tbuckley/cabot-search huggingface dataset:
The clinical-pathologic factors relevant to intraperitoneal chemotherapy in ovarian cancer: An analysis of two Gynecologic Oncology Group trials
Authors: D. Tewari, T. Chunqiao, D. K. Armstrong, M. Markman, T. J. Herzog, B. J. Monk
Journal: Journal of Clinical Oncology (2008)

5549 Objectives: Intraperitoneal chemotherapy (IP) has been recommended in the treatment of ovarian cancer with small volume or no residual disease based largely on key Gynecologic Oncology Group (GOG) clinical trials. The objective of this study was to assess the role of clinical-pathologic factors in the response of patients treated with intraperitoneal chemotherapy from two randomized GOG phase III trials comparing IP versus intravenous (IV) therapy. Methods: An exploratory analysis was performed on GOG protocols 114 and 172. The associations between clinical characteristics and progression-free survival (PFS) and overall survival (OS) were evaluated separately for IV and IP therapy and the pooled data was analyzed for associations between prognosis and clinical-pathologic factors. Results: 877 patients were included in the analysis with patient characteristics similar between both protocols. The PFS and OS were also comparable between the IV and IP arms of each trial. When both studies were combined, the median PFS was 25.1 vs. 20.0 months for IV and IP therapies, respectively (p=0.021) with a significant advantage in OS of 60.4 vs. 51.4 months towards the IP treatment (p=0.021). Clinical-pathologic factors were evaluated separately for IV and IP therapy on PFS and OS. Clear cell and mucinous histologies, gross residual disease, age greater than 60 and tumor grade adversely impacts prognosis. The risk of disease progression for IP was estimated to decrease by 19% as compared to IV (HR: 0.81, 95% CI: 0.70–0.94, p=0.006). A similar reduction was seen for risk of death (adjusted HR: 0.80, 95% CI: 0.68–0.94, p=0.007). GOG 172 patients who completed 6 IP cycles had a much longer survival compared to patients who received a combination of IP and IV therapy for 6 cycles. However, the clinical outcome did not differ between patients who had 1–2 IP cycles and who had 3–5 IP cycles. Conclusions: The clinical pathologic characteristics relevant to the prognosis in patients with ovarian cancer are similar between IV and IP therapies. Patients completing 6 cycles of IP therapy may receive the greatest advantage from IP treatment. The limitation of this exploratory analysis warrants the need for additional studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Gynecologic Oncology Group New Investigator Award
Biomarker analysis and final efficacy and safety results of a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase angiogenesis inhibitor
Authors: T. E. Hutson, I. D. Davis, J. H. Machiels, P. L. de Souza, K. Baker, W. Bordogna, R. Westlund, T. Crofts, L. Pandite, R. A. Figlin
Journal: Journal of Clinical Oncology (2008)

