tbuckley/cabot-search huggingface dataset:
Management of synchronous lung nodules in patients with potentially curable head and neck cancer
Authors: J. Dowell, H. Ha
Journal: Journal of Clinical Oncology (2007)

16503 The presence of a solitary pulmonary nodule in patients with otherwise curable head and neck cancer is a complex clinical scenario. We retrospectively reviewed the management of such patients at the Dallas VA Medical Center to determine if our process for selecting patients to treat with curative intent was in fact identifying patients with meaningful survivals. All patients presented at the institutional multimodality head and neck tumor board from 1998 - 2004 were reviewed. This insured more than 24 months follow up for each patient. Included patients had head and neck cancer that was felt to be potentially curable with either surgery and/or radiation or a combination of chemotherapy and radiation. In addition, all had a solitary lung nodule that was biopsy proven and potentially resectable lung cancer. Pretreatment imaging included CT scans of the head and neck and chest. Patients all had adequate renal, pulmonary, and performance status to tolerate planned treatment for their head and neck cancer and thoracotomy for their lung cancer. In all cases, the head and neck cancer was addressed first followed by treatment of the lung cancer. Twelve patients were identified with potentially curable head and neck cancer and a synchronous solitary pulmonary nodule that was biopsy proven lung cancer. Six of these patients were determined to be candidates for aggressive treatment of both cancers. The pathologic stage, survival, and management for the 6 patients were as follows: The synchronous occurrence of potentially curable head and neck and lung cancers was uncommon in our population. Using stringent criteria for selection of patients who might benefit from an aggressive approach to both cancers, we achieved reasonable outcomes with a median survival for the group of 29 months and with 4/6 patients (67%) surviving more than 2 years. Curative intent therapy should be offered to appropriately selected patients. [Table: see text] No significant financial relationships to disclose.
Cancer gene therapy with a retrovirally transduced IL2-IFNγ-secreting allogeneic tumorvaccine in patients with progressive hormone refractory prostate cancer—A phase I/II trial
Authors: B. Gansbacher, T. Brill, B. Eisele, H. Kuebler, H. van Randenborgh, R. Paul, R. Hartung, F. Fend, H. Pohla, D. Schendel
Journal: Journal of Clinical Oncology (2007)

5127 Background: The purpose of this study was to determine whether immunization with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-γ (IFN-γ), would be tolerated and able to induce a prolongation of PSA doubling time in patients with progressive hormone refractory prostate cancer. Methods: 30 HLA-A0201-matched patients with progressive, hormone refractory prostate cancer, demonstrating three successive elevations in prostate specific antigen (PSA) values, received four intradermal injections on days 1, 15, 29 and 92, and then every 90 days as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, 27 patients received 15 million cells. The primary efficacy criterion was the difference in PSA doubling time (PSA-DT) determined in the pre-treatment phase (before start of vaccination) and in the trial treatment phase (during vaccination). Results: The study was completed according to protocol. Immunostimulation could be demonstrated in most of the 30 patients (histological evaluation of injection site biopsies, serial ELISPOT analysis of PBMCs). During vaccination there was a significant prolongation of the PSA-DT compared to the pre-vaccination period that came to 81% (prolongation from 63 days to 114 days (p &lt; 0.0035; ITT)). Twenty two of 30 patients (73%) responded to the vaccine administration as judged by prolongation of PSA-DT. In the majority of patients the administration was followed by a period of PSA stabilisation that was up to 641 days (“PSA plateau”). No dose limiting or autoimmune toxicities were seen. The median overall survival time since first vaccination was 981 days (mean value: 770 days). Conclusions: This vaccine strategy showed a prolongation of PSA-DT and was found to be safe and well tolerated. The results of this trial warrant the vaccine’s further clinical development. No significant financial relationships to disclose.
Diabody vinorelbine conjugate (DVC) composed of vinorelbine-tartrate conjugated to anti-DNMT1/SHH di-diabody induce ADCC, CDC, AMP and inhibit DNA methylation
Authors: G. N. John, J. Giannios, E. Seraj, G. Kanelopulos, P. Ginopulos, N. Alexandropulos
Journal: Journal of Clinical Oncology (2007)

