tbuckley/cabot-search huggingface dataset:
Induction chemotherapy with or without chemoradiation in intermediate-risk rectal cancer patients defined by magnetic resonance imaging (MRI): A GEMCAD study.
Authors: C. Fernandez-Martos, M. Safont, J. Feliu, C. Pericay, M. Gallen, R. Vera, J. Maurel, J. Aparicio, M. P. Escudero, G. Brown
Journal: Journal of Clinical Oncology (2010)

TPS196 Background: Different treatment strategies may be indicated for intermediate-risk (T1–2N1, T3N0) versus moderately high- (T1–2N2, T3N1,T4N0) or high-risk patients (T3N2, T4N1–2) based on differential survival rates and rates of relapse (Gunderson et al JCO 22: 1785-1796, 2004). T3 tumors are prognostically inhomogeneous and patients with extramural penetration > 5 mms and extramural venous invasion (EMVI) are associated with increased risk of local relapse but especially with distant failure. Thin-slice high-resolution MRI can identify those patients accurately (Smith NJ. Br J Surg. 2008 95:229-36). Bevacizumab monotherapy has significant antivascular and vascular normalizing effects in rectal cancer (Willett et al. J Clin Oncol 27:3020-3026, 2009) and in combination with capecitabine and oxaliplatin (CAPOX) is a standard treatment for metastatic disease. Purpose: To evaluate the efficacy of induction CAPOX/bevacizumab with selective chemo/radiotherapy (CT/RT) in patients with intermediate-risk (T3) rectal adenocarcinoma. Methods: Main eligibility criteria: 1. Patient with measurable disease at the baseline visit. 2. Tumor that meets all the following criteria in MRI (3-mm slices) of the pelvis: Distal border of tumor > 5 cm from the external edge of the anus and below the sacral promontory and tumor ≥2 mm from the mesorectal fascia and one or both of the following: T3 > 5 mm extramural penetration or presence of EMVI. 3. Candidate for R0 surgery with sphincter preservation surgery. All pre- and post-treatment MRI scans are reviewed independently by one radiologist (G.B.). Treatment: Induction CAPOX with bevacizumab are given for 3 cycles over 9 weeks and one additional cycle without bevacizumab. Patients undergo re-staging within 3 weeks of their 4th cycle with MRI. Those who respond (i.e. complete or partial response) proceed to surgery between 4-6 weeks from the last chemotherapy dose. Patients with stable or progressive disease receive capecitabine/radiation. Design: Simon 2-stage: α=0.1 β=0.1; 28 evaluable pts 1st stage and 41 evaluable pts for 2nd stage. Primary Endpoint: Response rate (RECIST). To date 12 patients have been registered. No significant financial relationships to disclose.
Results of cardiac monitoring during phase I trials of a novel histone deacetylase (HDAC) inhibitor LBH589 in patients with advanced solid tumors and hematologic malignancies
Authors: T. Fischer, A. Patnaik, K. Bhalla, J. Beck, J. Morganroth, G. H. Laird, S. Sharma, J. W. Scott, M. Dugan, F. Giles
Journal: Journal of Clinical Oncology (2005)