5046 Background: The von Hippel-Lindau (VHL) protein, a key regulator of angiogenesis, is frequently functionally impaired in renal cell carcinoma (RCC), either by somatic DNA mutations or gene hypermethylation. This results in the accumulation of hypoxia inducible factor (HIF) and increased expression of pro-angiogenic factors. Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit. In a Phase II study in metastatic RCC dosed at pazopanib 800 mg QD (n=225) the PR rate at wk 12 was 27% [ASCO 2007; abstract #5031]. Final ORR and PFS (per RECIST) will be available early 2008. Circulating VEGF, sVEGF1–2, and CEC, and tumor tissue VHL gene variations were correlated with tumor response. Methods: Platelet-poor plasma and serum samples for VEGF, sVEGFR1, and sVEGFR2, were obtained on Day 1, wk 4, wk 8, and wk 12 (n=225). Serum samples for CEC were collected at baseline (n=63); the CEC population was defined as CD146+, CD105+, DAPI+ and CD45-. DNA was extracted from archived tumor tissue and analyzed for VHL mutations (n=78) and hypermethylations (n=69). Results were correlated with the maximum decrease in the sum of the longest diameter (SLD) and with response (CR, PR, SD, & PD) at 12 wks. Results: VHL gene variations (mutations or methylation) were observed in 90% (70/78) of pts with the following response distribution: 30% PR, 46% SD, 9% PD and 16% unknown/discontinued. Lack of VHL gene variation was observed in 10% (8/78) of pts with the following response distribution: 38% PR, 25% SD, 13% PD and 25% unknown/discontinued. At wk 12, a decrease in sVEGFR2 compared with baseline was significantly correlated with tumor response (P=0.00002). No significant correlation was observed between VEGF, sVEGFR1, CEC, and SLD/tumor response at wk 12. Conclusions: Decrease in sVEGFR2 was significantly correlated with tumor response. No correlation was observed between 12 wk response and VHL status or other soluble markers (sVEGFR1, VEGF and CEC). The biomarker analyses will be correlated with final ORR and PFS data. Final efficacy and safety data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Bayer, GlaxoSmithKline, Pfizer Oncology, Wyeth GlaxoSmithKline Bayer, Pfizer Oncology, Wyeth Bayer, GlaxoSmithKline, Pfizer Oncology, Wyeth
Case 22-1995
Authors: D.M. Shahian, E.J. Mark
Journal: New England Journal of Medicine (1995)

Presentation of CaseAn 82-year-old woman was admitted to the hospital because of odynophagia and a large superior mediastinal mass.The patient had severe kyphoscoliosis, with extensive intervertebral disk disease and associated degenerative changes. She had had intermittent heartburn for many years; an upper gastrointestinal series performed 41/2 years before admission was normal. Two-and-a-half months before admission the patient again reported heartburn, which was not relieved by small doses of antacid medication, and she began to have increasingly severe back pain centered around the first lumbar vertebral body. Examination showed a satisfactory and largely painless range of spinal motion . . .
Abstract P2-06-07: PRKCQ regulates taxol sensitivity of triple negative breast cancer cells via IL-6/Stat3 signaling
Authors: HY Irie, J Byerly
Journal: Cancer Research (2016)

Abstract Background/Rationale. While some patients with triple negative breast cancer achieve long-term remission with chemotherapy, many have cancers that are chemotherapy resistant. The lack of targeted therapies for this subtype also makes some triple negative cancers difficult to treat and control. PRKCQ, a member of the novel protein kinase C family, is preferentially expressed in triple negative breast cancers compared to ER+/Luminal cancers. We previously reported that PRKCQ expression drives growth-factor independent growth, anoikis resistance and migration of breast epithelial cells. In addition, PRKCQ is required for in vivo growth of triple negative breast cancers tumor xenografts. We sought to determine if PRKCQ expression modulates sensitivity of triple negative breast cancer cells to standard of care chemotherapy and whether PRKCQ inhibition could be a strategy to induce death of chemotherapy-resistant triple negative breast cancer cells. Methods. We determined the effects of modulating PRKCQ expression, using PRKCQ cDNA or shRNA vectors, on Doxorubicin or Taxol treatment-induced effects on triple negative breast cancer cells, including those that are relatively chemotherapy resistant at baseline. We determined the mechanisms by which PRKCQ expression regulates sensitivity to Taxol. Results. Increased PRKCQ expression in MCF-10A breast epithelial cells suppresses the apoptosis-inducing effects of Doxorubicin or Taxol treatment. PRKCQ-induced Taxol resistance is dependent on PRKCQ kinase activity. PRKCQ-expressing MCF-10A cells secrete enhanced levels of IL-6, leading to the autocrine activation of Stat3; IL-6/Stat3 activation is necessary for PRKCQ-induced resistance to Taxol. Finally, downregulation of PRKCQ sensitized MDA-231-Luc cells to Taxol treatment and induced apoptosis of these cells which are relatively resistant to Taxol at baseline. Conclusions. PRKCQ regulates sensitivity to standard of care chemotherapies used in the treatment of triple negative breast cancer. IL-6/Stat3 signaling induced by PRKCQ kinase activity is responsible for resistance to the effects of Taxol treatment. Targeting PRKCQ therefore could be an attractive strategy to overcome chemotherapy resistance of a subset of triple negative breast cancers. Citation Format: Irie HY, Byerly J. PRKCQ regulates taxol sensitivity of triple negative breast cancer cells via IL-6/Stat3 signaling. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-07.
Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia
Authors: Rainer Storb, H. Joachim Deeg, John Whitehead, Frederick Appelbaum, Patrick Beatty, William Bensinger, C. Dean Buckner, Reginald Clift, Kristine Doney, Vernon Farewell, John Hansen, Roger Hill, Lawrence Lum, Paul Martin, Robert McGuffin, Jean Sanders, Patricia Stewart, Keith Sullivan, Robert Witherspoon, Gary Yee, E. Donnall Thomas
Journal: New England Journal of Medicine (1986)

