tbuckley/cabot-search huggingface dataset:
Treating hematological malignancies with drugs inhibiting ribosome biogenesis: when and why
Authors: Enrico Derenzini, Alessandra Rossi, Davide Treré
Journal: Journal of Hematology & Oncology (2018)

It is well known that chemotherapy can cure only some cancers in advanced stage, mostly those with an intact p53 pathway. Hematological cancers such as lymphoma and certain forms of leukemia are paradigmatic examples of such scenario. Recent evidence indicates that the efficacy of many of the alkylating and intercalating agents, antimetabolites, topoisomerase, and kinase inhibitors used in cancer therapy is largely due to p53 stabilization and activation consequent to the inhibition of ribosome biogenesis. In this context, innovative drugs specifically hindering ribosome biogenesis showed preclinical activity and are currently in early clinical development in hematological malignancies. The mechanism of p53 stabilization after ribosome biogenesis inhibition is a multistep process, depending on specific factors that can be altered in tumor cells, which can affect the antitumor efficacy of ribosome biogenesis inhibitors (RiBi). In the present review, the basic mechanisms underlying the anticancer activity of RiBi are discussed based on the evidence deriving from available preclinical and clinical studies, with the purpose of defining when and why the treatment with drugs inhibiting ribosomal biogenesis could be highly effective in hematological malignancies.
Assessment of pulmonary function test abnormalities in adult survivors of childhood cancer.
Authors: Mylene Bassal, Eden Story, Lynn Chang, Vimoj Nair, Joseph Reisman, Nha Voduc, Dhenuka Radhakrishnan
Journal: Journal of Clinical Oncology (2018)

117 Background: As childhood cancer survival approaches 85%, it is increasingly recognized that childhood cancer survivors (CCS) are at risk for long-term therapy-related complications. Data suggest that pulmonary function test (PFT) abnormalities occur in as many as 84.1% of CCS. Our aim was to assess the prevalence and nature of respiratory abnormalities in adult CCS and to correlate these abnormalities with therapeutic exposures and health behaviors. Methods: Patients who received pulmonary toxic therapy routinely undergo PFTs at their first visit to the POGO AfterCare clinic in Ottawa, Canada. We conducted a retrospective review of all patients seen in clinic from August 2015 until December 2016. PFT results, treatment exposures and health habits were documented. We used NHANES-III prediction equations for PFT interpretation, with expiratory flows and lung volumes of ≥80% predicted as cutoffs for normal. Results: Of a total of 200 patients, 48 received pulmonary toxic therapy and 38 underwent PFTs. Mean age at the time of PFT was 28.8 years (18.5-57.5 years) and the mean time from diagnosis was 17.4 years (3.4-47.5 years). Although no patients reported respiratory symptoms, 42% (16/38) demonstrated a mild restrictive ventilatory defect, 11% (4/38) had mild airflow obstruction, 18% (7/38) had an isolated reduction in diffusion capacity and 1 patient had a moderate mixed obstructive/restrictive abnormality. Only 26% (10/38) had normal lung function. Of those with restrictive defects, all received radiation and 50% were also exposed to pulmonary toxic chemotherapy. All patients with obstructive defects received radiation therapy in combination with bleomycin. Tobacco or marijuana use was reported in 26% (10/38) of the cohort, and in 29% (8/28) of those with PFT abnormalities. Conclusions: PFT abnormalities are common among adult CCS who received pulmonary toxic therapy. Studies evaluating the change in pulmonary function abnormalities over time and their correlation to cardiopulmonary exercise testing and lung imaging are required to inform the health impact on these survivors.
Utilization of the sexual health service from the prostate cancer supportive care program: A chart review.
Authors: Jennifer Bossio, Christine Zarowski, Stacy Elliott, Lindsay Hedden, Phil Pollock, Maria Spillane, Eugenia Wu, Natalie Nunez, Anna Branch, Larry Goldenberg, Celestia S. Higano
Journal: Journal of Clinical Oncology (2018)

