tbuckley/cabot-search huggingface dataset:
Chronic myelomonocytic leukemia: Next-generation sequencing in 30 treatment-naive cases.
Authors: Priyanka Priyanka, Ashita Sinha, Joseph Khoury, Keyur Patel, Mark Routbort, Rajesh Singh, Rajyalakshmi Luthra, Naveen Pemmaraju, Koichi Takahashi, Tariq Muzzafar
Journal: Journal of Clinical Oncology (2014)

7051 Background: Chronic myelomonocytic leukemia (CMML) belongs to a subtype of myeloid neoplasms called myelodysplastic / myelproliferative neoplasms. While clonal cytogenetic abnormalities have been identified in CMML, these lack specificity. Recently, next generation sequencing (NGS) data has identified a number of mutations in CMML; however, their significance in pathogenesis and prognosis is not well characterized. Methods: We performed NGS in a set of 30 treatment naïve CMML cases presenting at a single institution from 09/2012 to 09/2013 as part of routine clinical work up. Genes analyzed included CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MPL, NPM1, NRAS, PDGFRA, PTPN11, TP53. Detection of frequently reported (hotspot) mutations in a total of 53 genes was performed on the DNA extracted from bone marrow aspirate specimens. PCR-based DNA analysis was performed for detection of FLT3 internal tandem duplications (ITD) and codon 835/836 point mutation; and CEBPA. Results: Of the 30 cases, median age at diagnosis was 71 years (range 42 - 81); male: female ratio was 1:2. Mean hematologic parameters are as follows: hemoglobin: 10.79 ± 2.4 g/dL, WBC: 21.87 ± 27.3 K/UL; absolute monocyte count 3.70 ± 4.4 K/UL; platelets 134.9 ± 86.05 K/UL. Median LDH (n=23 patients) was 667 IU/L (range 323 - 6075). Eleven (36.67%) patients had one, none (0%) had two, 1 (3.3%) had three, 2 (6.6%) had four mutations detected. No mutation was detected in 16 (53.33%) patients. The most frequently identified mutation was in NRAS (n=4; 11.4%) followed by JAK2 V617F (n=3; 10%). Other mutations observed were in PTPN11 and TP53 (n= 2 each; 6.6%) and NPM1 and KRAS (n=1 case each; 3.3%). With univariate analysis, LDH levels were significantly associated with JAK2V617F mutation (p<0.001) and deletions involving chromosome 13. Conclusions: CMML is a heterogeneous disease entity at a genetic level. The presence of multiple genetic mutations in a subset of cases may indicate evolution of the neoplastic clone. Longitudinal analysis to study progressive additional mutations in cases would help to delineate a model for molecular pathogenesis and could lead to developing improved tools for prognosis and treatment of CMML.
siRNA-mediated inhibition of TPX2 affects pancreatic cancer cell proliferation, tumorigenicity, and cell death
Authors: Steven Warner, Anastasia Sugeng, Bret Stephens, Stanley Nwokenkwo, Haiyong Han, Daniel Von Hoff
Journal: Cancer Research (2007)

4959  Pancreatic cancer is the fourth leading cause of cancer death among men and women in the United States and novel approaches are urgently needed to combat this disease. The Targeting Protein for Xklp2 (TPX2) is a microtubule-associated protein whose gene is amplified in a subset of pancreatic adenocarcinomas (PNAS 2005;102:9625-30). Studies have shown its requirement for cell cycle progression as a result of its interaction with proteins such as Aurora A kinase. We hypothesize that due to its gene amplification and its involvement in an established oncogenic signaling pathway, TPX2 is a co-conspirator with Aurora A kinase in contributing to pancreatic tumorigenesis. To test this hypothesis and further characterize the role of TPX2 in pancreatic cancer, we used a siRNA approach to evaluate the biological consequences of targeting its expression in pancreatic cancer cell lines. Two different TPX2-targeting siRNAs showed a 4- to 5-fold reduction in MIA PaCa-2 cell proliferation compared to cells treated with a non-silencing siRNA for 24-96 hrs. This effect on cell proliferation was also observed in PANC-1 cells but to a lesser extent. TPX2 inhibition by siRNA produced an 80% reduction in MIA PaCa-2 and PANC-1 colony formation in soft agar, suggesting it is involved in pancreatic cancer cell self-renewal and tumorigenicity. Furthermore, MIA PaCa-2 and PANC-1 cells treated with TPX2-targeting siRNAs underwent apoptosis as indicated by a dramatic induction of caspase-3 activity. These results suggest that TPX2 is an important contributor to pancreatic cancer growth, is a potential candidate oncogene, and is a prospective therapeutic target to treat this disease. We are vigorously pursuing therapeutic agents that disrupt TPX2 function in hopes of finding more effective treatment options for patients with pancreatic cancer. (Supported by NIH Grant CA 95031)
The effect of an ambulatory medical assistance during chemotherapy and follow-up among patient with diffuse large B-cell lymphoma on treatment adherence.
