R Leavitt, Raymund A C Roos, Rachael I Scahill, Sarah J Tabrizi, Henrik Zetterberg, Douglas Langbehn, Edward J Wild
Journal: The Lancet Neurology (2017)

BackgroundBlood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.MethodsWe did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.FindingsBaseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=–0·374, p<0·0001; Stroop word reading r=–0·248, p=0·0033), total functional capacity (r=–0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.
Effect of TCHL-based therapy on immune cell content in on-treatment, neoadjuvant-treated HER2-positive breast cancer patients.
Authors: Niamh M. Keegan, Sinead Toomey, Joanna Fay, Stephen F. Madden, Bruce Moran, Malgorzata Milewska, Sudipto Das, Darran O'Connor, M. John Kennedy, Colm Power, Arnold D. Hill, Keith Egan, Ausra Teiserskiene, Elaine Kay, John Crown, Alex J Eustace, Bryan Hennessy
Journal: Journal of Clinical Oncology (2017)

583 Background: In the TCHL trial (NCT01485926) 78 women with HER2-positive breast cancer (BC) underwent neo-adjuvant treatment with either TCH (Docetaxel, Carboplatin, Trastuzumab) or TCHL (TCH + Lapatinib) therapy. Of the 78 patients, 24 consented to an optional on-treatment biopsy 20 days after 1 cycle of therapy. We analysed the impact of tumour infiltrating lymphocytes (TILs) on pathological complete response (pCR) and also determined the impact of TCH/TCHL therapy on immune cell modulation after 20 days of treatment. Methods: We assessed TIL and stromal lymphocytes (SL) counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL. RNA libraries were generated, using the Truseq mRNA library prep kit on the Neoprep platform and sequenced on the NextSeq 500. We measured the transcriptomic profile of 8 pre and on-treatment sample pairs and then used the Microenvironment Cell Populations (MCP)-counter method to measure the abundance of 10 immune cell populations (T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells and fibroblasts). Results: We found that higher baseline levels of TILs (p = 0.045) but not SL were associated with an increased likelihood of a patient achieving a pCR to TCH/L based therapy. We found in day 20 on-treatment biopsies of women that subsequently went onto have a pCR that levels of SLs but not TILs were significantly higher (p = 0.049) than in those women who did not have a pCR. Finally we found significant increases in the level of monocytes (p = 0.05) and fibroblasts (p = 0.01), but not other immune cell populations, in the day 20 on-treatment biopsies in comparison with the mutated pre-treatment biopsies. Conclusions: In our study baseline TILs but not SLs have a predictive role in the likelihood of a patient achieving a pCR. We also found that TCHL based therapy significantly altered both monocytes and fibroblasts, indicating a possible role for these immune subtypes in response to TCHL therapy.
Duration of neoadjuvant endocrine therapy and breast cancer outcomes.
Authors: Sarah Schellhorn Mougalian, Pamela R. Soulos, Donald R. Lannin, Lajos Pusztai, Cary Philip Gross, Brigid K. Killelea
Journal: Journal of Clinical Oncology (2017)

e12129 Background: Interest in the use of neoadjuvant endocrine therapy (NET) has increased over the past decade, and recent studies have demonstrated similar response rates compared to neoadjuvant chemotherapy. We examined the associations between duration of NET and type of surgery and change from clinical stage to pathologic stage. Methods: We used the National Cancer Data Base to identify women diagnosed with stage II-III, ER and/or PR positive breast cancer who received endocrine therapy from 2004-2014 and underwent surgery. We classified patients according to timing and duration of NET. We performed logistic regression to examine the impact of NET duration on likelihood of 1) receiving breast conserving surgery (BCS) versus mastectomy and 2) being downstaged. Downstaging was defined as pathologic stage lower than clinical stage and upstaging as pathologic stage higher than clinical stage. Results: In our sample of 159,676 patients, 6584 received NET (4.1%). NET was more frequently used in older women with multiple comorbid conditions, larger tumors, and higher nodal stage. The highest rates of NET were in academic/research or integrated network cancer programs. Of patients who underwent NET, 26.5% received it for ≤3 months, 41.0% for 3-6 months, 27.7% for 6-12 months, and 4.9% for 12-24 months. Patients who received NET for 3-6, 6-12, and 12-24 months were all significantly more likely to receive BCS versus mastectomy than patients who did not receive NET (Table). Patients who underwent NET compared to adjuvant endocrine therapy were more likely to be downstaged (Table). Conclusions: The most common duration of NET was 3-6 months, but &gt;26% of patients received NET for less than 3 months. Longer durations of NET were strongly associated with BCS and downstaging. Further research is needed to determine the population of patients mostly likely to benefit from NET and the optimal length of treatment. [Table: see text]
Creatine and Creatinine Content of Transplanted Hepatomas and of Normal and Regenerating Liver
Authors: Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1942)