137 Background: Sexual dysfunction and psychological distress are two of the most important unmet supportive care needs of prostate cancer (PC) patients (pts). The Sexual Health Service (SHS) from the Prostate Cancer Supportive Care Program at the Vancouver Prostate Centre addresses the sexual recovery needs of PC pts and their partners via education and clinical service. This study explores patient characteristics and needs to better understand SHS utilization. Methods: Data was obtained from patient charts, semi-structured interviews, and patient-reported outcome measures from July 2013-June 2017. Analyses include descriptive statistics and pre-post comparisons via parametric (paired t-tests) or non-parametric (Wilcoxon) tests. Results: Data from 667 pts was analysed. Average age was 65yrs ( SD= 7.3, 43-88yrs) and most were in a relationship (79.6%; mean length = 30.5 yrs, SD= 15.2yrs, 9 mos–68yrs). Appointments were attended with partners (42.3%) or alone (56%) and most pts had undergone surgery for their PC (81.8%). Other treatments included radiation (18.2%), androgen deprivation therapy (13.3%), chemotherapy (1.0%), some had multiple treatments. Average time since end of PC treatment to first SHS appointment was 18 mos ( SD= 25.7mos; range, 0-17yrs). At the first SHS appointment, mean self-reported erectile functioning indicated severe dysfunction (IIEF scores: M =6.39, SD= 5.22). Pts reported significant decreases following PC treatment in: quality of erections, orgasm intensity, sexual desire, partner’s sexual desire, men’s sexual self-view, sexual body image and overall sexual satisfaction ( p’s &lt; .01). Patients also reported lower levels of partner intimacy ( p= .003). At first SHS appointment, 34.5% of patients reported one significant ongoing life stressor, and 23.8% reported more than one. Most common life stressors were health (29.4%), family (23.8%), work (15.3%), relationship (8.8%) and financial (6.9%). Conclusions: Analyses support the need for the SHS, as pts report declines in all realms of sexual wellbeing and ongoing life stressors. Findings improve our understanding of the long-term impacts of PC treatment and guide future treatment offerings.
Dynamic 18F-FET PET is a powerful imaging biomarker in gadolinium-negative gliomas
Authors: Mathias Kunz, Nathalie Lisa Albert, Marcus Unterrainer, Christian la Fougere, Rupert Egensperger, Ulrich Schüller, Juergen Lutz, Simone Kreth, Jörg-Christian Tonn, Friedrich-Wilhelm Kreth, Niklas Thon
Journal: Neuro-Oncology (2018)

We aimed to elucidate the place of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in prognostic models of gadolinium (Gd)-negative gliomas.In 98 patients with Gd-negative gliomas undergoing 18F-FET PET guided biopsy, time activity curves (TACs) of each tumor were qualitatively categorized as either increasing or decreasing. Additionally, post-hoc quantitative analyses were done using minimal time-to-peak (TTPmin) measurements. Prognostic factors were obtained from multivariate hazards models. The fit of the biospecimen- and imaging-derived models was compared.A homogeneous increasing, mixed, and homogeneous decreasing TAC pattern was seen in 51, 19, and 28 tumors, respectively. Mixed TAC tumors exhibited both increasing and decreasing TACs. Corresponding adjusted 5-year survival was 85%, 47%, and 19%, respectively (P < 0.001). Qualitative and quantitative TAC measurements were highly intercorrelated (P < 0.0001). TTPmin was longest (shortest) in the homogeneous increasing (decreasing) TAC group and in between in the mixed TAC group. TTPmin was longer in isocitrate dehydrogenase (IDH)-mutant tumors (P < 0.001). Outcome was similarly precisely predicted by biospecimen- and imaging-derived models. In the biospecimen model, World Health Organization (WHO) grade (P < 0.0001) and IDH status (P < 0.001) were predictors for survival. Outcome of homogeneous increasing (homogeneous decreasing) TAC tumors was nearly identical, with both TTPmin > 25 min (TTPmin ≤ 12.5 min) tumors and IDH-mutant grade II (IDH-wildtype) gliomas. Outcome of mixed TAC tumors matched that of both intermediate TTPmin (>12.5 min and ≤25 min) and IDH-mutant, grade III gliomas. Each of the 3 prognostic clusters differed significantly from the other ones of the respective models (P < 0.001).TAC measurements constitute a powerful biomarker independent from tumor grade and IDH status.
Is there a role for 21-gene recurrence score in mucinous carcinoma of breast?
Authors: Kelly Khai Li Yap, Melissa Koc, Janice M. Lu, Darcy V. Spicer
Journal: Journal of Clinical Oncology (2018)