Authors: Sebastien Lamy, Manuela Rueter, Pauline Jeanneau, Jean-claude Nogaro, Maryse Lapeyre-Mestre, Cecile Borel, Gisele Compaci, Cyrille Delpierre, Fabien Despas, Guy Laurent
Journal: Journal of Clinical Oncology (2014)

e19550 Background: The diffuse large B-cell lymphoma (DLBCL) is the most frequent and aggressive Non-Hodgkin Lymphoma (NHL). Moderate to severe chemotherapy-related adverse drug reactions (ADR) may occur during treatment and threaten its effectiveness. As ADR arrive commonly at home, this can delay or suspend treatment. In response to this problem, a telemedicine follow-up based on phone calls by a coordinating nurse (Ambulatory Medical Assistance: AMA) has been introduced in routine by the Toulouse University Hospital. The present study aimed to estimate the effect of AMA on treatment adherence among patients diagnosed with DLBCL treated by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP like chemotherapy in the Midi-Pyrenees’ region. Methods: This observational retrospective cohort study included 418 incident adult patients diagnosed between November 2006 and June 2011, with a follow-up until October 2013. Treatment adherence was assessed by relative dose intensity (RDI). A value under 85% was considered as a risk factor of poor prognosis. We compute a propensity score of being included in AMA, in order to control for potential confounding bias which could derive from the patients’ profiles and trajectories in the health care system. Bootstrap methods were used for computing the 95% confidence intervals. Results: The median follow-up was 2.8 years (maximum = 6.6 years). In the total sample, 72 (17.5%) patients had a RDI lower than 85% (9.3% in the AMA group versus 22.1% in the non-AMA group (p-value=0.001)). Results from the multivariate regression models weighted by the propensity scores showed that AMA was associated with better treatment adherences, OR [IC 95%] = 0.36 [0.13; 0.63]. Conclusions: Based on “in real life” data, this study suggests that treatment adherence of DLBCL patients treated by R-CHOP or R-CHOP-like chemotherapy could be improved by a telemedicine follow-up based on phone calls by a coordinating nurse like those implemented by the Toulouse University Hospital. This work was supported by the National Research Agency’s program “Investissement d’avenir” ANR-11-PHUC-001, from the French Government.