11503 Background: Hormone refractory breast cancer (HRBC) is incurable due to malignant stem cells,which represent a potential nidus for the recurrent cancer that arises after treatment failure. Methods: From 126 metastatic HRBC patients,we obtained CSCs from recurrent tumor reservoirs missed from current chemotherapy,which had eradicated bulky tumor foliage.HRBC-CSCs were treated with DVC composed of vinorelbine linked onto anti-DNMT1/anti-SHH di-diabody. Results: Post treatment ,we observed antibody dependent cellular toxicity (ADCC),complement dependent cellular toxicity (CDC) ,and antibody mediated phagocytosis (AMP) mediated by the di-diabody.Next,we observed inhibition of SHH, which is overexpressed in CSCs,blocking HH binding to PTCH,and signaling from SMO and GLI. DNMT1 was downregulated blocking DNA methylation.This inhibited hTERT transcription blocking the telomerase activity of CSCs. DNA demethylation reactivated DEAF-1 upregulating PTEN,which antagonised PKB/mTOR,PI3K/AKT,src/VEGF , HIF-1a/survivin angiogenic and antiapoptotic pathways leading to synergistic inhibition of telomerase activity. RKIP was re-expressed inhibiting Raf-1/MEK1–2/ERK1–2,NFkB and STAT3 leading to downregulation of CD46 mediating CDC. PTEN by inhibiting AKT,it upregulated Drg-1.Also,PTEN re-expression inhibited synergistically with vinorelbine,the oncogenes bcl-2,bcl-xL and mcl-1 leading to upregulation of bid,bax and bak. DNA demethylation reactivated CDH1,RASSF1A,EDNRB,Kip1/p27,RhoE,NKX31,DLC-1,GSTP1, TIG1,TAP,Necl-1,RARb,NTRK2,MFPC7–8,p16/Rb,p53/p21,DOC- 2/DAB2,BTG2,maspin and DEFB1. Ki67,BrdU and MTT exhibited inhibition of CSC proliferation. DFF,PARP,TUNEL,SEM and TEM exhibited PCD type I,II and III in CSCs.We observed aponecrosis based on lysosomal damage independent of caspases.PCR exhibited inhibition of CSC markers CD44/a2b1/CD133,b-catenin,Sca1,Notch-1 and methylation marker SCNN1B. Conclusions: DVC eradicated efficiently HRBC-CSCs. No significant financial relationships to disclose.
2000 Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Clinical Practice Guidelines
Authors: Howard Ozer, James O. Armitage, Charles L. Bennett, Jeffrey Crawford, George D. Demetri, Philip A. Pizzo, Charles A. Schiffer, Thomas J. Smith, George Somlo, James C. Wade, James L. Wade, Rodger J. Winn, Antoinette J. Wozniak, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2000)

Article Tools ASCO SPECIAL ARTICLE Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.20.3558 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11032599 2000 Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Clinical Practice Guidelines Howard OzerxHoward OzerSearch for articles by this author , James O. ArmitagexJames O. ArmitageSearch for articles by this author , Charles L. BennettxCharles L. BennettSearch for articles by this author , Jeffrey CrawfordxJeffrey CrawfordSearch for articles by this author , George D. DemetrixGeorge D. DemetriSearch for articles by this author , Philip A. PizzoxPhilip A. PizzoSearch for articles by this author , Charles A. SchifferxCharles A. SchifferSearch for articles by this author , Thomas J. SmithxThomas J. SmithSearch for articles by this author , George SomloxGeorge SomloSearch for articles by this author , James C. WadexJames C. WadeSearch for articles by this author , James L. Wade IIIxJames L. Wade IIISearch for articles by this author , Rodger J. WinnxRodger J. WinnSearch for articles by this author , Antoinette J. WozniakxAntoinette J. WozniakSearch for articles by this author , Mark R. SomerfieldxMark R. SomerfieldSearch for articles by this author , for the American Society of Clinical Oncology Growth Factors Expert PanelxSearch for articles by this author Show More From the American Society of Clinical Oncology. https://doi.org/10.1200/JCO.2000.18.20.3558 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical Oncology
Impact of planning the location of death in children with cancer
Authors: V. Dussel, J. M. Hilden, J. Watterson, C. Moore, J. C. Weeks, J. Wolfe
Journal: Journal of Clinical Oncology (2005)