We treated 93 patients who had acute non-lymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate post-grafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival. (N Engl J Med 1986; 314:729–35.)
Case 43-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, P.M. Hassoun, E.J. Mark
Journal: New England Journal of Medicine (1991)

Presentation of CaseA 27-year-old man with the acquired immunodeficiency syndrome (AIDS) was admitted to the hospital because of a cough, fever, and an abnormal radiograph of the chest.The patient was well until 8 1/2 months earlier, when he was first admitted to this hospital because of a headache, fever, cough, and dyspnea for two days. He had emigrated from Puerto Rico two months earlier, after his wife and child died of AIDS; his wife had received transfusions in the past after a gynecologic operation. The patient had lost 9 kg in weight during the previous two or three . . .
Mutation in the Gene for Bone Morphogenetic Protein Receptor II as a Cause of Primary Pulmonary Hypertension in a Large Kindred
Authors: John H. Newman, Lisa Wheeler, Kirk B. Lane, Emily Loyd, Radhika Gaddipati, John A. Phillips, James E. Loyd
Journal: New England Journal of Medicine (2001)

Most patients with primary pulmonary hypertension are thought to have sporadic, not inherited, disease. Because clinical disease develops in only 10 to 20 percent of persons carrying the gene for familial primary pulmonary hypertension, we hypothesized that many patients with apparently sporadic primary pulmonary hypertension may actually have familial primary pulmonary hypertension.
Consent, Informed Consent and the Consent Form
Authors: James M. Vaccarino
Journal: New England Journal of Medicine (1978)

The unpermitted, unprivileged touching of the person of another is a legal wrong or, technically, a battery. The defense to a charge of battery is consent. In the nonemergency medical encounter, however, such consent is ineffective as a defense1 without a full understanding of what it is that is being consented to. Hence, a distinction must be drawn between consent and informed consent, recognizing a legal obligation to obtain informed consent in a medical encounter.An enormous volume of litigation has involved yet another aspect of the concept: documentation of informed consent. By failing to distinguish between informed consent and . . .
Pseudohyperkalemia with Thrombocytosis
Authors: Roland H. Ingram, Masafumi Seki
Journal: New England Journal of Medicine (1962)

ELEVATED serum potassium levels usually result from deranged metabolic processes in renal or adrenal dysfunction whose detection often involves extensive laboratory investigation. Clinical and electrocardiographic findings are corroborative in these cases. Increased serum potassium values without such corollaries occur with the thrombocytosis of some myeloproliferative diseases.1 2 3 4 5 Appreciation of the extent to which potassium is released under certain conditions during thrombocyte degradation may prevent needless adrenal and renal evaluation.This report illustrates the relation between pseudohyperkalemia and thrombocytosis associated with myeloproliferative disease. Some laboratory studies on the mechanisms involved, serial observations of the changes during therapy and a review of the . . .
Dentin Hypersensitivity: Tunicate-Inspired Gallic Acid/Metal Ion Complex for Instant and Efficient Treatment of Dentin Hypersensitivity (Adv. Healthcare Mater. 8/2016)
Authors: Ekavianty Prajatelistia, Sung-Won Ju, Naresh D. Sanandiya, Sang Ho Jun, Jin-Soo Ahn, Dong Soo Hwang
Journal: Advanced Healthcare Materials (2016)