Abstract 12259: Epidemiology of Valvular Heart Diseases: A 30-Year Retrospective of Hospitalizations and In-Hospital Mortality in New York State
Authors: Phyllis G Supino, Ofek Y Hai, Nasimullah Khan, Jeffrey S Borer
Journal: Circulation (2014)

Background: Valvular heart disease (VHD) is among the most predictable causes of heart failure (HF) and an important cause of sudden death. Temporal trends of clinically significant VHD during the past three decades have not been defined. Methods: To obtain information for our region, we conducted a longitudinal analysis of all inpatient hospital records (79,689,879) obtained from the New York State (NYS) Statewide Planning and Research Cooperative System (SPARCS) database for years 1983 (first year reliable data were consistently available) through 2012 (last year data were complete). VHD cases (2,720,313) were identified from principal or secondary ICD-9 codes for aortic, mitral, tricuspid or pulmonic VHD. Linear regression was used to evaluate trends over time for VHD hospitalizations, valve surgery (VS) and in-hospital deaths. Logistic regression was used to predict mortality risk factors. Results: From 1983-2012, total hospitalizations decreased by ~500,000 cases; simultaneously, VHD hospitalizations increased markedly (34,395 in 1983 to 125,139 in 2012). Rate of increase was linear across all VHD categories = 4,248 new cases (12.4%)/yr, r 2 = 0.99, p&lt;.0001) through 2006 (peak= 132,323 cases), and then flattened through 2012. A parallel trend was found for VS, though no appreciable flattening occurred (2,582 cases in 1983 to 7,787 in 2012, linearized increase rate=207 VS [8.0%]/yr, r 2 =0.97, p&lt;.001). Both numbers of hospitalizations and performance of VS rose with patient age (p&lt;.001). Over the study interval, 123,787 patients with VHD died in the hospital, including 9,272 who died after VS; avg case fatality rates were 4.6% (all VHD) and 6.4% (VS). Deaths were independently associated with advancing age, nonelective admission and presence of associated HF (p&lt;.0001, all). Male gender predicted increased death risk among the general VHD population; female gender predicted death risk among those undergoing VS. Conclusions: The incidence of VHD hospitalization and VS in NYS has risen substantially since the early 1980s and can be expected to rise further as the population ages. Thus, intensive planning is needed to deal with public health implications of these trends as we attempt to meet the growing needs of this patient population.
Efficient Scale-up and Pre-Clinical Evaluation of NKG2C+ Adaptive NK Cell Expansion for Therapy Against High-Risk AML/MDS
Authors: Ebba Sohlberg, Alvaro Haroun-Izquierdo, Andreas T Björklund, Sarah Cooley, Merete Thune Wiiger, Jodie Peter Goodridge, Hanna Julie Hoel, Aline Pfefferle, Michael Chrobook, Veronika Kremer, Eva Hellström-Lindberg, Eivind Heggernes Ask, Blomberg Pontus, Bahram Valamehr, Karolin Guldevall, Hanna van Ooijen, Bjorn Onfelt, Evren Alici, Hans-Gustaf Ljunggren, Jeffrey S. Miller, Karl-Johan Malmberg
Journal: Blood (2018)
Social and contextual factors and their relationship with the use of palliative chemotherapy in patients with metastatic colorectal cancer (mCRC): A retrospective cohort study.
Authors: Shahid Ahmed, Nayyer Iqbal, Kamal Haider, Haji I. Chalchal, Duc Le, Riaz Alvi, Adnan Zaidi, Punam Pahwa
Journal: Journal of Clinical Oncology (2018)

849 Background: Although there is evidence that social and contextual factors such as living alone are associated with outcomes in cancer patients, little is known about their influence on the use of palliative chemotherapy in mCRC. We previously reported various patient-and tumor-related factors that correlate with the use of palliative chemotherapy in mCRC (Oncology. 2015;88:289). In this study we examine social and contextual factors including marital status, having children and distance to cancer center for their association with the use of chemotherapy in patients with mCRC. Methods: A cohort of 569 patients with mCRC diagnosed from 2006-2010 in Saskatchewan was evaluated. Logistic regression analyses were performed to assess relationship between the use of chemotherapy and various variables. Results: Median age was 69 yrs (IQR 59-77) and M:F was 59:41. 