tbuckley/cabot-search huggingface dataset:
Extent of cervical involvement in endometrial cancer as a predictor of outcome
Authors: J. S. Ferriss, W. Brix, M. Henretta, K. Hanley, M. Stoler, L. Duska, S. Modesitt
Journal: Journal of Clinical Oncology (2009)

e16566 Background: Endometrial cancer will affect 40,000 women this year. Extent of myometrial invasion and presence of cervical stromal disease are risk-factors for metastasis and recurrence. Uterine cervical involvement is often not known in advance of surgery, and superficial involvement may not be seen at frozen section. The objective of this study was to determine if the extent of cervical invasion is a predictor of outcome. Methods: The institutional cancer registry was searched for cases of stage II uterine cancer from 1996–2006. Inclusion criteria were endometrioid histology and clinical data and pathology available for evaluation. Demographics, extent of surgery, tumor grade, depth of myometrial invasion, presence of lymph-vascular space invasion (LVSI), and last follow up were collected. In addition, a gynecologic pathologist evaluated all slides to determine depth of cervical stromal invasion. Statistical analysis to compare predictors of outcome was performed. Results: There were 800 cases of endometrial cancer diagnosed from 1996–2006, 75 (9%) were stage II. Fifty two cases met all inclusion criteria. Mean age at diagnosis was 63.4 years. Mean BMI was 31.6. Ninety four percent were white, 4% black, and 2% Asian. All patients had a hysterectomy, 6 (11.5%) had a radical hysterectomy and 36 (69%) had lymphadenectomy performed. Eighteen (34.6%) were stage IIA and 32 (61.5%) were IIB. LVSI was seen in 15 (28.8%) cases. On pathologic review, 37.5% had no cervical stromal invasion, 42.5% had invasion of less than half and 20% had invasion of more than half of the cervical stroma. Forty patients (77%) received adjuvant radiation. There were 8 recurrences and 6 disease-related deaths. The mean follow up period was 30 months. Extent of cervical invasion did not correlate with recurrence or survival. Factors associated with increased risk of recurrence were: LVSI (p = 0.017), lack of lymph node sampling (p = 0.035), and age &gt;55 years (p = 0.027). Women with and without recurrence were compared and did not significantly differ. Conclusions: In this study with pathologic review, extent of cervical involvement in stage II endometrial cancer was not associated with increased risk of recurrence or death. Age &gt;55 years, lack of node sampling and presence of LVSI were predictors of recurrent disease. No significant financial relationships to disclose.
PTH-001 Endoscopic management and outcomes for patients with food bolus obstruction
Authors: Amgad Abdelrahman, Perminder S Phull
Journal: Endoscopy (2018)

<h3>Introduction</h3> Food Bolus Obstruction (FBO) often presents as an emergency, with an estimated incidence of 13 per 100 000 population (Longstreth <i>et al.</i> Gastrointest Endosc 2001;53:193–8). Endoscopic management is required in many cases, but carries a risk of complications. Our aim was to audit the management and outcomes for patients with FBO admitted to our institution. <h3>Methods</h3> We reviewed all cases presenting with FBO to the Emergency Department and/or admitted to the hospital between October 2014 and October 2017. Data was retrieved from the hospital electronic patient records for demographics, duration of stay, performance of endoscopy as well as the endoscopic findings, FBO removal technique and any complications. <h3>Results</h3> A total of 160 patients presenting with FBO were identified; 103 (64%) males and 57 (36%) Females, average age of 65 years. Of these, 55 (34%) patients passed the food bolus spontaneously without a referral for endoscopy. Of the 105 (66%) patients who had an endoscopy, data on the time of admission and the time of endoscopy was available for 62 (59%) patients. 11 (18%) patients had endoscopy within 4 hours and 51 (82%) within 24 hours. At endoscopy, an addition 32 (30%) patients were found to have passed the food bolus spontaneously, whilst 72 (70%) needed endoscopic intervention; the push technique was most often employed (33% of cases). Endoscopic therapy was effective in 66 (91.2%) patients. Of the 6 patients in whom initial endoscopic therapy was unsuccessful, 2 patients were intolerant of the procedure (one required an endoscopy under general anaesthetic, and the other patient underwent a repeat procedure the following day successfully); 2 patients had FBO at a high level requiring ENT referral; 2 patients sustained an oesophageal perforation). The underlying pathology was documented as benign stricture/web/Schatzki ring in 20 (19%) of cases, oesophagitis in 12 (11%), oesophageal malignancy in 9 (8%), hiatus hernia in 3 (3%), eosinophilic oesophagitis 1 (1%), oesophageal spasm 1 (1%), Barrett's oesophagus 1 (1%) and candidiasis in 1 (1%); 57 (55%) of patents had no underlying oesophageal abnormality. Endoscopic complications were seen in 4 (4%) patients – mucosal tear in 2 cases and perforation in 2 cases. The duration of hospital stay was 1 day in 136 (85%), 2 days in 16 (10%) and 3 or more days in 8 (4%) of cases. <h3>Conclusion</h3> FBO resolves spontaneously in around half of cases. Endoscopic therapy has a high success rate for the remaining patients, but is associated with a small risk of complications.
Role of Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer
Authors: Andreas du Bois, Thaïs Baert, Ignace Vergote
Journal: Journal of Clinical Oncology (2019)