8063 Background: Dying at a planned location is considered an indicator of high quality end-of-life care; however, the effects of being able to plan location of death (LOD) have not been studied. Objective: Describe child and care characteristics of families who were able to plan LOD, and explore if planning LOD is associated with better outcomes at the time of death (TOD). Methods: Retrospective survey conducted between 1997–2001, of 144 parents of children who died of cancer, cared for at Dana-Farber Cancer Institute/Children’s Hospital, Boston, or Children’s Hospitals and Clinics, St. Paul/Minneapolis. Parents were asked if they were able to plan LOD. To explore impact of planning LOD, univariate analysis were followed by multivariate models clustering by physician and adjusted for diagnosis (hematological cancer vs. other tumors), type of death (progressive vs. toxic), and parental report of oncologist’s overall quality of care (QC) (high vs. low). Outcomes analyzed included being very comfortable with LOD, having preferred a different LOD, being very prepared for circumstances at TOD, and reporting a very peaceful atmosphere at TOD. Results: Univariate analyses are presented below. Among the 22 parents who did not plan and would have preferred a different LOD, all child’s deaths were at a hospital (7 in ICU), and 62% would have wanted the death to be at home. In multivariate models, planning LOD was not associated with peacefulness or preparedness at TOD. Parents who were able to plan were significantly more likely to feel very comfortable with LOD (OR: 6.81, p<.001) and were less likely to have preferred a different LOD (OR 0.04, p<.001). Conclusions: Parents who are able to plan their child’s LOD are highly likely to accomplish this goal and do not regret the decision. However, over one third of parents were unable to plan LOD and the majority would have preferred their child to die at home. Allowing for opportunity to plan the child’s LOD may contribute to a better family experience when death is inevitable. No significant financial relationships to disclose.
Schedule-dependent effects of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001)
Authors: S. Di Cosimo, P. Matar, F. Rojo, M. Guzman, S. Rodriguez, J. Jimenez, J. Arribas, F. Cognetti, H. Lane, J. Baselga
Journal: Journal of Clinical Oncology (2004)

3074 Background: mTOR plays a critical role in transducing proliferative signals mediated through the PI3-K/AKT pathway. We have previously demonstrated that everolimus (E) decreased p-4E-BP1 and p-p70S6K levels, the two known downstream targets of mTOR, and inhibited tumor cell proliferation. Interestingly, E-treatment increased the p-AKT levels. We investigated whether the blockade of EGFR by gefitinib (G) could prevent E-induced p-AKT and to determine the optimal schedule of combining E and G. Methods: Cell growth inhibition and western blot assays were performed on BT-474, MDA-MB-468 and DU-145 cancer cell lines. For the simultaneous exposure, cells were incubated for 72 hours with G and/or E, at doses including the IC50 for each drug and cell type. For the sequential exposure, cells were treated with G for 48 hours, washed twice and incubated for a further 48 hours with E, and viceversa. Results were analysed using the combination index (CI) method. Results: The simultaneous treatment of BT-474 and DU-145 cells with G and E inhibited cell growth more than each drug alone, resulting in an additive antiproliferative effect (CI=1). Furthermore, the sequential treatment with G followed by E produced synergistic effects (CI<1) in both cell lines. On the other hand, the effect of the combination in MDA-MB-468 cells, which are relatively resistant to G, was synergistic when the drugs were added simultaneously, and additive in the sequential schedule G followed by E. The sequential treatment with E followed by G produced antagonistic effects (CI>1) in all cell lines. G, at its IC50 dose, completely prevented E -induced p-AKT. In addition, G markedly enhanced the E-mediated decrease in p-4E-BP1 and p-p70S6K. Conclusions: Everolimus is a promising candidate for use in combination with G either in G-sensitive or -resistant tumors. The antitumor interaction between these two agents appears to be sequence-dependent. The optimal therapeutic schedule of the combination may be G applied during or before E. In-vivo evaluation of G and E combination is currently ongoing. No significant financial relationships to disclose.
Abstract 142: Modeling Drug-Induced Long QT Syndrome with Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Francesca Stillitano, Ioannis Karakikes, Chi-wai Kong, Brett Martinelli, Ronald Li, Roger J Hajjar, Jean-Sebastien Hulot
Journal: Circulation Research (2013)