326 (57%) patients received chemotherapy. Significant differences were noted between the chemotherapy vs. no chemotherapy groups with respect to median age (62 vs. 76 year, p &lt; 0.001), WHO performance status (PS) &gt; 1 (18 vs. 58%, p &lt; 0.001), comorbid illness (24 vs 63%, p &lt; 0.001), low albumin (61 vs. 89%, p &lt; 0.001), anemia (61 vs. 87%, p &lt; 0.001), elevated alkaline phosphatase (53 vs. 84% &lt; 0.001), elevated creatinine (6 vs. 11%, p = 0.025), hyponatremia (20 vs. 14%, p = 0.03), primary tumor resection (61 vs 47%, p = 0.001), metastasectomy (21 vs. 9%, p &lt; 0.001), mean distance to cancer center (98.7±113.6 vs. 127.8±124.6 km, p &lt; 0.001), married/partnered (67 vs 33%, p &lt; 0.001), and having children (64 vs. 36%, p &lt; 0.001), respectively. On multivariate logistic regression analysis after adjustment of other variables, WHO PS &gt; 1 (HR 5.1; 95%CI: 3.1-81.), not having children (3.3, 1.78-6.2, &lt; 0.001), elevated alkaline phosphatase (HR 2.9; 95%CI: 1.8-4.8), and low albumin (HR 2.2; 95%CI: 1.2-3.8), were correlated with low rates of chemotherapy. Marital status or travel distance did not correlate with use of chemotherapy. Conclusions: Our results show that use of chemotherapy in patients with mCRC significantly varies in those with and without children. Future study are required to explore this difference.
Utilization of antineoplastic chemotherapy near the end of life in patients with solid tumors.
Authors: Shilpa Paul, Stephanie A. Sanders, David D. Stenehjem
Journal: Journal of Clinical Oncology (2014)

9524 Background: The American Society of Clinical Oncology considers cessation of cancer-directed therapy for patients with solid tumors who lack clinical benefit from further treatment as a key opportunity to improve care and reduce costs. This study evaluated the use of chemotherapy (chemo) in solid tumors near the end of life at the Huntsman Cancer Institute (HCI). Methods: Patients with breast (BC), non-small cell lung (NSCLC), melanoma (MEL), and ovarian (OC) cancer who received chemo within the last 365 days of life at HCI from 1995-2012 were evaluated. Comparison of chemo use in the last 30 days of life (EOLChemo) was compared across cancer types, stage at diagnosis and change in use over time (2007-2012). Kaplan-Meier analysis was used to assess overall survival (OS) from diagnosis in stage IV patients by EOLChemo utilization. Results: The study included a total of 856 patients with BC (n=271, 31.7%), NSCLC (n=237, 27.7%), MEL (n=263, 30.7%), and OC (n=85, 9.9%) who received chemo at HCI within the last year of life. Median age at diagnosis of cancer was 59 years (IQR 29-95) and the average age at death was 63 years (IQR 54-73). The median time from diagnosis of cancer to death was 19.9 months and median time from last chemo to death was 1.9 months (95% CI 57-68, IQR 0.8 – 4.0). Of all patients identified, 253 (29.6%) received EOLChemo. Utilization of EOLChemo was similar (p=0.2452) across cancer types: 72 (27%) BC, 73 (28%) MEL, 78 (33%) NSCLC, and 30 (35%) OC patients. Across all cancer types there was no significant increase in EOLChemo over the past 6 years (p=0.1634). More patients diagnosed with stage IV cancer (n=97, 46.4%) received EOLChemo than those diagnosed with stage I disease (n=21,10%), p=0.0115. Stage IV patients who received EOLChemo had reduced OS compared to those who received chemo greater than 30 days from death (6.8 vs 10.2 months, HR 1.49, CI 1.16-1.90, p=0.0018). Conclusions: Of all patients who received chemo in the last year of life, a high percentage (~30%) occurred in the last 30 days of life, irrespective of cancer type. Chemotherapy use in the last 30 days of life was associated with reduced OS. Increased efforts for cessation of chemo near the end of life are warranted.
Fotemustine (F) in the treatment of malignant melanoma nonassociated with B-RAF mutations.
