tbuckley/cabot-search huggingface dataset:
Interim results of a phase I/II randomized study of clofarabine, idarubicin, and cytarabine (CIA) versus fludarabine, idarubicin, and cytarabine (FIA) for newly diagnosed or relapsed patients (pts) with acute myeloid leukemia (AML).
Authors: Michael Mathisen, Hagop Kantarjian, Stefan Faderl, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M. Kadia, Naval Guastad Daver, Susan Mary O'Brien, Stephan Joseph Dorkhom, Sherry Pierce, Cynthia Lira, Jorge E. Cortes, Elias Jabbour
Journal: Journal of Clinical Oncology (2012)

6607 Background: Outcomes of pts with AML remain suboptimal. The addition of cladribine to 3+7 has been shown to improve complete remission (CR) rates and 3-year survival. The aim of this study was to assess the efficacy and safety of idarubicin + cytarabine (IA, idarubicin 10 mg/m 2 on days 1-3, cytarabine 1 g/m 2 on days 1-5) combined with two other nucleoside analogs, clofarabine (C) or fludarabine (F), in pts with newly diagnosed and relapsed/refractory (RR) AML. Methods: Pts with newly diagnosed or RR non-M3 AML with normal organ function were eligible. Pts with RR disease were treated in the phase I portion defining the MTD of C. The starting dose of C was 15 mg/m 2 with doses escalating to 25 mg/m 2 on days 1-5 in subsequent cohorts. During phase II, patients were randomized in a Bayesian design to C at the MTD with IA or fludarabine (F) at 30 mg/m 2 on days 1-5 with IA. Up to 6 consolidation cycles were planned according to an attenuated schedule using the same drugs. Dose adjustments were made for elderly pts or pts with poor PS. Results: 9 pts were enrolled in the phase I portion. The overall response rate (ORR) in this group was 44%. DLT were observed at C 20 mg/m 2 and included hand/foot syndrome (HFS), elevated bilirubin, and prolonged myelosuppression. The MTD was 15 mg/m 2 on days 1-5. 50 evaluable pts were enrolled (16 newly diagnosed, 34 RR) in the phase II. In the frontline cohort, median age was similar in both groups (C 56, F 55), as were the cytogenetic profiles. The CR rate was 100% in both groups (9 CIA, 7 FIA). Detailed efficacy information can be found in the Table. More than half of the RR cohort were receiving therapy as salvage 2 or higher, and most had short first CR durations. Notable toxicities included elevated liver function tests for both groups, and HFS in the C group. There were 4 deaths on study, though most pts were receiving therapy as second salvage and were over the age of 60. Conclusions: CIA and FIA are effective regimens for newly diagnosed or RR AML with manageable toxicity profiles. The ORR were 100% and 32% for newly diagnosed and RR AML pts, respectively, with low early mortality rates. The study is ongoing.
Characterizing benign breast disease in women at high risk for breast cancer.
Authors: S. A. Israel, H. Nassar, A. L. Gross, L. K. Jacobs, D. K. Armstrong, K. Visvanathan
Journal: Journal of Clinical Oncology (2010)