Long QT syndrome (LQTS) is characterized by prolonged cardiac repolarization time and increased risk of ventricular arrhythmia. LQTS can be either inherited or induced notably after drugs intake. Mutations in genes encoding cardiac ion channels have been reported to underlie inherited LQTS. In contrast, drug-induced LQTS (diLQTS) most frequently arises from altered function of the hERG channel; the risk of developing diLQTS varies largely between subjects and most people who have life-threatening diLQTS have no known genetic risk factors. We investigated whether the susceptibility to develop diLQTS observed in vivo can be recapitulated in vitro using patient-specific induced pluripotent stem cell (iPSC) technology. We collected skin fibroblasts from ten subjects who developed significant diLQTS after administration of Sotalol and/or Erythromycin. Ten other individuals who displayed no changes in QT interval after administration of the same drugs, were selected. iPSC were generated by retroviral delivery of Oct4, Sox2, Nanog and Klf4 in 17 of the 20 individuals. We report preliminary results obtained from iPSC-derived cardiomyocytes (iPSC-CMs) of two subjects. All experiments were performed in a blinded fashion without knowledge of the associated clinical phenotype. Cardiac differentiation of iPSC resulted in the generation of spontaneously beating embryoid bodies. iPSC-CMs showed positive staining for TNNT2, ACTN2 and Cx43. Gene expression analysis confirmed the expression of NKX2.5, MLC2v, MYH6 and MYH7, and of the relevant KCNH2 gene. The two lines had similar basal electrophysiological properties as assessed by measurements of action potential (AP) by patch-clamp technique and extracellular field potentials (FP) using micro-electrode array (MEA). E4031, a classical HERG blocker, significantly prolonged the FP duration (FPD) in a dose-dependent manner in both lines (EC50: 30.19 and 51.57 respectively). When both Sotalol and Erythromicin were used, FPD was prolonged in one of the two samples in a dose-dependent manner (EC50Sotalol: 100; EC50Erythr: 9.64) while drug response was blunted in the other cell line. This study suggests that patient-specific iPSC can be used to model the functional abnormalities observed in acquired diLQTS.
Preoperative radiation (Preop RT) in rectal cancer: Effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial
Authors: J. F. Bosset, G. Calais, L. Mineur, P. Maingon, L. Radosevic-Jelic, A. Daban, E. Bardet, A. Beny, J. C. Ollier, L. Collette
Journal: Journal of Clinical Oncology (2005)

3505 Background: This 2 x 2 factorial trial evaluates the addition of CT to preop RT and that of postop CT vs nil on overall survival (primary end-point) and progression-free survival (secondary end-point). Methods: Eligibility: age<80 y, WHO PS 0–1. Arm 1: preop RT 45 Gy in 5 weeks (w). Arm 2: preop RT + two 5 day CT courses (5-FU 350 mg/m2/d; LV: 20 mg/m2/d), the 1st and 5th w of RT. Arm 3: preop RT + four postop CT courses. Arm 4: preop RT-CT + postop CT. We analyzed surgical results, compliance to postop CT and 5-year outcome. The study was planned to detect a mortality hazard ratio of.0.73 (2-sided Logrank test, a=5%, 80% power). Results: 1011 patients entered the trial: median age 63 y; male/female 73.1%/27.9%. T. distance from anal verge: < 5 cm:49.8%; 6–10 cm:43.6%; >10 cm: 6.6 %. T stage: T3: 90%; T4:10%. The median Fup is 5.4 years. Conservative resection was 55.6% vs 52.4% with preop RT-CT and preop RT, respectively (p = 0.05). One patient in four did not start postop CT due to various reasons. Among those who started, 58.5% received planned CT. 5 y OS Results: Preop RT-CT vs preop RT: 65.6% vs 64.8% (P=0.798). Postop CT vs nil: 67.1% vs 63.2% (P=0.132); the curves diverge after 4 years. 5 y PFS Results: Preop RT-CT vs preop RT: 56.0% vs 54.4% (P=0.545). Postop CT vs nil: 58.1% vs 52.2% (P=0.145); the curves diverge after 2 years. 5-y local failure: The assumption of no interaction is not validated. Local failure rates decreased in the 3 groups with chemotherapy: 8.8%, 9.6% and 8.0% with either preop, postop. or both, respectively vs 17.1% without (P=0.002). Conclusion: Some form of CT benefit to local control. The results do not indicate the best timing and do not suggest a benefit of both preop and postop CT. In view of the benefit of preop CT on conservative surgery and the bad compliance to postop CT, preop CT-RT might be preferred. The data shows no significant effect of CT (pre and postop) on OS nor on PFS. More follow up is needed to confirm the suggested late divergence of PFS and OS in favour of adjuvant CT. Supported in part by a grant from the French Research Ministry (PHRC 1992) and by NCI grants 2U10-CA11488–22 through 5U10-CA11488–34. No significant financial relationships to disclose.
Plasmapheresis Is an Effective Approach Preventing Clinically Significant Tumor Lysis Syndrome during Induction Therapy in AML Patients with Hyperleukocytosis
Authors: Vera V Troitskaya, Elena N. Parovichnikova, Andrey N Sokolov, Alina V Kochno, Darima S Badmazhapova, Larisa A Kuzmina, Tatyana V Gaponova, Sergey K. Kravchenko, Valeri G. Savchenko
Journal: Blood (2014)
Adjuvant treatment in resected pancreatic adenocarcinoma: A retrospective analysis of survival and prognostic factors in 141 patients
Authors: A. Bujold, R. Létourneau, R. Lapointe, M. Dagenais, A. Roy, C. Lambert, D. Donath, B. Fortin, M. Tardif, M. Jolicoeur
Journal: Journal of Clinical Oncology (2007)