3106 Introduction: LBH589 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and inhibits hERG channel with an IC50 of 3.9 μM. Methods: In 2 phase I studies, LBH589 was administered as a 30 minute intravenous infusion on 2 schedules, days 1–3 and 8–10 of a 21 day cycle or days 1–3 and 15–17 of a 28 day cycle to adult pts with advanced solid malignancies (study 2101) or on a schedule of days 1–7 of a 21 day cycle to adult pts with hematologic malignancies (study 2102). Patients with impaired heart function were excluded, and drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (6 ECGs), and on days of dosing. ECG data were processed in a core lab by manual analysis. Results: 45 pts (median age: 60 yrs; 23 males, 22 females) were treated at 10 dose levels, range 1.2 - 20.0 mg/m2/day. PK analysis showed dose proportionality, T1/2 of 6 - 26 hr, and approximately 1.5 fold accumulation at steady state (day 3). PD analysis of PBL showed increased histone acetylation for 24 hours post-last dose at doses ≥ 4.8 mg.m2. A total of 1475 post-dose ECGs were performed. Central tendency analysis showed no change in QTcF on day 1; however, on day 3 of dosing, there was a dose related increase in QTcF of at most 20 msec. Frequency of outliers, QTcF > 500 msec and/or > 60 msec change from baseline, was 28% (12 pts) and occurred over a broad dose range, 4.8 mg/m2 - 20.0 mg/m2. Outlier ECGs occurred primarily on day 3 (7/12 pts) or later (3/12 pts) on days 4 or 5). Only 2 pts had outliers ECG on day 1. Six patients (14%) had QTc > 500 msec. Frquency of QTcF > 500 msec increased with dose. At doses ≤ 9 mg/m2, only 1 patient (1/33) had QTcF > 500 msec; while at doses > 9 mg/m2, 5 of 12 patients had QTcF > 500 msec. T wave and ST-T wave changes, primarily T wave flattening were frequently observed and were non-specific.Conclusions: LBH589 is a novel, potent HDAC inhibitor which was found to induce dose-related increases in QTcF of 20 msec or less at doses up to 20.0 mg/m2. Cardiac repolarization changes were delayed until day 3 perhaps due to a different mechanism effecting the hERG channel. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
Abstract 16980: Focal Impulse and Rotor Modulation for Atrial Fibrillation (AF) Ablation: Acute Response Based on Age and AF Type
Authors: Dan L Musat, Sanjiv Narayan, Kalyanam Shivkumar, Robert C Kowal, John M Miller, Suneet Mittal, Jonathan S Steinberg
Journal: Circulation (2013)

Introduction: Focal Impulse and Rotor Modulation (FIRM) is a novel intervention designed to map and ablate presumed fixed sources of atrial fibrillation (AF). Because it is not known if patients (p...
New consultant contract will exclude “opt-out” for weekend working, says government
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

The BMA has set itself up for a six week battle with the government over reforms to consultants’ contracts, after the health secretary said that a new contract would be imposed on the profession if negotiations over seven day working with the union were not fruitful.

Mark Porter, BMA council chair, called on Jeremy Hunt to “get real” over plans to introduce seven day services in the NHS. He said that, while doctors supported seven day hospital services, the government had repeatedly failed to respond to requests to outline how the plans would be staffed and funded.

In a report published on 16 July the Review Body on Doctors’ and Dentists’ Remuneration said that the “opt-out” clause in the 2003 consultant contract, which enables a consultant to choose whether or not to provide non-emergency care at weekends, should be removed.1

The report was published on the same day that Hunt delivered a speech at the King’s Fund on his vision for the NHS over …
Efficacy of SMIP-016, a novel CD37-directed biologic therapy, in human NHL tumor xenograft models
Authors: D. S. Barone, C. Nilsson, J. Ledbetter, M. Hayden-Ledbetter, K. Mohler
Journal: Journal of Clinical Oncology (2006)