1506 Background: Benign breast disease (BBD) is an established risk factor for breast cancer, with the highest risk associated with atypical proliferative subtypes. In the general population, atypical hyperplasia (AH) is associated with a 20-50% increase in invasive breast cancer risk persisting at least 25 years post biopsy. Limited information exists on the prevalence and characteristics of BBD in women at high risk for breast cancer. Methods: In an ongoing prospective study of women with a family history of breast cancer and/or a BRCA1/2 mutation who attend the Breast and Ovarian Surveillance Service (BOSS) at Johns Hopkins (n = 953), we identified 575 women who reported having at least one breast surgical procedure at the time of enrollment. 66% of these women had 2 or more relatives with breast and/or ovarian cancer. 257 breast cancer cases and 170 cases of incident BBD were subsequently confirmed based on pathology report. Slides were then obtained for re-review and evaluation of specific histological features. Results: The incidence of biopsy proven BBD was 18% and the median age at diagnosis was 44.2 years (range: 16-87 years), while the incidence of breast cancer on first biopsy was 27% with a median age of 46.9 years (range: 23-76 years). Of the BBD cases, 58% were non-proliferative, 27% were proliferative non-atypical lesions, and 15% were AH. The median age at diagnosis was significantly higher in women with proliferative BBD (46.8 years) as compared to non-proliferative (41.4 years) (p = 0.01). 27.3% of women had at least one additional BBD diagnosis (range: 1-4) within 10 years of their incident BBD. 26.5% of women with BBD developed breast cancer within a median time of 6 years (range: 0- 31 years) following their incident biopsy. A significantly higher proportion of women with AH progressed to breast cancer (44%) as compared to non- proliferative cases (16.3%) within 10 years post BBD (p = 0.006). Conclusions: In this high-risk population, we observed a high incidence of AH subtypes at a young age, a significant proportion of whom subsequently developed breast cancer in a short period of time as compared to what is reported in the general population. No significant financial relationships to disclose.
Abstract 13659: Transition in Mechanism of Flow-Mediated Dilation During Stress in Humans: Role of Ceramide
Authors: Julie Freed, Andreas Beyer, David Gutterman
Journal: Circulation (2012)

Flow-mediated dilation, (FMD; the ability of the vasculature to dilate to increased shear stress in an endothelium-dependent manner), maintains vascular homeostasis and is inversely related to future cardiovascular events. Our laboratory has discovered that risk factors for, or the presence of CAD, causes a transition in the mediator of FMD from NO to mitochondrial-derived H2O2. Ceramide, a signaling lipid product of sphingomyelinase, stimulates mitochondrial H2O2 formation and is increased in CAD. We tested the hypothesis that ceramide is critical for this transition of FMD from NO to H2O2. Small adipose arterioles (100-200µm) from patients with or without CAD were prepared for videomicroscopy. Vessels were preconstricted with endothelin-1, and changes in internal diameter to flow were recorded. In non-CAD arterioles, L-NAME inhibited FMD (17.8±13.7 of maximal dilator capacity, n=4, p<0.01, one-way ANOVA*) versus vehicle (72.2±11.3, n=3), whereas FMD was unaffected by PEG-Catalase (500 Units) (76.6±5.5, ...
A retrospective analysis of epidemiology and treatment patterns for gastric cancer at a tertiary health care center in India
Authors: R. Digumarti, S. J. Rajappa, S. Uppalapati, A. Surath
Journal: Journal of Clinical Oncology (2006)

4086 Background: Gastric cancer is the second most common gastrointestinal cancer in our hospital based cancer registry. This retrospective analysis aims at studying the epidemiology and treatment patterns for gastric cancer at our hospital, which is a tertiary care cancer center for the state of Andhra Pradesh in south India. Methods: A retrospective analysis of the case records of 125 consecutive patients with gastric cancer who presented to our department between Jan 2004 and Dec 2005 were analysed. Data regarding epidemiology, stages at diagnosis and treatment plans were collected. Patients with early gastric cancer received 5FU based chemoradiation or chemotherapy only. Palliative chemotherapy included 5FU/cisplatin based regimens. Results: A total of 125 patients were analysed. The median age was 61years (range 18–82 years). 71% were males and 29% females. Being a tertiary care center, 92% were referred with a confirmed diagnosis on endoscopic biopsy. 30% were smokers, 11% consumed alcohol, 40% had both habits while 29% had neither. The most common part of the stomach involved was the antro-pyloric region (44%) followed by the body (30%), GE junction/cardia (20%) while 6% had diffuse involvement including linitis plastica. At diagnosis, 35% were early stage, 56% metastatic and 8% locally advanced tumors. 90% patients who had surgery for early stage disease had T2,3 tumors. One third had inadequate nodal staging.70% of patients who had curative resections underwent adjuvant chemoradiation and 30% had chemotherapy only. Of all patients with metastatic disease, 65% palliative chemotherapy while 45% opted for best supportive care. Conclusions: The distribution of tumors within the stomach is similar to Japanese data, which may reflect the common etiological factors like high salt diet. The fact that one third of patients had inadequate nodal dissection stresses the relevance of adjuvant chamoradiotherapy protocols. The high incidence of smoking as a contributory factor in the etiology reflects the need for aggressive anti tobacco legislation. The study reiterates the need for inexpensive and novel therapies for palliation of symptoms in patients with advanced disease and widens the scope for collaborative clinical trials. No significant financial relationships to disclose.
STUDIES ON ANTIBODY PRODUCTION
Authors: Charles T. Ambrose, Albert H. Coons
Journal: The Journal of Experimental Medicine (1963)