e12538 Background: 21-gene recurrence score (RS) is widely used in hormone-receptor positive, lymph node negative invasive breast cancer to guide treatment. Many have expanded its use to patients with 1 to 3 positive lymph nodes. Invasive mucinous carcinoma (IMC) is associated with better prognosis compared to invasive ductal carcinoma (IDC). It is likely that this histologic subtype was under-represented in the validation cohorts given its overall low incidence. We sought to identify if the 21-gene recurrence score is prognostic and/or predictive in invasive mucinous carcinoma. Methods: This was a retrospective analysis of all localized and regional IMC cases that included RS. Data were sourced from the 2004-2013 SEER registries. Differences in patient and tumor characteristics were assessed by RS groups. Kaplan-Meier analysis and log-rank testing were performed to compare differences in breast cancer-specific survival (BCSS) and overall survival (OS) by RS groups. Results: A total of 1210 patients meet the inclusion criteria. Baseline characteristics were comparable to IDC, although a higher proportion of low-grade tumors were observed (59.3% IMC vs 27.2% IDC) and less patients received chemotherapy (15.7% IMC vs 24.5% IDC). Younger age, high-grade and lack of PR expression are more likely to be associated with high RS. The median follow-up was 50 months. Only 6 disease-specific deaths were observed (3 in low risk and 3 in intermediate risk). Twenty-eight deaths from any cause were observed, none of which were from high-risk patients. There was no BCSS or OS differences across the 3 RS groups (log-rank p = 0.76 and p = 0.11 respectively). Conclusions: IMC is more likely to be low-grade, and less likely to receive chemotherapy. There was no survival difference across the RS groups, suggesting RS may not be prognostic in IMC. Our results are highly limited by the small number of deaths. Cancer-specific deaths and 5- and 10- year survival rates Risk Group 5-year survival 10-year survival N failed N censored Survival Rate (SE) LR P-value N failed N censored Survival Rate (SE) LR P-value Low 1 485 0.998 (0.002) 0.50 3 772 0.992 (0.004) 0.76 Intermediate 2 208 0.993 (0.005) 3 382 0.985 (0.009) High 0 23 1.000 (0) 0 38 1.000 (0)
TBCRC026: Phase II clinical trial assessing the correlation of standardized uptake value (SUV) on positron emission tomography (PET) with pathological complete response (pCR) to pertuzumab and trastuzumab in patients with primary operable HER2-positive breast cancer.
Authors: Roisin M. Connolly, Jeffrey P. Leal, Lilja Solnes, Chiung-Yu Huang, Ashley Carpenter, Katy Gaffney, Vandana Gupta Abramson, Lisa A. Carey, Minetta C. Liu, Mothaffar F. Rimawi, Jennifer M. Specht, Anna Maria Storniolo, Vicente Valero, Christos Vaklavas, Melissa Camp, Robert S. Miller, Antonio C. Wolff, Ashley Cimino-Mathews, Richard L. Wahl, Vered Stearns
Journal: Journal of Clinical Oncology (2018)