2565 Background: Small Modular Immuno-Pharmaceuticals (SMIP) biopharmaceuticals belong to a novel proprietary biologic compound class that retain Fc mediated effector functions and are smaller than monoclonal antibodies. SMIP-016 is a SMIP product candidate that binds to CD37 on human B cells and has potent ADCC and apoptotic activity in vitro. CD-37 is known to be over-expressed in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). We have evaluated the activity of SMIP-016 in established human tumor xenograft models in nude mice. Methods: Nude mice were injected subcutaneously with either Ramos or Daudi tumor cells. At approximately 7 days post tumor inoculation the mice were randomized to groups with roughly equivalent mean tumor volumes (&gt;200mm 3 ) and were treated with SMIP-016 or rituximab as a comparator. Groups were evaluated for median survival time (MST), tumor volume and percentage of tumor-free animals. Results: In nude mice bearing Daudi tumors, SMIP-016 treated mice showed a significant improvement in MST compared to control mice (p &lt; 0.0001). Nude mice bearing Ramos tumors treated with SMIP-016 also demonstrated a significant enhancement in their median survival time (MST) in comparison to control mice (p &lt; 0.0001). In addition, mice receiving SMIP-016 administered in combination with rituximab in this model demonstrated improvements in survival time over either single agent therapy alone. Conclusions: SMIP-016 is effective in treating established tumors in these human tumor xenograft models. Addition of SMIP-016 to rituximab therapy resulted in enhanced survival times compared to animals treated with rituximab alone. [Table: see text]
Utilization of gastrostomy tubes during chemoradiotherapy for head and neck cancer: The University of Pittsburgh experience
Authors: B. T. McLaughlin, J. Diacopoulos, R. Carrau, D. E. Heron, R. P. Smith, M. K. Gibson, R. L. Ferris, J. R. Grandis, J. T. Johnson, A. E. Argiris
Journal: Journal of Clinical Oncology (2008)

20657 Background: Mucositis and dysphagia are common complications of CRT for HNC that may necessitate nutritional support with a gastrostomy tube (G-tube). Our institutional policy is to recommend against prophylactic G-tubes unless patients (pts) have progressive weight loss and dysphagia prior to CRT initiation. Progressive weight loss of >10–15% and/or severe dysphagia are indications for G-tube placement during CRT. Methods: We reviewed records of pts who underwent and completed CRT with curative intent, which included at least one traditional chemotherapeutic, for previously untreated HNC of any histology at a University hospital practice from 5/05 to 6/07. The timing and duration of G-tube placement as well as treatment-related complications were noted. Supportive care included close monitoring by an experienced team, swallowing exercises, opioid analgesics, mouth care, and intravenous hydration. Results: We identified and analyzed a total of 80 pts who received CRT; 59 as primary therapy (27 with induction therapy) and 21 as postoperative. Characteristics: 73/80 pts had squamous cell carcinoma; stage II, 1; stage III, 19; stage IV, 60; median age 57 years (20–82). Primary site: oral cavity, 19; oropharynx, 27; larynx, 12; hypopharynx, 5; nasopharynx, 7; unknown, 3; other, 7. RT doses ranged from 59.4–74 Gy (median 70 Gy). CRT regimens included cisplatin with or without cetuximab, 50; carboplatin, 11; cisplatin/paclitaxel, 3; pemetrexed/cetuximab, 14; docetaxel/erlotinib, 2. Grade 3 mucositis developed in 39% of pts. 33 G-tubes (41%) were placed (15 prior to CRT and 18 during CRT); 32 via percutaneous endoscopic gastrostomy; site infection or tube displacement occurred in 3 cases; esophageal dilatations were performed in 6 pts. Of 65 pts without prophylactic G-tubes, 18 (28%) required G-tube placement during CRT at a median of 30 days (17–41); median weight loss was 12% from baseline; 7/18 (39%) were in place at 6 months and 1 (6%) at 12 months. 8/15 pts (53%) who had prophylactic G-tubes required its use 12 months later. Conclusions: With aggressive supportive care, it is feasible to avoid G-tubes in the majority of pts undergoing CRT for HNC. Pts who require G-tube placement during CRT are unlikely to remain long-term dependent on G-tube use. No significant financial relationships to disclose.
Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma.
Authors: N V Cheung, G Heller
Journal: Journal of Clinical Oncology (1991)

