tbuckley/cabot-search huggingface dataset:
Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium
Authors: J. A. Wallace, G. Locker, S. Nattam, K. Kasza, K. Wade-Oliver, W. M. Stadler, E. E. Vokes, H. L. Kindler
Journal: Journal of Clinical Oncology (2007)

4608 Background: The ras oncogene is mutated in about 90% of PC, leading to constitutive activation of the Ras-Raf-MAPK signal transduction pathway. Sorafenib an inhibitor of B-raf, VEGFR2, and PDGFR-B, has in vitro activity against PC cell lines dependent on mutant Ras activation, and has anti-tumor activity in PC xenograft models. In a phase I trial of SG, 57% of PC patients (pts) had stable disease (SD) (Siu, 2003). Methods: We conducted a multi-center phase II trial of SG in advanced PC pts who had: no prior chemotherapy for metastatic disease, PS 0–1, measurable disease. Primary endpoint: response. The Simon 2-stage trial design required 1 response in 12 evaluable pts for 2 nd stage. Pts received S 400 mg orally twice daily days (D) 1–28, and G 1000 mg/m 2 over 30 minutes D 1, 8, 15 Q28D. CT scans: Q2 cycles. 17 pts enrolled at 4 sites 9/04–12/05. Pt characteristics: male 47%; median age 62 (range 50–85); PS 0 24% 1 76%; stage IV 94%; prior radiation 12%; liver metastases 81%. Results: 17 pts evaluable for toxicity, 13 for response. 61 cycles of SG have been given (median 2, range 1–12). There were no objective responses; 3 pts (23%) had SD. 1 pt with SD remains on treatment after 12 cycles. Median overall survival: 4.0 months (95% CI: 3.4, 5.9). Median progression-free survival: 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 hematologic toxicities (% pts): neutropenia 29%; thrombocytopenia 6%; neutropenic fever 0%. Grade 3 non- hematologic toxicities: thrombosis 18%; fatigue 18%; rash 12%; dehydration 12%; nausea 12%; hand-foot syndrome 12%; hypertension 6%; diarrhea 6%; GI bleeding 6%. Conclusion: The study did not meet response criteria to proceed to a second stage of accrual. SG is inactive, though well-tolerated, in advanced PC pts. Supported by NCI grant N01-CM-62201. [Table: see text]
Anticoagulation Prophylaxis With Enoxaparin For Patients With Acute Lymphoblastic Leukemia Receiving Asparaginase-Based Intensification Therapy
Authors: Hassan Sibai, Jack T Seki, Eshetu G Atenafu, Karen W.L. Yee, Andre C Schuh, Vikas Gupta, Mark D. Minden, Aaron D. Schimmer, Joseph M. Brandwein
Journal: Blood (2013)
Molecular Staging of Early Colon Cancer on the Basis of Sentinel Node Analysis: A Multicenter Phase II Trial
Authors: Anton J. Bilchik, Sukamal Saha, David Wiese, James A. Stonecypher, Thomas F. Wood, Stuart Sostrin, Roderick R. Turner, He-Jing Wang, Donald L. Morton, Dave S.B. Hoon
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: β-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10 − 3 to 10 − 4 μg of RNA and one to five tumor cells in 10 7 lymphocytes of healthy donors. RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P &lt; .04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.
Lessons learned from unintended consequences about erasing the stigma of mental illness
Authors: Patrick W. Corrigan
Journal: World Psychiatry (2016)

Advocates and scientists have partnered to develop and evaluate programs meant to erase the egregious effects of the different forms of stigma. Enough evidence has been collected to yield lessons about approaches to stigma change. Some of the most insightful of these lessons emerge from unintended consequences of good intentioned approaches, and are the focus of this paper. They include the limited benefits of education especially when compared to contact, beating stigma is more than changing words, beware pity as a message, understand the competing agendas of stigma change, replace ideas of normalcy with solidarity, and avoid framing self‐stigma as the problem of people with mental illness and not of society. The paper ends with consideration of the back seat role that psychiatrists and other mental health providers should have in stigma change.
Inhibition by Bovine Endothelial Cells of Degradation by HT-1080 Fibrosarcoma Cells of Extracellular Matrix Proteins&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Margaret Heisel, Walter E. Laug, Peter A. Jones
 6
Journal: JNCI Journal of the National Cancer Institute (1983)