Article Tools REVIEW ARTICLES Gynecologic Cancer Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.19.00022 Journal of Clinical Oncology - published online before print August 12, 2019 PMID: 31403864 Role of Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer Andreas du Bois, MD, PhD1xAndreas du BoisSearch for articles by this author; Thaïs Baert, MD, PhD1,2xThaïs BaertSearch for articles by this author; and Ignace Vergote, MD, PhD2,3xIgnace VergoteSearch for articles by this author Show More 1Kliniken Essen-Mitte, Essen, Germany2Katholieke Universiteit Leuven, Leuven, Belgium3Universitaire Ziekenhuizen Leuven, Leuven, Belgium https://doi.org/10.1200/JCO.19.00022 First Page Full Text PDF Figures and Tables © 2019 by American Society of Clinical Oncology
Pharmacological evaluation of iso-oxazole-dehydelone as a potent third generation microtubule stabilization epothilone antitumor agent
Authors: Ting-Chao Chou, Xiuguo Zhang, Nian Wu, Ye Ingrid Yin, Yong Li, Dan Zhang, David C. Myles, Samuel J. Danishefsky
Journal: Cancer Research (2006)

509  Overexpression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies related to oxygen deficiency. Since increased HIF-1 expression correlates with advanced disease stage, increased angiogenesis and poor prognosis, HIF-1 and its signaling pathway have become targets for cancer chemotherapy. In this study, we identified noscapine to be a novel small molecule inhibitor of the HIF-1 pathway based on its structure-function relationships with HIF-1 pathway inhibitors belonging to benzylisoquinoline class of plant metabolites and/or to microtubule binding agents. We demonstrate that noscapine treatment of human glioma U87MG and T98G cell lines exposed to the hypoxic mimetic agent, CoCl2, inhibits hypoxia-mediated HIF-1α expression and transcriptional activity as measured by decreased secretion of VEGF, a HIF-1 target gene. Inhibition of hypoxia-mediated HIF-1α expression was due, in part, to its ability to inhibit accumulation of HIF-1α in the nucleus and target it for degradation via the proteasome. One mechanism of action of microtubule binding agents is their antiangiogenic activity associated with disruption of endothelial tubule formation. Here we show that noscapine has similar properties in vitro. Thus, noscapine may possess novel antiangiogenic activity associated with two broad mechanisms of action. First, by decreasing HIF-1α expression in hypoxic tumor cells, upregulation of target genes, such as VEGF, would be decreased concomitant with its associated angiogenic activity. Second, by inhibiting endothelial cells from forming blood vessels in response to VEGF stimulation, it may limit the process of neo-vascularization, correlating with antitumor activity in vivo. For more than 75 years, noscapine has traditionally been used as an oral cough suppressant with no known toxic side effects in man. Thus, the studies reported here have found a novel function for an old drug. Given its low toxicity profile, its demonstrated antitumor activity in several animal models of cancer and its potential to inhibit the HIF-1 pathway, noscapine should be considered as an antiangiogenic chemotherapy for glioma.
Impact of Pre-Emptive Rituximab Treatment for Epstein-Barr Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: A Longitudinal Study of 110 Patients
Authors: Nicolas Stocker, Myriam Labopin, Inès Boussen, Baptiste Lamarthée, Florent Malard, Agnès Bonnin, Vincent Marechal, Corinne Amiel, Frédérique Quignon, Joël Gozlan, Giorgia Battipaglia, Remy Duléry, Federica Giannotti, Annalisa Ruggeri, Béatrice Gaugler, Mohamad Mohty, Eolia Brissot
Journal: Blood (2017)
Modulation of cortical and subcortical brain areas at low and high exercise intensities
Authors: Eduardo Bodnariuc Fontes, Henrique Bortolotti, Kell Grandjean da Costa, Brunno Machado de Campos, Gabriela K Castanho, Rodrigo Hohl, Timothy Noakes, Li Li Min
Journal: British Journal of Sports Medicine (2019)

