tbuckley/cabot-search huggingface dataset:
Identification of quality care indicators in prostate cancer.
Authors: Vicente Guillem, Eduardo Diaz Rubio, Carlos Camps, Javier Cassinello, Daniel E. Castellano, Alfredo Carrato, Pedro Gascon
Journal: Journal of Clinical Oncology (2017)

213 Background: Despite the attempts made to improve prostate cancer management with the development and implementation of clinical practice guidelines, the inefficiencies and differences that usually occur in ordinary clinical care of patients with prostate cancer significantly contribute to increase the variations in the patterns of care and patients outcomes, and costs to the health system. The goal of this project was to establish parameters for improving the care of patients with prostate cancer through the development and validation of quality indicators for the management of this disease. Methods: The ECO Foundation is a platform of experts representing the major Spanish hospitals involved in the treatment of cancer patients. A multidisciplinary group of experts supported by ECO, extracted potential indicators for prostate cancer care from the relevant medical literature. After two consecutive rounds of rating in a modified Delphi approach, followed by a consensus discussion, the expert panel prioritized the indicators selected. Results: Forty indicators were selected with a high level of agreement. They were grouped into four main groups: general, localized disease, metastasized disease, and results-related indicators. Only two indicators did not reach an agreement or disagreement. The indicators with the highest level of agreement ( &gt; 95%) were the appropriateness of diagnostic confirmation through the pathology report; patient participation in clinical decisions; complete re-staging with study of regional and bone extension; or the establishment of individual therapeutic plan with multidisciplinary participation. Conclusions: We conclude that currently available prostate cancer quality indicators represent clinical practices that are necessary for high-quality care in prostate cancer. The finalized indicator list can be directly adopted or adapted for deployment within a performance improvement program.
Large cell neuroendocrine carcinoma of the lung. A clinicopathologic and immunohistochemical study of 95 cases with particular interest on the expression of targeted tyrosine kinases Kit, PDGFR-alpha and –beta and Met
Authors: S. Tamberi, L. Longo, A. Marchioni, M. Bavieri, E. Zanasi, E. Meschiari, M. Pifferi, M. Migaldi, A. Cavazza, G. Rossi
Journal: Journal of Clinical Oncology (2004)

7032 Background: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a controversial variant of large cell carcinoma. Although it shares many biological findings with small cell carcinoma, it is treated as conventional non-small cell lung cancer, but novel therapies are needed. We analyzed the biologic behavior and the role of several tyrosine kinases (TK) for which exists a selective inhibitor in a large series of LCNEC. Methods: 95 surgically resected LCNEC fulfilling the histologic criteria of the 1999-WHO classification of lung tumors were retrospectively reviewed. Neuroendocrine differentiation was detected by immunohistochemistry (chromogranin, synaptophysin, NCAM). Kit (CD117), PDGFR-A, PDGFR-B, and Met expression was performed on paraffin-embedded sections and a tumor was considered positive when at least 30% of tumor cells showed a strong immunoreactivity. Results: 86 were males, 9 females (median age, 65 years). Sixty patients were in stage I (20 IA, 40 IB), 21 in stage II (11 IIA, 10 IIB), and 14 in stage III (11 IIIA, 3 IIIB). Overall, the median survival was 18 months (22.5 months/stage I, 16/stage II, 10/stage III) and 65 patients died of disease. 76 patients experienced distant and/or local tumor recurrence. Tumor stage (p=0.005) and size (p=0.02) significantly correlated with overall survival. Kit expression was noted in 62 cases (65%), PDGFR-A in 57 (60%), PDGFR-B in 77 (81%) and Met in 45 (47%). However, only Met significantly correlated with overall survival (p=0.02) and lymphnode involvement (p=0.02). LCNEC co-expressing all TK (23%) had the lowest overall survival (median, 10.5 months), while the 3 cases completely unstained had the best median survival (88 months). Conclusions: Despite radical surgery, LCNEC shows a poor outcome requiring a multimodal therapeutic approach. TK-inhibitors (TK-I) could represent a promising alternative in this oncologic field, especially in older patients or in the adjuvant setting, since a high rate of LCNEC co-express Kit, PDGFR-A, PDGFR-B, and Met in different combinations. No significant financial relationships to disclose.
Single nucleotide polymorphisms of the EpCAM-coding gene <i>TACSTD1</i> in patients with ovarian cancer and their potential implications in clinical practice.
Authors: Martin Leonhard Heubner, Pauline Wimberger, Sabine Kasimir-Bauer, Bernhard B Singer, Peter Ruf, Rainer Kimmig, Winfried Siffert
Journal: Journal of Clinical Oncology (2014)