We examined the efficacy of five commonly used drugs, teniposide (VM26), cisplatin (CDDP), cyclophosphamide (CPM), doxorubicin (DOXO), and vincristine (VCR) in a retrospective analysis of 44 clinical trials of induction chemotherapy for stage IV neuroblastoma patients newly diagnosed at older than 1 year of age. Dose intensity (DI) of each drug was calculated as milligrams per square meter per week. Linear regression analyses showed that the Dls of VM26 and CDDP had the greatest influence on clinical outcomes (ie, proportion of major response, median survival, and median progression-free survival [PFS]), while those of CPM and DOXO were less significant. VCR had no influence on the three clinical end points. Although many protocols extended treatment to more than 1 year, none of these end points correlated positively with the duration of therapy. Twenty-one weeks appeared adequate for achieving superior response, median survival, and median PFS. These results suggest that maximal dose intensification of selective drugs over a short duration may improve the outcome of patients with poor-risk neuroblastoma.
Outcome comparisons of four radiation therapy oncology group (RTOG) trials in patients with stage IV-T4 head and neck (H/N) cancer: Encouraging results using intra-arterial (IA) cisplatin (P) and concurrent radiation therapy (RT)
Authors: P. Kumar, J. Harris, A. S. Garden, K. Fu, K. T. Robbins, T. Pajak, K. K. Ang
Journal: Journal of Clinical Oncology (2004)

5527 Background: We conducted a comparison of overall survival (OS) and local-regional tumor control (LC) outcomes in patients with stage IV-T4 disease originating from the oral cavity, oropharynx or hypopharynx among 4 RTOG H/N trials using RT +/- chemotherapy. Methods: The four compared RTOG trials and their treatment regimens were as follows: 1. RTOG 8117–standard fractionated (SFX) RT [66 –73.8 Gy] & 3 cycles of concurrent IV P (100 mg/m2); 2. RTOG 9003 –SFX RT (70 Gy in 7 weeks) alone [Arm 1], & accelerated fractionated (fx) RT with concomitant boost (AFX-C) [72 Gy in 42 fxs over 6 weeks] [Arm 4]; 3. RTOG 9703–concurrent SFX RT (70 Gy/7 weeks in arms 1 and 3, and q other week over 13 weeks in arm 2] with IV daily P (10 mg/m2) / 5-FU (400 mg/m2 d/ CI last 2 wks of RT) [Arm 1], q other week of IV 5-FU (800 mg/m2/d x 5 days) / Hydroxyurea (1 gm po bid x 6 days) [Arm 2], or weekly IV P (20 mg/m2) / Taxol (30 mg/m2) [Arm 3]; & 4. RTOG 9615 –intra-arterial (IA) weekly P (100 mg/m2) x 4 weeks with SFX RT (70 Gy/7 weeks) [RADPLAT therapy]. Results: The estimated 2 year LC rates & OS are shown in Table 1. Using a Cox proportional hazards model stratified by RPA class, RADPLAT therapy reduced death rates by > 50% when compared with Protocols 9003 & 8117, and by 21% when compared to arm 1 of Protocol 9703; there was virtually no reduction in death rates when compared with arms 2 & 3 of Protocol 9703 (0.8% and 1.8%, respectively). Conclusions: RADPLAT therapy improves LC and OS when compared to RT alone (SFX or concomitant boost) and improves OS when compared to IV cisplatin and SFX RT. Additionally, LC and OS using RADPLAT therapy appear comparable to contemporary chemoradiation regimens. Further testing in a phase III randomized trial comparing RADPLAT therapy to IV chemotherapy and RT is warranted to validate our findings. No significant financial relationships to disclose.
Immunocytochemical localization of vacuolar H-ATPase in the opossum (Monodelphis domestica) kidney
Authors: B Bastani, L Yang, G Steinhardt
Journal: Journal of the American Society of Nephrology (1994)

With two different antibodies (a monoclonal antibody to the C terminus of the 31-kd subunit of H-ATPase and a polyclonal rabbit antiserum to whole bovine H-ATPase) the vacuolar-type H-ATPase pump in the different nephron segments of the gray short-tailed (Monodelphis domestica) opossum kidney has been immunocytochemically localized. There was moderate staining of the brush border and subvillar invaginations in the proximal convoluted tubules (PCT) of the opossum kidney only with the rabbit antiserum and not with the monoclonal antibody. This was in contrast to the rat kidney, where both antibodies showed significant staining of the brush border and subvillar invaginations. There was very minimal staining in the apical region of the thick ascending limb cells of the opossum as compared with a mild degree present in the rat kidney. The pattern and intensity of staining were similar in the remaining distal nephron segments with the only difference being that type A intercalated cells in the outer and inner medullary collecting ducts were less polarized in the opossum kidney. These findings suggest that different isoforms of H-ATPase exist in the brush border of the PCT versus the intercalated cells of the collecting duct in the opossum and between the PCT of opossum and rat kidneys.
Interactions and dynamics of hedgehog and Wnt pathway activation levels in ovarian cancer cell lines.
Authors: S. Schmid, F. Zhang, M. Zhang, B. He, D. Jablons, N. Teng
Journal: Journal of Clinical Oncology (2010)