Introduction The brain plays a key role in the perceptual regulation of exercise, yet neuroimaging techniques have only demonstrated superficial brain areas responses during exercise, and little is known about the modulation of the deeper brain areas at different intensities. Objectives/methods Using a specially designed functional MRI (fMRI) cycling ergometer, we have determined the sequence in which the cortical and subcortical brain regions are modulated at low and high ratings perceived exertion (RPE) during an incremental exercise protocol. Results Additional to the activation of the classical motor control regions (motor, somatosensory, premotor and supplementary motor cortices and cerebellum), we found the activation of the regions associated with autonomic regulation (ie, insular cortex) (ie, positive blood-oxygen-level-dependent (BOLD) signal) during exercise. Also, we showed reduced activation (negative BOLD signal) of cognitive-related areas (prefrontal cortex), an effect that increased during exercise at a higher perceived intensity (RPE 13–17 on Borg Scale). The motor cortex remained active throughout the exercise protocol whereas the cerebellum was activated only at low intensity (RPE 6–12), not at high intensity (RPE 13–17). Conclusions These findings describe the sequence in which different brain areas become activated or deactivated during exercise of increasing intensity, including subcortical areas measured with fMRI analysis.
CD40 Agonist Antibodies in Cancer Immunotherapy
Authors: Robert H. Vonderheide
Journal: Annual Review of Medicine (2019)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 antibodies of varying formulations have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, readily managed in the outpatient setting. Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with melanoma, and major tumor regressions have been observed in patients with pancreatic cancer, mesothelioma, and other tumors in combination with chemotherapy. In a recent study of chemotherapy plus CD40 mAb, with or without PD-1 mAb, the objective response rate in patients with untreated, metastatic pancreatic cancer was &gt;50%. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an in situ vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert so-called cold tumors to hot ones (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.
Phase I/II trial of initial treatment with chemo-radiation in patients with highly advanced gastric adenocarcinoma
Authors: Kohshi Kumagai, Yoshiro Saikawa, Ryo Ito, Takahiro Igarashi, Tsuyoshi Kiyota, Rieko Nakamura, Masaki Ohashi, Norihito Wada, Masashi Yoshida, Tetsuro Kubota, Koichiro Kumai, Masaki Kitajima
Journal: Cancer Research (2007)