Medium conditioned by bovine arterial endothelial cells inhibited the degradation by human fibrosarcoma cells of living cultures of rat smooth muscle cells or their cell-free extracellular matrices. Endothelial cell-conditioned medium had no effect on the growth kinetics of fibrosarcoma cells, and the inhibitory influence of conditioned medium on matrix degradation was greatest with low numbers of tumor cells. Conditioned medium inhibited the production of tumor cell plasminogen activators, enzymes previously found to play a role in matrix glycoprotein degradation. The endothelial factor was heat- and acid-stable and non-dialyzable, and mixing experiments showed that it did not directly inactivate the tumor cell plasminogen activator. Endothelial cells may therefore modulate the production of proteolytic enzymes important in the implantation stage of tumor metastasis.
The impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: A retrospective Japan clear cell carcinoma study.
Authors: M. Takano, T. Sugiyama, N. Yaegashi, S. Sagae, K. Kuzuya, Y. Udagawa, H. Tsuda, M. Suzuki, T. Goto, Y. Kikuchi
Journal: Journal of Clinical Oncology (2010)

5052 Background: Ovarian clear-cell carcinoma (CCC) is regarded as grade 3 tumor, and NCCN Clinical Practice Guidelines recommended adjuvant chemotherapy for the tumor, even at stage Ia. However, CCC often showed chemo-resistant phenotype, and the effect of adjuvant chemotherapy still remained uncertain. Methods: CCC cases treated at collaborating institutions during the period 1995-2005 were retrospectively identified. After central pathologic review, survival analysis was estimated by Kaplan-Meier methods, and prognostic factors were evaluated using a Cox regression model. Results: Among 219 patients with stage I CCC, 195 cases received adjuvant chemotherapy (C+), and 24 cases (C-) did not. C+ group had 77 pT1a and 118 pT1c cases, and C- group included 18 pT1a and 6 pT1c tumors (p < 0.001). Mean age was 52.3 years in C+ and 56.9 years in C- (p = 0.02). During mean follow-up period of 48 months (range; 7-130), relapse was observed in one case (4%) of C- and 35 cases (18%) of C+ group. There were no statistical differences of relapse-free survival (RFS) and overall survival (OS) between C+ and C-. Multivariate analysis revealed that peritoneal cytology status (p = 0.02) and pT status (p = 0.04) were independent prognostic factors for RFS, however, adjuvant chemotherapy was not a prognostic factor (p = 0.80). Conclusions: Although the present study was a limited retrospective study, it suggested adjuvant chemotherapy had little impact upon not only OS but also RFS of CCC patients. Further strategy, such as molecular targeting agents, are needed to improve survival of CCC. No significant financial relationships to disclose.
Commissioning's identity crisis
Authors: N. Edwards
Journal: BMJ (2015)

If current trends continue, holding on to the N in NHS may become much more difficult



Almost since its inception, in the early 1990s, NHS commissioning—the process of buying and planning healthcare for local areas—has suffered from a crisis of identity and confidence. Critics have denounced it as unnecessary bureaucracy; even those involved have questioned its purpose or effectiveness; and frequent mergers and wholesale reorganisations of the bodies involved in commissioning have destroyed organisational memory, removed talented staff, and disillusioned many of the few clinicians who could be persuaded to become involved.

Almost 25 years after the “purchaser-provider split” in England, questions are yet again being asked about the purpose of commissioning as attempts are made to sort out the muddle left by former health secretary Andrew Lansley’s reorganisation, which in 2013 abolished primary care trusts and handed commissioning to GP led groups. Politicians and officials are clear that they want to revisit commissioning policy without the pain and embarrassment of having to legislate again or undertake any visible reorganisation.

You might think that the NHS would be better served if it spent less time on such recondite and self referential stuff. But the absence of a strategic body able to pull together local organisations is proving …
Pharmacokinetics (PK) and safety of tesetaxel, an orally administered taxane, in a study examining a range of doses including the active phase II dose
Authors: M. Beeram, A. Qureshi, A. Patnaik, K. Papadopoulos, A. W. Tolcher
Journal: Journal of Clinical Oncology (2009)