e15515 Background: To assess the interactions and dynamics of the hedgehog (Hh) and Wnt pathway activation levels in three ovarian carcinoma cell lines (SKOV3, IGROV, OVCAR5) treated with two different Hh inhibitors. Methods: Three ovarian cancer cell lines (SKOV3, IGROV, OVCAR5) were cultured and treated over 24, 48, 72 and 96 hours respectively with 20 mM Cyclopamine, 20 mM FN (novel small molecule inhibitor of Gli) or 20 mM DMSO as control. The cells were harvested and mRNA was extracted. Quantitative RT-PCR was performed to determine the gene expression levels of the Hh (GLI1, PTCH1, SMO) and Wnt (AXIN2, FGF9) signaling mediators during the treatment. Results: SKOV3 and IGROV showed a statistically significant decrease in cell proliferation during the treatment, whereas OVCAR5 cells merely slowed down, however not significantly. In SKOV3 the Hh genes remained unchanged with both compounds during the first 48 hours, while the Wnt genes were stable under cyclopamine and moderately suppressed by FN. Both compounds however induced a sharp upregulation of GLI1 on day 3 followed by a significant increase in PTCH1 and SMO on day 4. Cyclopamine additionally induced a significant upregulation of the Wnt genes on day 4. Looking at IGROV, the Cyclopamine treated cells showed an over time significant increasing expression of GLI1 as well as of the Wnt genes. FN did not alter the expression of the Hh genes at all which remained at the level of untreated IGROV cells. The Wnt gene expression of IGROV however surged over time impressively under FN treatment. The experiment with OVCAR5 a cell line that has a downregulated Hh pathway and an upregulated Wnt pathway showed unaltered gene expression levels compared to untreated OVCAR5 cells for both compounds throughout the experiment. Conclusions: Besides demonstrating the significant effects of the two Hh Inhibitors on the proliferation rate of two of the three studied ovarian cancer cell lines, we could demonstrate the evolution of drug resistance by either upregulation of the Hedgehog pathway itself or by using the upregulation of the Wnt pathway as escape route. Shutting off such evasion maneuvers of resistant ovarian cancer cells may be pivotal to developing targeted therapies in ovarian cancer. No significant financial relationships to disclose.
Phase I study of E7389/gemcitabine combination in patients with advanced solid tumors
Authors: R. Goel, E. Chen, S. Welch, S. Laurie, L. Siu, D. Jonker, R. Srinivasan, L. Wang, P. Ivy, A. Oza
Journal: Journal of Clinical Oncology (2009)