2654  As it is reported that the median survival time (MST) of clinical stage IV gastric cancer patients after curative surgery is less than 1 year, the outcome of highly advanced gastric cancer patients is still poor, regardless of adjuvant chemotherapy with conventional anticancer agents. A recent development of novel anticancer agents has improved a therapeutic outcome for advanced gastric cancer. The present main drug in Japan is S-1, which consists of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)]. S-1 is easily used at outpatient with high efficacy rate and low toxicity, and it is also noted that S-1 shows better efficacy in combination with other anticancer drugs than S-1 alone. As chemo-radiation therapy has been recognized as one of the standard therapies for gastric cancer, radiation combined with effective chemotherapeutic regimens including S-1 will be an attractive therapy for such patients with poor prognosis with highly advanced gastric cancer.  This is the first report of the phase I/II study to attempt clarifying the beneficial effect and the toxicity with chemo-radiation therapy including S-1 in highly advanced gastric cancer patients. In the study, after determination of the recommended dose of low-dose CDDP at 6mg/m2/day in the phase I study, 30 cases with stage IIIB or IV gastric cancer were treated with S-1 at 80mg-120mg/body/day for 3 weeks, CDDP at 6mg/m2/day div, for 5 days followed by 2-day interval, and 40Gy (20 fraction of 2 Gy) radiation for 4 weeks, irradiating primary tumor and perigastric lymph nodes.  Clinical evaluation after the therapy showed 19 PRs (partial response), 8 NCs (no change), and 1 PD (progressive disease), resulting in 65.5% (19/29cases) of efficacy rate. Eight out of 30 patients underwent surgery, and 3 of these 8 patients showed a pathologically complete response (grade 3 effect) and the other 3 patients showed a partial response (grade 2 effect), suggesting that a high histological response (6/8 cases; 75.0%) is expected by the chemo-radiation. MST of these patients from the initial treatment reached to 18 months, suggesting a good prognostic outcome for such patients with expected poor prognosis. Approximately, 60% of the patients showed grade 3, 4 of bone marrow toxicity and 20% showed grade 3, 4 of gastrointestinal toxicity, while the most of the patients showed improvement of QOL including appetite.  Chemo-radiation with effective chemotherapeutic regimen with S-1 will be a potent regimen for obtaining high histological response with tolerable toxicity, and improving QOL in highly advanced gastric cancer patients.
The influence of the proton pump inhibitor pantoprazole on the distribution of doxorubicin in solid tumors with and without expression of P-glycoprotein
Authors: Krupa Patel, Ian Tannock
Journal: Cancer Research (2008)

3233  Background: Anti-cancer drugs gain access to solid tumors via the blood, and must penetrate tissue to reach all viable cancer cells. Limited drug distribution is an important cause of drug resistance in solid tumors1. Basic drugs (such as doxorubicin) may be sequestered in acidic organelles, and this may contribute to drug resistance by (i) diverting drugs from their target DNA and (ii) decreasing drug that is available for penetration to more distant cells. P-glycoprotein (PgP) is expressed on endosomal membranes of PgP expressing cells, and sequestration of drugs in acidic endosomes contributes to drug resistance in such cells2. Proton pump inhibitors, such as pantoprazole (PPZ), raise endosomal pH and decrease sequestration of basic drugs in acidic compartments3, 4, this may allow more drug to interact with DNA while decreased net cellular uptake of drug may allow greater penetration to cells distant from blood vessels. Here we investigate whether PPZ enhances the distribution of doxorubicin in solid tumors.  Methods: Wild-type and PgP overexpressing multilayered cell cultures (MCCs) were used to evaluate the penetration of radiolabeled doxorubicin with and without pre-treatment with PPZ. Nude mice bearing MCF-7 human mammary tumors with high or low expression of PgP were treated with doxorubicin with or without prior PPZ or PgP inhibitors. Tumors were excised, frozen, sectioned and imaged for doxorubicin and for CD31 (a blood vessel marker) using immunofluorescence. The relationship between doxorubicin and distance to the nearest blood vessel was quantified in tumor sections1.  Results: Doxorubicin had better tissue penetration in MCC and tumors that over-expressed PgP than in wild type MCC or tumors, presumably due to lower cellular uptake of drug by cells. Reversal of PgP with classical inhibitors (e.g. verapamil, PSC-833) decreased penetration of doxorubicin in MCC and tumors. Pretreatment with PPZ markedly increased penetration of doxorubicin in PgP-overexpressing (but not wild-type) MCCs and tumors. Studies of the effect of PPZ on doxorubicin-induced growth delay of wild-type and PgP-expressing tumors are in progress.  Conclusions/Discussion: Pantoprazole (in contrast to classical PgP inhibitors) leads to better distribution of doxorubicin in PgP overexpressing MCCs and solid tumors. This is presumably because of decreased sequestration of drug in acidic organelles and decreased uptake of drug by proximal cells. Use of PPZ to enhance the distribution and cytotoxicity of doxorubicin in tumors that express PgP might be a novel and effective treatment strategy.  1 Tredan O et al, JNCI 2007;99: 4441-54. 2Rajagopal A, Simon SM, Mol Biol Cell 2003;14: 3389-99. 3Lee CM, Tannock IF, Br J Cancer 2006;94:863-9 4Luciani F et al, JNCI 2004;96:1702-13
Functional characterization of somatic nonsense mutations of p53
Authors: Mingde Luo, Baojin Fu, Clark Henderson, Alison Klein, Jennifer Pietenpol, Christine Iacobuzio-Donahue
Journal: Cancer Research (2007)