e16515 Background: The tumorassociated antigen EpCAM is overexpressed in many epithelial neoplasms including ovarian cancer. It is believed to be involved in carcinogenesis and tumor progression. In this study we screened the corresponding gene TACSTD1, for single nucleotide polymorphisms (SNPs) which could alter ovarian cancer risk, impact upon disease progression or alter binding to the EpCAM-binding therapeutic antibody catumaxomab. Methods: Overlapping DNA-fragments of 10 healthy volunteers including the promoter region and all exons were analyzed to detect SNPs. Ovarian cancer patients (n=117) and age matched healthy controls (n=115) were genotyped by restriction fragment length polymorphism and pyrosequencing. Quantitative real-time PCR was carried out to detect potential associations with TACSTD1-mRNA expression. FACS analysis of stably transfected Hek293 cells was conducted with the antibody HO-3 –the EpCAM binding arm of catumaxomab - to determine antibody binding. Results: Upon analyzing DNA-fragments, one SNP was found in Exon 3 (4461T>C; rs1126497), resulting in an aminoacid exchange in position 115 (Met115Thr). Another polymorphism was found in the 3’UTR (17225A>G; rs1421) of the gene. Genotyping of patients and controls did not reveal significant differences in genotype distribution. Regarding 17225A>G, the homozygous AA-genotype was associated with diminished progression free survival (PFS) in ovarian cancer patients compared to G-allele carriers. TACSTD1-mRNA expression levels in ovarian cancer specimens did not show genotype-dependent differences. Clinical parameters such as overall survival, FIGO-stage, grading, and age at diagnosis did not differ significantly between the genotypes. FACS analysis of transfected Hek293 cells overexpressing the EpCAM 115Met/Thr phenotype showed binding of HO-3 to both phenotypes. Conclusions: The AA-genotype of 17225A>G may be associated with diminished PFS in ovarian cancer patients. The aminoacid exchange resulting from 4461T>C does not appear to alter binding of HO-3, suggesting that treatment with catumaxomab can be offered to patients regardless of their genotype.
Association of screening for psychosocial distress in patients with newly diagnosed stage IV NSCLC and survival.
Authors: William F. Pirl, Joseph A. Greer, Emily R. Gallagher, Jennifer S. Temel, Lara Traeger, Inga Tolin Lennes
Journal: Journal of Clinical Oncology (2012)

9030 Background: While screening for psychosocial distress has become an ASCO QOPI indicator of quality cancer care, data has yet to show an association with improved cancer outcomes. We examined the relationship between adherence to the QOPI measure for assessment of emotional well-being and survival in a sample of patients with newly diagnosed stage IV NSCLC. Methods: From 8/07 to 9/10, we recruited consecutive new patients in a multidisciplinary thoracic oncology clinic to participate in a research database for which patients completed self-report instruments for depression (PHQ-9) and anxiety (GAD-7) at their first oncology visit. We then performed a QOPI chart audit for patients with stage IV NSCLC who received care at our institution. To adhere to the QOPI measure, oncologists were required to document their own assessment of patient emotional well-being (without access to patient self-report data) within one month of the first office visit. Survival was calculated from first oncology visit to death. Cox proportional hazards models were used to test associations with survival. Results: 243 patients completed baseline assessments and had follow up. Emotional well-being was assessed in 90 (37%). Median survival of those with an emotional assessment was 12 months vs. 10 months for those without (p=.03). Yet, emotional assessment was associated with younger age (p=.01) and higher depression (p=.05) and anxiety scores (p=.03). Controlling for age, sex, performance status, smoking, primary oncology provider, PHQ-9, and GAD-7, having an assessment of emotional well-being was associated with improved survival (HR .68, 95% CI .49-.93, p=.02). Although higher PHQ-9 scores were independently associated with worse survival (HR 1.05, 95% CI 1.02-1.08, p=.004), neither depression nor anxiety moderated the relationship between clinician screening and survival. Conclusions: In this large prospective study of patients with newly diagnosed stage IV NSCLC, adherence to the QOPI measure for assessment of emotional well-being was associated with a survival benefit. This benefit appears to extend to all patients, not just those with depression and anxiety. Randomized trials are needed to confirm these findings.
Should Cancer Centers start their own specialty pharmacy? Quality and economic data from the oral chemotherapy program at Smilow Cancer Hospital and Yale New Haven Health System.
Authors: Kerin B. Adelson, Martha Stutsky, Monica Fradkin, Michelle Renee Harrison, Osama Abdelghany, Bret Morrow, Mandeep Smith, Renee Havriliak, Stephanie Kregling, Catherine A. Lyons, Anne C. Chiang, Howard Cohen
Journal: Journal of Clinical Oncology (2017)