Many adults suffer from dentin hypersensitivity during their lifetime, which causes intense and unpleasant pain. A facile and efficient dentin hypersensitivity treatment is presented by J.-S. Ahn, D. S. Wang, and team on page 919. The approach is based on complexes of gallic acid and metal ions, inspired by the tunicate-self healing process.
ATPS-07NEO214, ROLIPRAM CONJUGATED TO PERILLYL ALCOHOL, IS A NOVEL DRUG CYTOTOXIC FOR GLIOMAS BY TARGETING THE DEATH RECEPTOR MEDIATED TRAIL PATHWAY
Authors: Hee-Yeon Cho, Weijun Wang, Mickey Huang, Shayane Santiago, Axel H. Schönthal, Florence M. Hofman, Thomas C. Chen
Journal: Neuro-Oncology (2015)

Glioblastoma multiforme (GBM) is a primary brain tumor with a poor prognosis. Treatment with temozolomide (TMZ) usually results in drug resistance and tumor recurrence. This study shows that NEO214, rolipram conjugated to perillyl alcohol, is cytotoxic for a wide range of different TMZ-resistant glioma cells. This conjugate is significantly more effective than either rolipram, perillyl alcohol or the mixture of these agents, demonstrating that NEO214 is a novel entity. NEO214 is effective for drug resistant tumor cells, but not toxic to normal astrocytes or endothelial cells. To identify the mechanism of cell death, effects of NEO214 on death receptor (DR)5 expression were examined. The results show that NEO214 significantly increased the expression of DR5 in both TMZ-sensitive and TMZ-resistant glioma cells. In addition, tumor cells treated with NEO214 and immunostained for DR5 demonstrated over 90% positivity. To show that DR5 receptors were functional, the interaction with the receptor ligand, TRAIL, with NEO214 was tested. The results showed that NEO214 plus TRAIL induced a dramatic increase in cell death. TRAIL alone was not cytotoxic to cells. The combination of NEO214 plus TRAIL resulted in a 60–80% decrease in cell survival. NEO214-treated glioma cells also exhibited an increase in CHOP, marker for ER stress activation. Downregulation of CHOP expression correlated with DR5 expression suggesting that ER stress may be involved in stimulating DR5 expression. To determine effects of NEO214 in vivo, glioma cells were implanted subcutaneously into animals, and treated with NEO214 or vehicle. Results showed that NEO214 caused a significant delay in tumor growth. These results demonstrate that NEO214 is an effective drug against a wide range of different TMZ- resistant gliomas, the combination of NEO214 and TRAIL is very effective in enhancing tumor cytotoxicity, and NEO214 is active in vivo causing significant delays in tumor progression.
AB0753 Diffusing Weight Magnetic Resonance Imaging May Suggest the Treatment Strategy in Ankylosing Spondylitis
Authors: S.Y. Lee, W.T. Chung, S.W. Lee
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> With the advanced MRI techniques, pathologic features can be detected at an early stage and quantitatively evaluated, resulting in the advantages of early diagnosis and prompt treatment. <h3>Objectives</h3> This study aimed to determine the value of diffusion-weighted MR imaging (DWI) in determined of ankylosing spondylitis (AS) treatment strategy and assess the role of quantitative MRI in the evaluation of AS treatment outcome. <h3>Methods</h3> 18 patients with the diagnosis of early AS were included in this study. Disease activity was measured according to clinical instruments and laboratory tests. For each patient, both inflamed sacroiliac (S-I) joint lesion was checked quantitatively at first diagnosis by diffusion-weighted imaging (DWI) measuring the apparent diffusion coefficient (ADC) and by dynamic contrast-enhanced imaging (DCEI) with evaluation of the enhancement factor (f<sub>enh</sub>) and enhancement gradient (g<sub>enh</sub>). All patients were revaluated by pelvis computer tomography (CT) for bone change in S-I joint, after two year. <h3>Results</h3> Clinical and quantitative MRI parameters diminished significantly with regression of the inflammatory activity. Median ADC values in AS patients were (1.118±0.122)×10<sup>-3</sup> mm<sup>2</sup>/s in S-I joint. The high ADC (&gt;1.118±0.122)×10<sup>-3</sup> mm<sup>2</sup>/s, f<sub>enh</sub> (&gt;1.65) and g<sub>enh</sub> (2.09%/S) were associated severe disease activity (high BASDIA), and early administration of biologics (p&lt;0.05). In each individual, the high ADC, f<sub>enh</sub> and g<sub>enh</sub> of S-I joint lesion was associated more severe localized pain than the other S-I joint, despite treatment (p&lt;0.05). Paradoxically, early administration of biologics group that had high ADC, f<sub>enh</sub>, g<sub>enh</sub> and high disease activity, had minimal bone change of S-I joint, compared to only NSAIDs used group in pelvis CT finding. <h3>Conclusions</h3> Diffusion-weighted imaging and DCEI were shown to be effective in quantifying changes in inflammation in S-I joint at the diagnosis of AS, and could be convenient for assessing treatment strategy. To the best of our knowledge this is the first time DWI was used to evaluate the treatment strategy and treatment outcome of AS. <h3>Acknowledgements</h3> No <h3>Disclosure of Interest</h3> None declared
Targeting stat3 signaling in human prostate cancer cells using tyrosine kinase inhibitors
Authors: K. Qureshi, S. Lee, W. Lou, D. Trump, A. Gao
Journal: Journal of Clinical Oncology (2004)