When lymph node fragments from previously immunized rabbits were stimulated in vitro to produce a secondary response, the continuous presence of 50 microg/ml (0.15 mM) of chloramphenicol in the medium during the entire incubation period of 15 to 21 days produced nearly complete suppression of the response. Concentrations as low as 5 microg/ml (0.015 mM) produced approximately 80 per cent suppression of the response. When 50 microg/ml of chloramphenicol was present during only the first 6 days of culture, the secondary response was reduced 90 per cent. When it was absent for the first 6 days but present for the next 9 to 15 days, the response was reduced only 40 per cent. Since over 95 per cent of the antibody of the secondary response in most experiments appeared in the medium after the 6th day, chloramphenicol apparently inhibits antibody production by interfering with some early phase of the response. It is suggested that this interference involves messenger RNA and that animal cells have appeared resistant to this drug only because their complement of messenger RNA present when the drug has been added is stable over the short periods during which protein synthesis has usually been studied.
Clinical process analysis: Embedding performance improvement skills for measurable and sustainable change.
Authors: Beverly A Hayes, Courtney Barnes, Gina Aranzamendez, Laurie Kaufman, Valerie Haywood, Duke Rohe
Journal: Journal of Clinical Oncology (2013)

67 Background: The Clinical Process Analysis methodology, based on Time Driven Activity Based Costing (Kaplan), aligns data reporting with frontline processes to drive improvement in clinical quality and financial performance. After the completion of 6 ambulatory centers (with 6 in progress), the program evolved to include a Performance Improvement (PI) Phase. The goal: embed PI skills in all clinical operations; provide resources for PI project initiation, facilitation, and sustainability; and continue collaboration with MD Anderson Cancer Center process owners through measurable improvement in safety, timeliness, effectiveness, efficiency, equity and patient-centeredness. (IOM 2001). Methods: The center and the CPA Team utilize institutional dashboards and multiple data resources to establish the project scope. The scope is converted to a Blueprint which outlines a timeline of the project, a list of required resources, and center-specific data. The CPA Team interviews frontline staff, clinical leadership and financial teams to create a current state process flow chart. Opportunities for Improvement (OFI), operational and clinical variations, cycle times and other management reporting metrics are included on the charts, as well as patient experience audio, as gathered by an MD Anderson marketing team. OFIs are evaluated, categorized, and prioritized by clinical leadership, and the CPA Team works with the center’s designated PI team to develop and implement Quick Fixes, PDSA and more extensive projects. Results: In 6 completed ambulatory centers in FY13: 176 Opportunities for Improvement, $936,463 Savings. Summary reports provide direct labor costs and estimated times, per resource type, for center activities. Per MDs, managers, staff and financial experts, other uses for process flow charts include: tracking patient flow; resource utilization; customer satisfaction; patient education; and on-boarding staff. Conclusions: In FY14, the CPA Program will focus on patient access in 15 centers, gathering data to identify trends and common themes to implement Best Practices across the institution.
Prediction of oesophageal variceal bleeding by measuring spleen stiffness in patients with liver cirrhosis
Authors: Yoshitaka Takuma, Kazuhiro Nouso, Youichi Morimoto, Junko Tomokuni, Akiko Sahara, Hiroyuki Takabatake, Akira Doi, Kazuhiro Matsueda, Hiroshi Yamamoto
Journal: Gut (2015)

Letter to the Editor

We read with interest the guidelines by Tripathi et al 1 and the leading article by Rosselli et al ,2 reporting the role of transient elastography for the diagnosis of oesophageal varices (OV).