108 Background: Recent focus has shown that oral chemotherapy is high risk for medical error. Our QOPI certification process identified that oral oncologic processes were marked by: lack of documentation in the EMR, patients receiving refills from third party pharmacies after prescription discontinuation, incorrect self-administration of medications due to lack of education, delivery delays, high copays, and underuse of available patient assistance programs. Methods: A multidisciplinary task force developed a program to expedite drug access, standardize consent, and ensure clinical support including education, adherence and toxicity monitoring. We expanded an existing health-system pharmacy to provide specialty services. Treatment protocols were created for every oral oncologic drug, which are routed to a clinical oncology pharmacist and the specialty pharmacy. Nursing and pharmacist verify all orders. Medication Assistance Program for copay support. Day 1, 5 and 21 pharmacist to patient calls. Multidisciplinary flow sheet documentation. Results: Today, 80% of our patients receive medication within 72 hours. Specialty pharmacists monitor toxicity even for patients whose prescriptions are filled by other pharmacies. Pharmacists have prevented more than 400 prescription errors. Today, monthly revenue before cost for the oral chemotherapy program is nearly than $4 million. The total revenue since initiation in February 2015 is over $44 million, yielding an approximately $9 million margin after costs. Funding through the medication assistance program exceeded $1 million thus far in 2016, with an average of 140 patients receiving assistance each month. Conclusions: A patient-centered multidisciplinary model integrating clinical, operational, financial, and IT resources optimized care for patients receiving oral oncologic therapy. This project transferred revenue from for-profit third party pharmacies to our non-profit health system, and revenue is used to provide enhanced education, monitoring, and patient assistance. Our collaborative improvement model can be adapted to many practice settings.
Preliminary results of phase II trial of concomitant administration of intra-vesical reduced dose Bacillus Calmette- Guerin (BCG) and interferon a 2B (IFN) in the prevention of recurrence of superficial bladder cancer
Authors: S. Bazarbashi, M. Raja, S. Kattan, M. Rahal, A. El-Weshi, C. Pai, K. Rehman, M. Aslam, K. Othman, K. Hanash
Journal: Journal of Clinical Oncology (2004)

4716 Background: to evaluate the recurrence rate, disease free survival and toxicity of concurrent intravesical instillation of reduced dose BCG and IFN when administered for the prevention of recurrence of superficial transitional cell carcinoma of urinary bladder. Methods: eligible patients (pts) must have histologically confirmed either T1 or Ta lesion with one of the following: size more than 3 cm, more than 3 tumors, tumor grade = 2 or have recurred in < one year. No prior intravesical therapy was allowed. Pts must have adequate bone marrow, kidney and liver function. All pts signed informed consent. Treatment consist of transuretheral resection of visible tumors followed by 6 weekly instillation of 27 mg of BCG (Theracys, cannaught, Canada) mixed with 10 million units of IFN and installed for 2 hour intravesically. Cystoscopy is done at 3 months and if negative a 3 weekly consolidation treatments were given. Follow up is done clinically, by cystoscopy and urine cytology. Results: 12 pts enrolled to date, 10 evaluable for response. Median age58 years (41–78), All were males. Median performance status 1 . Four pts had Ta and 6 T1. Tumor grade: III:4 pts, II: 5 pts and I: one patient. Median number of tumors is 2. One patient had concomitant Tis. Median follow up 9 months (range 3–15). No patient relapsed to date. Toxicity was mild. Only 2 pts had grade 3 increased urinary frequency. Conclusion: despite the short follow up and the small number of pts this initial results are very encouraging and warrant continued accrual. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Potentiation of apoptosis inducing activity of BL-193, an inhibitor of Bcl-X<sub>L</sub> protein, by genistein in pancreatic cancer cells
Authors: K.-L. Ellis, R. Mohammad, S. Wang, X. Wu, J. Chen, J. Min, F. H. Sarkar
Journal: Journal of Clinical Oncology (2004)