Creatine and Creatinine Content of Transplanted Hepatomas and of Normal and Regenerating Liver Get access Jesse P. Greenstein Jesse P. Greenstein senior biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 3, December 1942, Pages 287–291, https://doi.org/10.1093/jnci/3.3.287 Published: 01 December 1942
EarlyR genomic signature to predict pathological complete response following neoadjuvant anthracycline-taxane chemotherapy in estrogen-receptor positive (ER+) breast cancer.
Authors: Steven Allen Buechler, Sunil S. Badve, Yesim Gokmen-Polar
Journal: Journal of Clinical Oncology (2017)

579 Background: EarlyR is a prognostic signature computed from expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR that stratifies ER+ breast cancer (BC) into EarlyR Low , EarlyR Int , and EarlyR High risk strata. Here, we show that EarlyR is also predictive of pathological complete response (pCR) following neoadjuvant anthracycline-taxane (AT) based chemotherapy. Methods: The ability of EarlyR gene signature to predict pCR was assessed in Affymetrix microarrays datasets (GSE25065, GSE25066, GSE20194, GSE20271; n = 541, pCR = 42 (7.8%) collectively labeled as Cohort A) derived from patients with ER+ breast cancer treated with neoadjuvant TFAC or FEC. For 2 of these datasets (GSE25065, GSE25066 (n = 291)) distant metastasis-free survival (DMFS) results were also available. The DMFS data in cohort A were compared to that of BC patients not treated with chemotherapy (denoted Cohort B, n = 1269) derived from ER+ samples from 7 GEO datasets (GSE3494, GSE7390, GSE12093, GSE6532, GSE2034, GSE11121, GSE17705). Results: In cohort A, EarlyR is a significant predictor of pCR (p = 1.0 x 10 -6 ) (EarlyR Low , n = 273, pCR = 5, 1.8%; EarlyR Int , n = 11, pCR = 1, 9.1% and EarlyR High , n = 256, pCR = 36, 14.1%). Notably, 86% of the 42 cases with pCR have EarlyR High . Of the 291 patients with 8-year DMFS data from Cohort A, who had received chemotherapy, the survival of EarlyR High [0.79 (95%CI 0.70-0.89)] was nearly the same as that of EarlyR Low [0.82 (95%CI 0.74-0.90)]. In contrast, in cohort B, who were not treated with chemotherapy, 8-year DMFS is significantly (p = 5 x 10 -15 ) lower in EarlyR High [0.57 (95%CI 0.51-0.64)] than in EarlyR Low [0.81 (95%CI 0.78-0.84)]. Conclusions: EarlyR is a strong predictor of pathological complete response in patients treated with TFAC or FEC. In addition, EarlyR also predicts poor DMFS outcomes for patients in EarlyR High not receiving chemotherapy. More importantly, neoadjuvant chemotherapy dramatically improved survival of patients in EarlyR High . These results document that EarlyR identifies a set of patients, EarlyR High , with a high risk of distant metastasis, who are also likely to respond favorably to chemotherapy.
New structural classes of antituberculosis agents
Authors: Vajinder Kumar, Sanjay Patel, Rahul Jain
Journal: Medicinal Research Reviews (2017)

Abstract Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis , researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold‐containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti‐TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti‐TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references.