Before screening endoscopy, non-invasive measures are needed to ascertain cirrhotic patients at high risk for oesophageal variceal bleeding (OVB) to decrease the number receiving unnecessary prophylactic treatments. In our recent study,3 spleen stiffness (SS) evaluated by acoustic radiation force impulse (ARFI) imaging was shown to be closely correlated with the presence of OV. This study aimed to evaluate SS determined by ARFI imaging as a predictor of OVB. We measured SS in 446 cirrhotic patients and followed them prospectively at Kurashiki Central Hospital between 2010 and 2014. We examined the diagnostic accuracy of SS for predicting OVB …
Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate
Authors: S. Chi, S. Gardner, L. Y. Ji, R. Sposto, G. Dhall, J. Finlay
Journal: Journal of Clinical Oncology (2007)

9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients &lt; 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (&gt;6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED &gt;5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.
A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results
Authors: J. S. Renshaw, A. Patnaik, M. Gordon, M. Beeram, D. Fischer, A. Gianella-Borradori, C. Lin, D. Mendelson
Journal: Journal of Clinical Oncology (2007)

14130 Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes from parent to daughter cell and have been linked to tumorigenesis. Aurora kinase A is commonly amplified in solid tumors and has been established as an oncogene. Aurora B is often overexpressed and leads to defects in mitosis and increased tumor invasiveness. AS703569 is an orally available, highly potent inhibitor of aurora kinases A and B and several other kinases. AS703569 has been shown in vitro and in tumor xenograft models to inhibit proliferation and to trigger apoptosis of several tumor types. We report on the initial results of a phase I study of AS703569 in patients with solid tumors. The study objectives are to determine for each of 2 different dosing regimens the MTD and to evaluate safety, PK and pharmacodynamic effects. Methods: This is a phase I, two arm, dose-escalation study. Cohorts of 3 patients ≥18 years old with advanced solid tumors are being assigned to one of 2 dosing regimens. The dose escalation follows a modified Fibonacci scheme. The starting dose level is 6 mg/m 2 p.o. per 21-day cycle divided in 2 or 3 doses (regimen 1: dosing on days 1, 8 or regimen 2: dosing on days 1, 2, 3). Patients with stable disease or response will be offered additional cycles. Results: A total of 15 patients have been included to date. The tumor types represent a typical widespread in phase I trials, including 3 cases of uterine/cervical cancer and 2 cases of breast cancer. The first 2 cohorts of 3 patients on dose level 1 (regimen 1 and 2) have been treated with no dose-limiting toxicities (DLTs) or serious adverse events (SAEs). Dose-escalation is proceeding for both regimens with 9 patients treated on dose level 2, 6 in regimen 1 where due to a DLT (likely disease-related and unlikely related to AS703569) the cohort was expanded, and 3 in regimen 2. Thus far, only two patients were withdrawn from the study due to disease progression and one patient withdrew consent. Two patients are ongoing at 4+ cycles and one at 3+. Conclusions: Treatment of patients in this phase I study of the aurora kinase inhibitor AS703569 at dose level 1 and 2 has been well tolerated over several cycles. Dose escalation is ongoing and analysis of PK and pharmacodynamics will be reported. No significant financial relationships to disclose.
Mismatch repair (MMR) and base excision repair (BER) protein expression correlates with clinical response to dacarbazine (DTIC)/temozolomide (TMZ) therapy of patients with metastatic melanoma
Authors: R. W. Sobol, H. Tawbi, D. M. Jukic, K. Mule, R. Mascari, J. M. Kirkwood
Journal: Journal of Clinical Oncology (2006)