511 Background: Predictive biomarkers to identify patients with HER2-positive breast cancer (BC) that may be treated with targeted therapy alone are of great interest. We hypothesized that early changes in tumor standardized uptake values corrected for lean body mass (SULmax) on FDG-PET/CT would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT) in early stage BC. Methods: The multicenter phase II TBCRC026 trial administered 4 cycles of neoadjuvant PT in women with stage II/III, ER-negative, HER2-positive BC (NCT01937117). FDG-PET/CT were performed at baseline and C1D15. Primary Objective: Correlate baseline and change in SULmax on PET with pCR (no invasive cancer breast/axilla). We correlated baseline, D15 and % reduction in SULmax with pCR using logistic regression and compared median values between those with pCR vs no pCR using Wilcoxon rank-sum tests. We evaluated odds ratio (OR), positive (PPV) and negative predictive value (NPV) with selected cutoffs for response assessment. Fisher’s exact tests evaluated null hypothesis that OR = 1. Results: Between 01/2014-08/2017, 88 enrolled (83 evaluable) with median age 58 (range 29-82), median tumor size 3.9cm (range 2-15). 85% (75/88) completed all 4 cycles PT. pCR after PT alone was 34% (28/83). In an intent to treat analysis (n = 83 evaluable), baseline SULmax did not predict pCR. We observed a significant difference in median % reduction in SULmax between pCR vs no pCR (63.8 % vs 33.5%, p < 0.001), and higher proportion of SULmax reduction ≥40% in pCR vs no pCR (86% vs 54%, p < 0.001, OR 7.2, PPV 49%, NPV 88%). We observed a significant difference in median D15 SULmax between pCR vs no pCR (1.6 vs 3.9, p < 0.001), and a higher proportion of D15 SULmax ≤ 3 in pCR vs no pCR (93% vs 62%, p < 0.001, OR 21, PPV 55%, NPV 94%). Conclusions: Percent reduction and D15 SULmax significantly differ between those with pCR versus not, after 4 cycles PT, in ER-negative/HER2-positive BC. This strategy, once optimized, may facilitate escalation and de-escalation of therapy in this setting. Clinical trial information: NCT01937117.
Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia
Authors: Isabelle Laverdière, Meaghan Boileau, Andrea L. Neumann, Héloïse Frison, Amanda Mitchell, Stanley W. K. Ng, Jean C. Y. Wang, Mark D. Minden, Kolja Eppert
Journal: Blood Cancer Journal (2018)

Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.
N6-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development
Authors: Yi Niu, Arabella Wan, Ziyou Lin, Xiongbin Lu, Guohui Wan
Journal: Acta Pharmaceutica Sinica B (2018)

N6-Methyladenosine (m6A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6A modification methyltransferase, demethylase and proteins that preferentially recognize m6A modification as "writers", "erasers" and "readers", respectively. Altered expression levels of the m6A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6A modification regulators for cancer drug development.
Transcriptomic signature of tumor infiltrating lymphocytes determines prognosis in localized breast cancer.
Authors: Caroline Truntzer, Nicolas Isambert, Francois Ghiringhelli
Journal: Journal of Clinical Oncology (2018)

e12507 Background: Tumor infiltrated lymphocytes (TILs) assessed by histology are known to have a prognostic impact on relapse-free survival in triple negative and HER2+ breast cancers. This information should be taken into account for further decision on adjuvant therapy administration. However, due to intratumoral heterogeneity and subjective semi-quantitative evaluation, the reproducibility of such data in clinical practice raises question. In this study, we propose a transcriptomic signature that could be a standardized mirror of TILs. Methods: Using 1928 transcriptomic profiles of pure immune cells, we generated genes signatures specific of lymphocytes, myeloids, stromal and cancer cells. We then computed a score based on these signatures and tested its correlation with the total TILs estimated for patients from public and private studies. The transcriptomic RNA TILs (tRNA TILS) score was then computed on patients from two public transcriptomic datasets (CIT, n = 420; Metabric, n = 1980) and its capacity to predict relapse-free (RFS) or overall (OS) survival was evaluated through multivariate Cox models adjusted on classical clinical variables such as the size of the tumor, lymph node involvement and PAM50 molecular classification. Results: A high RNA TILs score significantly correlated with the presence of a high level of TILs assessed by histology. This score predicted a good prognostic value in triple-negative and HER2+ patients on both data cohorts. The RNA TILS score was independently associated with prognostic (OS ou RFS) of the disease (p = 0,015) when adjusted on classical clinical variables. This remained true when patients were categorized by the type of treatment. Conclusions: Our work demonstrates that determination of a TILs score based a transcriptomic signature is a valuable prognostic marker in triple-negative and HER2+ breast cancers in adjuvant setting.
Histone Variant H2A.Z Is Required for the Maintenance of Smooth Muscle Cell Identity as Revealed by Single-Cell Transcriptomics
Authors: Fang Yao, Peng Yu, Yue Li, Xinli Yuan, Zheng Li, Tao Zhang, Fei Liu, Yingbao Wang, Yin Wang, Dandan Li, Baihui Ma, Chang Shu, Wei Kong, Bingying Zhou, Li Wang
Journal: Circulation (2018)