e13535 Background: Tesetaxel is an orally active taxane with potent cytotoxic activity against various cancer cell lines in vitro, including cell lines and xenografts of human tumors that over-express P-glycoprotein. Tesetaxel displays markedly lower neurotoxicity than docetaxel in preclinical models. In Phase 2 studies, 2nd-line therapy with tesetaxel (27–35 mg/m 2 every 3 weeks) was associated with overall response rates of 20% and 38% in patients (pts) with gastric and breast cancer, respectively. Neutropenia was the most common serious adverse event. We are conducting a dose-ranging study to examine the PK and safety of tesetaxel at doses including and just below the previously established MTD of 27 mg/m 2 . Methods: Eligibility criteria include advanced solid tumors, ECOG PS ≤ 2, and adequate organ function. The starting dose is 18 mg/m 2 , which is being escalated in increments of 3 mg/m 2 to a maximum of 27 mg/m 2 . Tesetaxel is given for a minimum of 2 cycles; pts with response or stable disease may receive up to 2 more cycles. Plasma is assayed at various times to determine concentrations of parent drug and metabolites. A total of 12 patients will be entered into the dose-escalation phase, with sample expansion to 12 pts at the MTD. Results: Ongoing enrollment is expected to be completed in Q1 2009. Our group's prior study of tesetaxel 18 mg/m 2 and 27 to 40 mg/m 2 has shown that tesetaxel displays dose-proportional absorption and has a long terminal plasma half-life (mean approximately 180 hrs). We expect to confirm these data over a narrow dose range and to examine the data for correlations between PK and the duration and severity of neutropenia. Conclusions: Tesetaxel is an orally active taxane that eliminates infusion reactions and the associated need for premedication. It may overcome inherent or clinically acquired resistance to prototype taxanes and may prove to have reduced taxane-associated peripheral neuropathy in the clinical setting. Essential to future tesetaxel studies, this study will determine whether correlations between key PK parameters and dose-limiting reactions exist. [Table: see text]
Changes in tumor biological markers during primary systemic chemotherapy (PST)
Authors: E. Solomayer, H. Neubauer, V. Beck, J. Huober, U. Vogel, T. Fehm
Journal: Journal of Clinical Oncology (2006)

20035 Background: Tumorbiological factors including HER2, estrogen receptor and progesterone receptor status are routinely determined prior neoadjuvant chemotherapy. Based on these results adjuvant treatment decisions regarding trastuzumab and endocrine therapy are made. However, the expression of these markers may be altered by cytotoxic therapy. Therefore, tumorbiological factors including HER2, ER, PR, ki-67 were studied in 87 patients treated before and after primary systemic therapy. Method: Corresponding cut-core biopsies and postchemotherapy surgical specimens were available from 87 patients treated with neoadjuvant chemotherapy. HER2, ER, PR and ki-67 were immunohistochemically assessed. Results: Pathological response rate was 69%. No significant changes were seen for ER receptor expression. Four tumors positive for ER changed to ER negative. In contrast, 13 initially PR-positive tumors were classified PR-negative after cytotoxic therapy (p &lt; 0.05). A significant change was also observed for HER2 status. Eleven tumors which were negative prior to PST did overexpress HER2 in the post chemotherapy surgical specimen. Median ki-67 index decreased from 30% before PST to 13% after treatment (p &lt; 0.01). Only reduction of ki-67 was associated with pathological response to PST. Conclusion: HER2 status as well as ER and PR status should be reevaluated on post-chemotherapy surgical specimens since changes can be observed. The clinical relevance of these changes regarding therapy response to adjuvant endocrine therapy or trastuzumab has yet to be determined. No significant financial relationships to disclose.
춘계학술대회 : 구연 ; 간암 : 적은 잔여 간용적이 예상되는 간세포암종 환자에서 간문맥 색전술 후 시행한 간절제술과 경동맥화학색전술의 비교
Authors: 서동대, 이한주, 장명국, 민현주, 김강모, 임영석, 정영화, 이영상, 서동진, 고기영, 이영주, 이승규
Journal: Clinical and Molecular Hepatology (2007)
Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
Authors: Cecile Chartier, Janak Raval, Fumiko Axelrod, Chris Bond, Jennifer Cain, Cristina Dee-Hoskins, Shirley Ma, Marcus M. Fischer, Jalpa Shah, Jie Wei, May Ji, Andrew Lam, Michelle Stroud, Wan-Ching Yen, Pete Yeung, Belinda Cancilla, Gilbert O'Young, Min Wang, Ann M. Kapoun, John Lewicki, Timothy Hoey, Austin Gurney
Journal: Cancer Research (2016)

Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis.
High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin's disease patients: an Italian study group report.
Authors: A M Carella, A M Congiu, E Gaozza, P Mazza, P Ricci, G Visani, G Meloni, G Cimino, L Mangoni, P Coser
Journal: Journal of Clinical Oncology (1988)