8015 Background: The non-classical alkylators DTIC and TMZ exert their cytotoxic effect through methylation of DNA bases. DNA damage is repaired by direct reversal of the O6-MeG lesion by the protein O6-methylguanine-DNA methyltransferase (MGMT/AGT); recognition of alkylation-damage-induced replication errors by the MMR pathway and excision repair of alkylated bases (N7-MeG and N3-MeA) conducted by the BER pathway. We report the results of a study evaluating the correlation between MGMT, MMR and BER protein expression in tumor tissue of patients (pts) with metastatic melanoma and documented clinical response to chemotherapy. Methods: Frozen tumor tissue was obtained from 17 pts with metastatic melanoma treated with DTIC/TMZ. Tumors were classified as sensitive (S) if pts showed stable disease (SD), partial response (PR) or complete response (CR) by RECIST criteria; and resistant (R) if progressive disease (PD) was observed after 2 cycles of treatment with DTIC/TMZ. Immunohistochemical staining for MGMT, MLH1 (MMR), and DNA polymerase-ß (pol-ß, BER) was performed. Levels of expression were assessed by a pathologist blinded to response data. Fisher’s Exact and Wilcoxon Rank Sum statistical tests were used to assess correlations. Results: 9 tumors were considered to be sensitive (S) and 7 resistant (R). Clinical response was found to significantly correlate with functional MMR (increased MLH1 expression): 7 of 9 S tumors had high MLH1 expression as compared to 1 of 7 R (p-value=0.015). Clinical response was also found to be inversely correlated with pol-ß expression: 6 of 9 S tumors expressed low levels of pol-ß as compared to 1 of 7 R tumors (p-value=0.08). MGMT expression did not seem to correlate with response. Conclusions: The presence of a functional MMR pathway is a requirement for the cytotoxic effect of alkylating agents and was significantly correlated with clinical response. Decreased BER potential (pol-ß expression) was correlated with increased sensitivity to alkylator-based chemotherapy. These findings lend additional support to the view that DNA repair status correlates with response to alkylator-based chemotherapy for melanoma. No significant financial relationships to disclose.
Clinical relevance of TNM staging system according to breast cancer (BC) subtypes.
Authors: Y. Park, S. Lee, J. Kong, E. Cho, Y. Choi, J. Lee, S. Nam, J. Yang, J. Ahn, Y. Im
Journal: Journal of Clinical Oncology (2010)

632 Background: Understanding recent advances of tumor biology allow us to divide breast cancer (BC) into at least five subtypes. Different therapeutic approaches are needed based on these molecular subtypes. There has been reported that the association between nodal spread and tumor size was disrupted in BRCA related BC and triple negative breast cancer (TNBC) shows characteristically early relapse and poor prognosis. Therefore, the AJCC TNM staging system might not be equally effective as a prognostic indicator for all subtypes of BC. The aim of our study was to evaluate the usefulness of the TNM staging according to BC subtypes. Methods: We conducted a retrospective analysis of medical records of patients with histologically confirmed invasive BC who received curative surgery at Samsung Medical Center from 2000 to 2004. Relapse-free survivals (RFS) according to TNM stage were analyzed based on BC subtypes. Results: Of the 2,428 patients who had received surgery, 1,879 invasive BC patients who were available clinicopathologic data including immunohistochemical stainings were included. These patients were analyzed according to three subtypes; HR (hormone receptor)+, HER2+, and triple- negative (ER-/PgR-/HER2-) groups. As the stage was advanced, the slope of each stage of the Kaplan-Meier survival curves for RFS in patients with HR+ and HER2+ steadily steepened. In contrast, RFS curves merged from stage I to stage IIIA in TNBC patients without separation. There was only wide separation of RFS curves between stage I-IIIA and stage IIIB-IIIC in TNBC. Staging effect was more profound in HER2+ than in HR+ patients. At stage I and II, the HER2+ and TNBC had significantly worse outcomes than HR+ patients. The RFS curve of TNBC patients at stage III was in between HR+ and HER2+ patients. When the stage III was sub-analyzed, stage IIIA TNBC patients did not have a worse outcome than other subtypes, which is similar to those with HR+ patients. At stages IIIB and IIIC, the TNBC had worse outcomes than HR+ and similar to those with HER2+ patients. Conclusions: The currently used TNM staging system might not be enough for encompassing the tumor biology and for predicting clinical outcomes to make therapeutic decisions for all breast cancers, especially for TNBC patients. No significant financial relationships to disclose.