Authors: Yana V Svetitskaya, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2014)

e20033 Background: Treatment of non-associated B-RAF mutation malignant melanoma (MM) is still a great problem. F has a high distribution ratio, sufficiently high spread into the tumor cells and through the blood-brain barrier. Methods: Eligibility criteria included disseminated skin and eye melanoma non-associated with B-RAF – mutations (T2-4N0-3M1), ECOG≤2, adequate hepatic, renal and bone marrow functions. F was administrated 100 mg/m2, IV D1,8,15, continued after 4 weeks break q3w till disease progression. Antitumor response, safety, progression free (PFS) and overall survival (OS) were evaluated. Results: 41 patients (41 women) were recruited in 2008 – 2013, mean age 48.5±5.4 yrs. 1st line treatment was administrated to 17.1 % (7), 2nd - 56.1% (23), 3rd - 26.8% (11). Disease control was 75.6% (31): CR – 16.1% (5), PR - 29.1%(9), SD - 54.8%(17), PD - 24.4%(10). OS was 36.4±3.2 mos, PFS -21.2±2.5 mos. OS in the 1st line therapy was 17.2±2.5 mos, 2nd – 10.8±2.8 mos, 3rd – 8.4±3.2 mos, PFS in the 1 st line therapy – 11.2±2.5 mos, 2nd – 5.8±2.8 mos, 3rd – 4.2±2.4 mos (p < 0.005). Common toxicities were: leukopenia 2/3 Gr (18.1%), thrombocytopenia 2/3 Gr (20%), nausea 1/2 Gr (16.8%), vomiting 2 Gr(12.3%), general weakness ½ Gr (23.1%), transaminase elevation 1 Gr (6.9%). None of treatment was interrupted because of side effects. Conclusions: F therapy is an optimal method of treatment in non-associated with B-RAF mutations MM. F toxicity is basically hematological: leukopenia, thrombocytopenia and more seldom anemia, which are reversible and predictable.
PI3Kinase Alpha and Delta Promote Hematopoietic Stem Activation Under Stress
Authors: Shayda Hemmati, Taneisha Sinclair, Meng Tong, Boris Bartholdy, Rachel Okabe, Kristina Ames, Leanne Ostrodka, Tamanna Haque, Imit Kaur, Anupriya Agarwal, Jean Zhao, Thomas Roberts, Kira Gritsman
Journal: Blood (2018)
Cell-Type Specific Mechanisms of Hematopoietic Stem Cell (HSC) Expansion Underpin Progressive Disease in Myelodysplastic Syndromes (MDS) and Provide a Rationale for Targeted Therapies
Authors: Irene Ganan-Gomez, Ana Alfonso, Hui Yang, Andrea Santoni, Valentina Marchica, Elena Fiorini, Guillermo Montalban-Bravo, Yamini Ogoti, Ganiraju Manyam, Shan Jiang, Naran Bao, Christopher Jackson, Ashley Rose, Rashmi Kanagal-Shamanna, Carlos E. Bueso-Ramos, Benedetta Cambò, Nicola Giuliani, Monica Crugnola, Marina Y. Konopleva, Karen Clise-Dwyer, Guillermo Garcia-Manero, Simona Colla
Journal: Blood (2018)
Immunofluorescence analysis of P53-binding protein 1 (53BP1) in thyroid follicular tumors: Possibility for preoperative diagnosis.