Histone variants endow chromatin with specific structures, and play essential roles in development and diseases. However, little is known about their roles in controlling cell identity in vascular diseases.Given the cell heterogeneity in atherosclerotic lesions, we applied single-cell RNA-Sequencing to analyze diseased human arteries, and identified histone variant H2A.Z as a key histone signature to maintain vascular smooth muscle cell (VSMC) identity.We show that H2A.Z occupies genomic regions near VSMC marker genes, and its occupancy is decreased in VSMCs undergoing dedifferentiation. Mechanistically, H2A.Z occupancy preferentially promotes nucleosome turnover, and facilitates the recruitment of SMAD3 and MED1, thereby activating VSMC marker gene expression. In addition, H2A.Z expression is dramatically reduced at both mRNA and protein levels in diseased human vascular tissues compared to those in normal arteries. Notably, in vivo overexpression of H2A.Z rescues injury-induced loss of VSMC identity and neointima formation.Together, our data introduce dynamic occupancy of a histone variant as a novel regulatory basis contributing to cell fate decisions, and imply H2A.Z as a potential intervention node for vascular diseases.
18F-FDG PET Brain in a Patient With Fatal Familial Insomnia
Authors: Wei Ying Tham, Yee-Liang Thian, Pavanni Ratnagopal, Wanying Xie
Journal: Clinical Nuclear Medicine (2018)

A 57-year-old woman presented with a 3-month history of cognitive impairment, daytime somnolence, and violent sleep behavior. Her first- and second-degree relatives had similar symptoms prior to their premature deaths. Her MRI scan of the brain showed no significant abnormality. Electroencephalogram showed loss of slow-wave activity. Functional brain imaging performed with F-FDG PET was fused with her MRI scans. This demonstrated profound hypometabolism in bilateral thalami and the posterior cingulate cortex, which is pathognomonic for familial fatal insomnia. Hypometabolism in the temporal lobes suggests a long-standing course of the disease. Genetic testing confirmed a mutation of the prion-protein gene (PRNP).
175 Years of Progress in PTSD Therapeutics: Learning From the Past
Authors: Murray B. Stein, Barbara O. Rothbaum
Journal: American Journal of Psychiatry (2018)

Traumatic stressors have always been a part of the human experience. What is now referred to as posttraumatic stress disorder (PTSD) was first studied in the context of military trauma during the Civil War and World War I but most extensively in World War II. Much of what we know about the medical and psychological management of PTSD has its origins in military psychiatric approaches, and a review of these practices reveals important tenets that should be applied in current treatment for both military and nonmilitary PTSD. These practices include intervention as soon as possible after the traumatic exposure, provision for a safe and supportive therapeutic milieu designed for an individual’s relatively rapid return to his or her responsibilities and normal activities, and using a combination of pharmacotherapy and psychotherapy (especially exposure to the traumatic memory). A review of current guidelines for treatment of PTSD reveals that few treatments are endorsed with great certainty, owing in large part to a paucity of clinical trials, particularly of pharmacotherapy. This shortcoming must be addressed to enable translation of promising discoveries in the neuroscience of fear into the therapeutic advances patients need and deserve. [AJP at 175: Remembering Our Past As We Envision Our Future March 1947: Psychiatric Experience in the War, 1941–1946 Brig. General William C. Menninger “Another observation which can be made as a result of our experience, is that if intensive treatment was provided early, in an environment in which the expectation of recovery prevailed, remarkable results were obtained.” (Am J Psychiatry 1947; 103:577–586)]