Fifty patients with recurrent Hodgkin's disease have been treated with high-dose therapy followed by autologous bone marrow transplantation. Forty-one patients had extranodal sites of relapse and 31 patients had constitutional symptoms. Two patients had been treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), lomustine, vinblastine, procarbazine, and prednisone (CcVPP), and radiation; 16 patients with MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), radiation, and lomustine, etoposide, and prednisone (CEP); 20 patients with alternating MOPP/ABVD, and 12 patients with alternating MOPP/ABVD followed by CEP and radiation. Eighteen patients had progressive disease during alternating MOPP/ABVD protocol alone or during conventional salvage therapy; 32 patients had had a complete remission with first-line therapy but later relapsed, 25 of them having received conventional salvage therapy; 12 achieved no response or progression ("resistant-relapse" patients); and 13 responded partially or completely ("sensitive-relapse" patients). Complete remission occurred in 24 patients (48%) with a median duration of 24 months and 16 patients (32%) achieved partial response with a median duration of 9 months, for an overall response rate of 80%. Ten patients failed to respond and died in progressive disease 1 to 10 months (median, 6 months) after transplantation. Toxicity was significant including infections (20%), liver enzymes and alkaline phosphatase elevations (100%), and carmustine lung toxicity (7%). There were two treatment-related deaths; one patient died of Pseudomonas aeruginosa septicemia and another patient died of cerebral hemorrhage. These results validate the procedure of high-dose therapy followed by autologous bone marrow transplantation in inducing remission in these advanced, highly-treated patients. Clearly, the question of whether high-dose therapy and transplantation will eventually supersede new conventional salvage therapies will be addressed after controlled clinical studies.
Association Between BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia and Cardiovascular Events, Major Molecular Response, and Overall Survival
Authors: Jonathan Douxfils, Hélène Haguet, François Mullier, Christian Chatelain, Carlos Graux, Jean-Michel Dogné
Journal: JAMA Oncology (2016)

A phase 3 trial with ponatinib in patients with chronic myeloid leukemia (CML) was interrupted due to an important increase of vascular occlusive events. A similar risk was also suspected with nilotinib, another BCR-ABL tyrosine kinase inhibitor (TKI) used in patients with CML.To assess the risk of vascular occlusive events in patients with CML treated by new generations of TKIs and provide an overall assessment of the clinical benefit.Two independent reviewers selected studies from PubMed, Scopus, and the Cochrane library database from their inception to October 21, 2014. Abstracts published during the past 3 years at international congresses and a trial register were also searched.Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO 2014 protocol: CRD42014014147. Among the 249 abstracts identified, 10 studies fulfilled the established criteria.Two investigators independently extracted data using a standard form.Information extracted included study and patients characteristics, type of intervention and data on vascular occlusive events, overall survival, and major molecular response (MMR). The meta-analysis was performed using a fixed-effects model. Odds ratios (ORs) with 95% CIs were computed using the Peto method.Ten randomized clinical trials (3043 patients) were analyzed. Risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML. No significant difference was found with bosutinib (OR, 2.77; 95% CI, 0.39-19.77). New-generation TKIs increased the rate of MMR at 1 year compared with imatinib (overall OR, 2.22; 95% CI, 1.87 to 2.63). No statistical difference in overall survival at 1 year was found (overall OR, 1.20; 95% CI, 0.63-2.29). Inaccessibility to individual data and time-to-event data and differences in evaluation criteria between studies could have introduced bias.Dasatinib, nilotinib, and ponatinib increase vascular occlusive events. New-generation TKIs improve MMR but not the overall survival at 1 year in patients with CML.
Corticosteroid insensitivity in airway smooth muscle cells from severe asthma is dependent on stimulus and cytokine product
Authors: Christos Rossios, David Gibeon, Kian Fan Chung, Ian M. Adcock
Journal: European Respiratory Journal (2014)

Background: Severe asthma is characterised by poor therapeutic response to corticosteroid (CS) therapy. We have previously demonstrated that airway smooth muscle (ASM) cells from severe asthma patients are more insensitive to CSs as demonstrated by its inhibition of TNFα-induced CCL11 release.

Aims & Objectives: We determined whether this CS insensitivity is also observed with different stimuli using Poly(I:C) and TNFα, and with a wide range of cytokine/chemokine release panel. The response of ASM cells from severe asthmatics (n=15) was compared to those of non-severe asthmatics (n=7), idiopathic cough subjects (n=6) and healthy subjects (n=12).

Methods: ASM cells were exposed to 10-8 M fluticasone propionate (FP) for 2 hrs, prior to overnight stimulation with either 1 μg/ml Poly(I:C) or 1 ng/ml TNFα. Supernatants were collected for 32-Plex assay by Luminex and cells were harvested for RNA extraction and transcriptomic analysis.

Results: At baseline, CX3CL1, CCL11, CXCL8, and IL-6 release was lower in severe asthmatic ASM cells compared to those of healthy subjects. Conversely, EGF and MIP-1β release was higher. Poly(I:C) and/or TNFα induced the release of most analytes tested. FP did not affect Poly(I:C)-induced CXCL10 or CXCL8 release, whereas Poly(I:C)-induced GM-CSF, IL-6 and MIP-1α was significantly reduced by FP in severe asthmatic ASM cells. TNFα-induced CXCL8, CXCL10 and CX3CL1 release was not affected by FP. On the contrary, FP had a significant effect on TNFα-induced IL-6 and GRO release.

Conclusion: A differential corticosteroid signature has been identified in severe asthma, which is stimulus and analyte-dependent.