e13509 Background: E7389 (E) is a synthetic analogue of halichondrin B, an investigational tubulin-based antimitotic drug. Gemcitabine (G) is a nucleoside analogue clinically active in several human tumours. These two drugs exhibit synergistic cytotoxic effects against the H522 non-small cell lung cancer (NSCLC) xenografts. Methods: A phase I study of these two drugs in combination was initiated in patients with advanced solid tumours. Two prior chemotherapy regimens for metastatic disease were allowed. Results: Patient characteristics: male 11/female 10; median age 59 (range 28–84); performance status 0 /1/2: n=1/13/7; prior chemotherapy 21, prior radiotherapy 7, prior immunotherapy 1; tumour types: ovarian cancer 3, endometrial cancer 3, NSCLC 3, gastric/esophageal adenocarcinoma 3, miscellaneous 9. Total number of cycles given 52, median cycles/patient (range) 2 (1, 8). Cohort (CT) 1: E/G given days 1,8,15 q28 days. Due to DLT, regimen changed in CT 2 with E/G given days 1, 8 q21 days. Cycles (C) given: median 2 range 1–8, total 52. Response: partial response 1 (ovarian cancer), stable 8 [minor response 4 (NSCLC 2, endometrial cancer 1, head and neck cancer 1)], progression 8, inevaluable 4. Conclusions: Further phase II investigation of this regimen should be considered at a dose of E 1.0 g/m 2 /G 1000 mg/m 2 q 3 weeks. [Table: see text] No significant financial relationships to disclose.
Development of Teratomas From Embryos Transplanted Into Outbred and Inbred Adult Hamsters&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Ivan Damjanov
Journal: JNCI Journal of the National Cancer Institute (1978)

Six- to 8½-day inbred MHA/SsLak and outbred Syrian golden hamster embryos and 14-day fetal lungs, testes, and portions of small intestine were transplanted into cheek pouches or under kidney capsules of adult recipients. Embryonic grafts gave rise to benign teratomas, irrespective of the age of the embryo, transplantation site, and the strain or stock of recipient. Fetal lung and testis grew little in extrauterine sites, whereas fetal intestine formed large mucus-filled cysts lined with proliferating and apparently functionally active epithelium.
Phase I-II study of two consecutive courses of high-dose epipodophyllotoxin, ifosfamide, and carboplatin with autologous bone marrow transplantation for treatment of adult patients with solid tumors.
Authors: J P Lotz, D Machover, B Malassagne, B Hingh, R Donsimoni, Y Gumus, J Gerota, Y Lam, M Tulliez, H Marsiglia
Journal: Journal of Clinical Oncology (1991)

We describe a phase I-II study of two consecutive 5-day courses of a three-drug regimen of ifosfamide (IFM), carboplatin (CBDCA), and either etoposide (VP-16) (regimen 1) or teniposide (VM-26) (regimen 2) in high doses together with autologous bone marrow transplantation (ABMT), for previously treated patients with ovarian carcinoma (OC), germ cell tumors (GCT), gestational trophoblastic disease (GTD), or oat cell carcinoma (OCC). Forty-four patients entered the study. Two patients with OC received regimen 1, and 22 were given regimen 2. Sixteen patients with GCT, two with GTD, and two with OCC were treated with regimen 1. Six patients (13%) died of toxicity. Nephropathy and esophagitis were the dose-limiting toxic effects. The maximum-tolerated doses (MTDs) were 1,500 and 200 mg/m2/d for 5 days for IFM and CBDCA, respectively, in combination with VP-16 250 mg/m2/d for 5 days (regimen 1), and 150, 1,500, and 200 mg/m2/d for 5 days for VM-26, IFM, and CBDCA, respectively (regimen 2). The response rate of patients with OC was 78% (complete response [CR], 14%). For patients previously resistant to chemotherapy, the response rate was 70%. There were no long-term disease-free survivors among patients with OC. The response rate of patients with GCT was 60% (CR, 33%). All responders with GCT were resistant to previous chemotherapy. Unmaintained CRs lasted 2, 6, 8+, 27+, and 37+ months. Of the two patients with GTD, one with previous resistance to chemotherapy attained a CR of 18+ months. One patient with OCC attained a CR lasting 6 months. The regimen possesses great antitumor activity. It produced CRs of long duration in a number of patients with GCT and GTD who were previously resistant to chemotherapy.
Do Unexpected and Cryptic FISH Lesions Of Chromosomally Normal MDS Patients Have Any Prognostic Relevance?
Authors: Paolo Bernasconi, Irene Dambruoso, Marina Boni, Paola Maria Cavigliano, Ilaria Giardini, Barbara Rocca, Rita Zappatore, Celeste Calvello, Marilena Caresana, Antonella Orlando, Mirko Farina, Roberta Sciarra
Journal: Blood (2013)