3133 Background: Several important survival molecules such as NF-κB and Bcl-XL are highly activated in pancreas cancer. NF-κB is responsible for transcriptional activation of many tumor-promoting genes including Bcl-XL. We have previously shown that genistein down regulates the activation of NF-κB, and in turn decreases Bcl-XL. We have also shown that a small molecule inhibitor (SMI) BL-193 is a potent inhibitor of Bcl-XL,and to a lesser degree of Bcl-2. Therefore, we hypothesize that inactivation of NF-κB by genistein leads to decreased transcription of Bcl-XL,which will lead to the induction of apoptotic cell death. We also hypothesize that complete inactivation of Bcl-XLmay not be achievable by genistein treatment alone, therefore further inactivation of residual Bcl-XLby BL-193 may lead to complete inactivation of Bcl-XL, thereby enhancing the killing of pancreatic cancer cells. Methods: Results: In support of our hypotheses, we have shown by MTT assay that 30 μM genistein exposure of BxPC-3 pancreatic cancer cells for 24 hours caused inhibition in cell growth. We have also demonstrated that treatment with 3μM BL-193 alone for 72 hours caused significant growth inhibition. Moreover, cells pre-treated for 24 hours with genistein followed by 72 hours of BL-193 demonstrated significantly greater growth inhibition compared to either agent alone. The observed growth inhibition could be due to either cell cycle arrest or induction of apoptosis hence we determined the degree of apoptosis induced by these agents alone or in combination as analyzed by Histone-DNA ELISA. We found that BL-193-induced apoptosis was much more pronounced in cells pre-treated with genistein, and the results were correlated with genistein-induced inactivation of NF-κB and Bcl-XL. Conclusions: These results are consistent with our hypotheses and suggest that pre-treatment of pancreatic cancer cells with genistein down regulates NF-κB and Bcl-XL, which may play important roles in potentiating the apoptosis-inducing effect of BL-193. No significant financial relationships to disclose.
Control of tumor suppressor protein PTEN by dimethlysulfoxide in HL-60 cells
Authors: J. Park, Y.-R. Lee, H.-J. Shim, H.-W. Rho, J.-W. Park, M.-K. Han, E.-C. Jhee, M. H. Lee, K. Park, J.-S. Kim
Journal: Journal of Clinical Oncology (2004)

3156 Background: Dimethylsulfoxide (DMSO) has been used in the treatment of several types of cancer for several decades. However, the mechanism(s) responsible for its anti-tumoral action remains unknown. A novel tumor suppressor gene, PTEN/MMAC, on chromosome 10q23 encodes a phosphatidylinositol-3'-phosphatase (PTEN) that dephosphorylates the D3 position of phosphatidylinositol-3,4,5-triphosphate (PIP3), the second messenger downstream from phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB)/Akt. PKB/Akt is a Ser/Thr protein kinase implicated in mediating biological responses, including the inhibition of apoptosis and the stimulation of cell growth. The present study was designed to evaluate whether DMSO controls PTEN expression in malignant cell lines. Methods: HL-60 cells were treated with DMSO, and PTEN expression determined by western- and northern-blot analysis. NF-κB activation was measured by electrophoretic mobility shift assay. To investigate the prevention of DMSO-induced PTEN upregulation in HL-60 cells, we blocked NF-κB activity with a p65 antisense oligonucleotide and pyrrolidine dithiocarbamate (PDTC). Results: DMSO strongly induced PTEN expression through NF-κB activation in HL-60 cells. Treatment of HL-60 cells with DMSO caused significant NF-κB activation and induced an increase in PTEN expression in a time- and dose-dependent manner. Interestingly, blocking NF-κB activity prevented the DMSO-induced upregulation of PTEN, indicating that the upregulation of PTEN expression by DMSO is NF-κB-dependent. Conclusion: These results suggest that DMSO is an important stimulator of the tumor suppressor protein PTEN in leukemia cells. These studies form the basis for further investigations to improve the anti-tumor effects of DMSO against such cancers as leukemia and various kinds of solid tumors. No significant financial relationships to disclose.
Abstract P086: Serca1a Expression Exacerbates Cardiac Arrhythmia and Leads to Heart Failure and Early Mortality in a Mouse Model of Exercise-Induced Sudden Cardiac Death
Authors: Anuradha Kalyanasundaram, Veronique Lacombe, Andriy Belevych, Bjorn C Knollmann, Muthu Periasamy, Sandor Gyorke
Journal: Circulation Research (2011)