4554  We used publicly available information from the IARC TP53 database and experimental validation to characterize the functional consequences of somatic nonsense mutations of p53. Of 21,587 mutations reported in p53, 1571 (7.4%) are nonsense mutations the majority of which occurred at CpG sites (59%) or resulted from a transition event (61%). The distribution of nonsense mutations showed a significant correlation with the predicted ability to trigger Nonsense Mediated Decay (NMD) in that they occurred in NMD-competent regions of the p53 coding sequence more frequently than expected due to chance (p
Weekly cetuximab (CET) plus oxaliplatin (OX), infusional 5-fluorouracil (5-FU) and radiation therapy (RT) as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A phase I study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: F. Lordick, C. Meyer zum Büschenfelde, P. Thuss-Patience, N. Röthling, H. Geinitz, V. Budach, G. Schumacher, H. Friess, J. R. Siewert, C. Peschel
Journal: Journal of Clinical Oncology (2009)

e15507 Background: CET, a chimeric monoclonal IgG1 antibody that targets the epidermal growth factor receptor (EGFR), has proven activity in a variety of SCC models in vitro and in vivo and has also been shown to enhance the activity of both chemo- and radiotherapy. Methods: Patients (pts) with locally advanced ESCC received CET for 2 weeks at an initial dose of 400mg/m 2 (d - 15) i.v. followed by 250mg/m 2 (d -8) before they started a neoadjuvant dose escalation regimen. Pts received weekly CET 250mg/m2 plus RT 25 x 1.8 Gy (cumulative dose 45 Gy) d1–33. Cohort 1–3 received escalating doses of OX 45–50 mg/m 2 d1,8,22,29 plus 5-FU 180–200–225 mg/m 2 /d; d1–5,8–12,15–19,22–26,29–33). Surgery was scheduled 4–6 weeks after RT. Toxicity was assessed according to NCI-CTC. Response was categorized according to the histopathologic score. Results: 15 pts were enrolled (2 female, 13 male; mean age 62 years, ECOG-PS 0 or 1). All pts had locally advanced SCC (uT2–4, cNx, cM0–1a) of the cervical (n=1), the upper (n=5) or the distal (n=7) esophagus. 6 pts were treated in cohort 1 and 3 pts in cohort 2 without any dose limiting toxicity (DLT). Of 6 pts treated in cohort 3, 1 pt developed grade 3 diarrhea and mucositis. All other observed toxicities were mild or moderate: anemia n=12, neutropenia n=2, thrombocytopenia n=3, nausea/vomiting n=8, mucositis n=6, diarrhea n=4, neuropathy n=4, hand-foot-syndrome n=8, skin rash n=14, no infection and no infusion-related reactions were observed. 12 pts underwent abdomino-thoracic esophagectomy with no postop. mortality; 3 pts were not resected. 8/12 resected pts had an R0 resection (67%) and 4 pts (33%) achieved a histopathological complete response (score 1a). Conclusions: 2 weeks of CET (400mg/m 2 and 250mg/m 2 ) followed by weekly CET (250mg/m 2 ) plus OX 50mg/m 2 d1,8,22,29, 5-FU 225 mg/m 2 /d d1–5,8–12,15–19,22–26,29–33 and RT 45 Gy (1.8Gy/f) was shown to be safe as neoadjuvant treatment for locally advanced ESCC. The anti-tumor activity of this regimen is promising and is being further investigated in an ongoing phase II study. [Table: see text]