3138 Background: Patients with advanced prostate cancer initially respond to androgen ablation therapy but later relapse with androgen-independent disease (AIPC). There is evidence that cytokine mediated signaling plays an important role in the acquisition of AIPC. Interleukin-6 (IL-6) a cytokine, promotes androgen independent cell growth by activating the androgen receptor and protecting cells from apoptosis. In prostate cancer cells IL-6 activates several major pathways( JAK-STAT, PI3-AKT, and MAPK). Stat3, a member of the STAT protein family, is constitutively active in prostate cancer, particularly in AIPC. Stat3 is a major mediator of IL-6-induced signaling in prostate cancer cells;IL-6 induced AR-mediated gene activation requires activated stat3. Thus IL-6/Stat3 signaling pathways may be important molecular targets in prostate cancer. We evaluated two Stat3 signaling inhibitors: AG490 and JSI-124( cucurbitacin). AG490 is a tyrosine kinase inhibitor selective for the JAK family kinases. Methods: We evaluated the effects of AG490 on the growth of prostate cancer cells that express activated stat3 in vitro and in vivo. We chose to study the human(LNCaP, DU145, PC3,CWR22Rv1 and rat (Dunning G, AT1, AT2, AT6.1, AT3.1, MatLyLu) prostate cell lines. Results: AG490 abrogated Stat3 activity and inhibited the growth of human and prostate cancer cell lines with an IC50 from 20–40 uM. To study the effects in vivo, we inoculated DU145 cells subcutaneously into the flanks of male nude mice. Once tumors reached a size of 0.5cm3 they either received AG490 (0.5mg/mice i.p daily for 14 days) or vehicle (DMSO/RPMI) only. AG490 suppressed tumor growth by 50% (p<0.01). AG490 administration did not cause any toxicity. We studied the effects of JSI-124 in human prostate cancer cell lines: LNCaP, DU145, PC3 and CWR22Rv1.We established the IC50 to range 0.5 to 1.0 uM. We also evaluated the potential for synergistic effects of JSI-124 and cytotoxic chemotherapy drugs in DU145 cell lines. Our data indicate no synergistic interaction between JSI-124 and docetaxel, mitoxantrone or gemcitabine. Conclusions: These data suggest that targeting IL-6/Stat3 signaling is an opportunity in the development of new treatments for AIPC. No significant financial relationships to disclose.