15104 Background: Resectable pancreatic adenocarcinoma (PA) remains highly lethal. It is debatable whether adjuvant therapy can improve prognosis. Furthermore, what treatment should be delivered and for whom it is indicated is still of controversy. Methods: Between 1992–2004, retrospective data from the 141 patients who had a PA resected with curative intent in our centres were reviewed. Adjuvant treatment was as follows: 41 had chemoradiation (CRT), 1 neoadjuvant CRT, 10 chemotherapy alone (CT), 1 radiotherapy alone, and for 7 adjuvant treatment is unknown. The other 81 patients were observed. Overall survival (OS), relapse-free survival (RFS), locoregional and distant failure-free survival (LRFFS and DFFS) were analysed according to published prognostic factors. Kaplan-Meier curves with log-rank tests and Chi-2 coefficients were computed for the analysis. Results: Median age at diagnosis was 61 years. Overall, 63% of the patients were node positive, 67% had lymphovascular invasion (LVI), 71% had elevated CA-19.9 values and 50% operative blood loss &gt;550cc. Table 1 displays these prognostics factors by treatment groups. For the entire cohort, median OS was 16.9 months; 1-year and 3-year OS were 76% and 43% respectively. No influence of treatment arm was found on OS (p=0.71). Negative nodes, normal CA-19.9 values, absence of LVI and blood loss &lt;=550cc had all a positive influence on OS (all p&lt;0.05). RFS and DFFS were not affected by adjuvant treatment (p=0.61 and 0.68, resp.), but a lower LRFFS was associated with it (p=0.006). Conclusions: In this retrospective analysis, despite the imbalance of prognostic factors among treatment groups, toward more ill patients in CT and CRT arms, there is no difference in OS, DFS and DFFS between arms. Therefore, adjuvant treatment seems to counterbalance the effect of poor prognostic factors. A randomized prospective trial would be needed to further address the issue. [Table: see text] No significant financial relationships to disclose.
GPs to discuss possible industrial action in crisis summit
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The chair of the BMA’s General Practitioners Committee has warned the government that the future sustainability of UK general practice is “in serious question,” ahead of a crisis summit later this month.

Chaand Nagpaul said that the first special meeting in 13 years of local medical committees (the statutory bodies that represent GPs locally)—due to take place on 30 January—highlighted the severity of the current crisis in general practice and would bring to the fore “an issue that can no longer be ignored by politicians.”

The meeting has been organised by the BMA in response to growing concern among members of local medical committees that rising demand from patients, stretched resources, and over-regulation were harming the care of patients and causing widespread burnout in the profession, leading to ongoing problems with recruitment and retention. …
Reimagining Electronic Clinical Communication in the Post-Pager, Smartphone Era
Authors: Raman R. Khanna, Robert M. Wachter, Michael Blum
Journal: JAMA (2016)

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