Authors: Ryota Otsubo, Katsuya Matsuda, Shiro Miura, Hisakazu Shindo, Mitsuyoshi Hirokawa, Akira Miyauchi, Takeshi Nagayasu, Masahiro Nakashima
Journal: Journal of Clinical Oncology (2014)

e17036 Background: It is almost impossible to preoperatively diagnose thyroid follicular tumors (FTs), because the criteria for distinguishing these lesions are based on histological evidence of capsular or vascular invasion and metastasis but not on nuclear atypia. We have reported a usefulness of immunofluorescence (IF) analysis for type of 53BP1 expression, which belongs to DNA damage response (DDR) molecules, to estimate the genomic instability (GIN) in diverse tumorigenesis. The expression of 53BP1 nuclear foci (NF) has been found to reflect DNA double strand break caused by various stresses. This study aimed to clarify the possibility of IF analysis of 53BP1 expression in preoperative diagnosis of FTs. Methods: A total of 64 surgically resected thyroid tissues, including7 non-tumorous thyroids (NT), 27 follicular adenomas (FA), 24 minimally invasive follicular carcinomas (MFC) and 6 widely invasive follicular carcinomas (WFC) were available for this study. The pattern of 53BP1 expression was classified into two types: (1) low DDR type, one or two NF; (2) high DDR type, three or more NF and/or large NF more than 1.0μm. Furthermore, we performed genome-wide copy number aberration (CNA) analysis in 7 MFC and 7 FA showing different type of 53BP1 expression by array-based comparative genomic hybridization (aCGH). Results: Follicular cells showing NF were significantly increased at the marginal portion beneath capsule of FA/FC including invasive site of FC as compared with mid portion of FA/FC which was located 2mm or more apart from the capsule and NT. Interestingly, the mean incidence of cells with high DDR type at the marginal portion were more significantly (p<0.01) associated with malignant potency of FTs (WFC: 9.4%, MFC: 7.6%, FA:1.8%, NT: 0.3%). aCGH analysis also demonstrated significantly (p=0.01) higher length of total CNA in MFC (mean: 1.20%) as compared with FA (mean: 0.06%), suggesting an association between GIN and high DDR type of 53BP1 expression by IF. Conclusions: The type of 53BP1 expression by IF method seems to reflect GIN level to estimate malignant potency of FTs. This method may be useful for preoperative diagnosis with fine-needle aspiration cytology for FTs.
The landscape of precision medicine cancer clinical trials in the United States.
Authors: Nitin Roper, Kristian Stensland, Ryan Hendricks, Matt D. Galsky
Journal: Journal of Clinical Oncology (2014)

1547 Background: Advances in tumor biology and high throughput genomic analysis have ushered in the era of precision cancer medicine. Little is currently known, however, about the landscape of prospective “precision medicine” cancer clinical trials in the U.S. Methods: We identified all adult interventional cancer trials registered on clinicaltrials.gov between September 2005 and May 2013. Trials were classified as “precision medicine” if testing for a specific genomic or protein alteration in tumor tissue was required for enrollment. Characteristics such as type of genomic/proteomic alteration tested, masking, phase, sponsor, accrual and cancer subtype were ascertained for each trial. Results: Of the initial 18,797 trials identified, 9,094 (48%) were eligible for inclusion. 905 (10%) were classified as precision medicine trials and 8,189 (90%) were non-precision medicine trials. Compared with non-precision medicine trials, precision medicine trials were more likely to be phase II (OR 1.44 (1.25-1.65), p<0.0001) or phase III (OR 1.27 (1.01-1.60), p=0.0419), randomized (OR 1.19 (1.02-1.38), p=0.0270), sponsored by industry (OR 1.37 (1.19-1.58), p<0.0001), and multi-center (OR 1.63 (1.41-1.88), p<0.0001). The percentage of precision medicine trials compared to the total number of trials increased from 5% in 2006 to 17% in 2013. Precision medicine trials required testing for 33 unique genomic/proteomic aberrations for enrollment. The most common cancer subtypes were breast (40%), skin (15%), lung (9%), and hematologic (6%). Conclusions: The proportion of adult cancer clinical trials in the U.S. requiring the presence of a specific genomic/proteomic tumor aberration for enrollment has increased substantially over the past several years. However, such trials still represent a small minority of studies performed within the cancer clinical trials enterprise.
Quantification of Plasma Proteins from Idiopathic Multicentric Castleman Disease Flares and Remissions Reveals 'Chemokine Storm' and Separates Clinical Subtypes
Authors: Sheila K Pierson, Aaron James Stonestrom, Jason R Ruth, Dustin Shilling, Hongzhe Li, Yue Ren, Katie Stone, Frits van Rhee, David C Fajgenbaum
Journal: Blood (2017)