Abnormal calcium (Ca 2+ ) handling has been implicated in a range of cardiac diseases, including heart failure, a disease state characterized by compromised systolic and/or diastolic myocardial function and pathological remodeling. Excessive diastolic SR calcium release via the Ryanodine receptor (RyR2) has been suggested to deplete the SR Ca 2+ store thereby reducing cardiac contractility. Although abnormal RyR2 activity and elevated SR Ca 2+ leak are characteristic features of advanced heart failure (HF) in both humans and animal models, clear evidence is lacking whether altered RyR2 function plays a causal role in HF development. Indeed, while nearly 80 mutations in RyR2 have been identified and associated with SR Ca 2+ leak, none of these mutations have been reliably linked to HF. One possible explanation for this is that the SR Ca 2+ leak caused by the mutations is too small and/or compensated by other processes involved in Ca 2+ homeostasis. In the present study we sought to generate a genetic model with chronically increased diastolic release by combining overexpression of the fast skeletal muscle isoform of SERCA, SERCA1a, with ablation of CASQ2. Strikingly, the new hybrid strain (CASQ2 null/1a) exhibit early mortality (avg dying age 39.30days) due to heart failure preceded by pathological remodeling including eccentric hypertrophy, significant dilation of the atrial and ventricular chambers, necrosis induced cell death and widespread fibrosis. Animals are susceptible to ventricular arrhythmias at baseline in the absence of adrenergic triggers and show significant systolic dysfunction. Similarly, cardiomyocytes display increased SR Ca 2+ load along with significant disturbances in RyR2 mediated Ca 2+ release at baseline and are increasingly prone to spontaneous calcium waves. Our results demonstrate that excessive Ca 2+ leak via the RyR2 can lead to severe contractile dysfunction and heart failure. Since abnormal RyR2 activity has been implicated in human HF, our results suggest that up-regulation of SERCA activity as a therapy for HF must be advocated with extreme caution.
Combination of trabectedin (T) and doxorubicin (D) for the treatment of patients with soft tissue sarcoma (STS): Safety and efficacy analysis
Authors: J. Blay, M. von Mehren, B. L. Samuels, M. P. Fanucchi, I. L. Ray-Coquard, B. Buckley, L. Gilles, C. Lebedinsky, Y. A. Elsayed, A. Le Cesne
Journal: Journal of Clinical Oncology (2007)

10078 Background: T is a novel marine-derived DNA minor-groove binder that interferes with gene activation, nucleotide excision repair, and induces DNA strand breaks and cell cycle arrest in S and G2. T is active in STS and exhibits preclinical synergy with D. The objective of this study was to determine the combination regimen that is tolerable and associated with manageable neutropenia. Other objectives included safety, clinical activity and pharmacokinetics (PK) Methods: This was a dose escalation phase I study. Eligible patients (pts) had metastatic or recurrent STS, PS 0–1, and adequate organ function. Pts with more than 1 prior chemotherapy, prior anthracyclines or radiation to more than 20% of bone marrow were excluded. On day 1 of each 3-week cycle, pts received D starting at 60 mg/m 2 followed by T starting at 0.9 mg/m 2 . Incremental doses were explored. D was discontinued after 6–8 cycles. Treatment was administered as an outpatient. PK samples were collected. A modified dose escalation and dose modifications were implemented Results: Forty one pts were treated in three sequential cohorts. In cohort 1 (D60 mg/m 2 + T0.9 mg/m 2 ), 4/11 pts without G-CSF experienced unmanageable neutropenia and subsequently prophylactic G-CSF was instituted. No unmanageable neutropenia was seen in the subsequent18 evaluable pts in this cohort. 1/13 and 2/6 DLTs were seen in cohort 2(D60 mg/m 2 + T1.1 mg/m 2 ) and cohort 3(D60 mg/m 2 + T1.3 mg/m 2 ) respectively. The most frequent grade 3/4 AEs were: neutropenia(71%), ALT elevation(46%), thrombocytopenia34%), AST(24%), anemia (22%), Febrile neutropenia (17%). One pt discontinued due to grade 3 asthenia. The MTD and recommended dose is D60 mg/m 2 + T1.1 mg/m 2 . Anti-tumor activity included 17% ORR (1 CR and 6 PR), 80% stable disease (45% SD&gt;6 months). Median PFS is 8.9 months (95% CI 5.6–11.8). 3-month and 6-month PFS are 85.4% and 58.2% respectively. Mature overall survival and PK data will be presented Conclusions: The combination of T and D with G-CSF support is safe, tolerable and active in pts with metastatic or recurrent STS [Table: see text]