tbuckley/cabot-search huggingface dataset:
Nuclear localization of Kaiso as a prognostic biomarker and promotion of EMT in infiltrating ductal breast carcinomas.
Authors: Jacqueline Jones, Honghe Wang, Balu Karanam, Shaniece Theodore, Windy Marie Dean-Colomb, Danny R. Welch, William E. Grizzle, Clayton Yates
Journal: Journal of Clinical Oncology (2014)

e22061 Background: The expression and biological consequences of Kaiso, a novel BTB-POZ bi-modal transcription factor, in infiltrating ductal carcinomas (IDCs) have not been widely investigated. Methods: Kaiso expression and subcellular localization was determined in 146 normal tissues, 376 IDCs, and 85 lymph node metastases by immunohistochemistry. Semi-quantitative analysis of staining was evaluated with clinicopathological features of IDCs using Chi-square analysis and Kaplan Meier Curves. MCF-7 cells were induced to overexpression Kaiso, whereas MDA-MB-468 and MDA-MB-231 cells were treated with si-Kaiso or si-Scr and assayed for cell migration, invasion, RNA and protein expression. Chromatin Immunoprecipitation assay was performed in MDA-MB-231 cells to determine the direct interaction of Kaiso with methylated sequences within E-cadherin promoter. Results: Kaiso expression in both the cytoplasmic and nuclear compartments correlated with age <48 (cytoplasmic p<0.0093; nuclear p< 0.0001) and moderate differentiation (cytoplasmic p<0.0042; nuclear p<0.0001), However, only nuclear Kaiso correlated with poor prognostic factors, i.e., race (African Americans) (p<0.0001), poor differentiation (p<0.0001), and metastases (p<0.0001). Nuclear Kaiso was also associated with worse overall survival (p<0.0019), with African American patients displaying worse survival rates relative to Caucasian patients (p<0.029). Over-expression of Kaiso in MCF-7 cells increased cell migration and invasion, but treatment of MDA-MB-468 and MDA-MB-231 cells with si-Kaiso decreased cell migration and invasion. Treatment also induced the expression of E-cadherin and a reversal of mesenchymal associated cadherins, N-cadherin and cadherin 11, as well as decreased vitmenin expression. Further, Kaiso directly bound to methylated sequences in the E-cadherin promoter, an effect prevented by 5-aza-2-deoxycytidine. Lastly, immunofluorescence co-staining of poorly differentiated IDCs demonstrated that nuclear Kaiso is associated with a loss of E-cadherin expression. Conclusions: Collectively, these findings support an oncogenic role for Kaiso in promoting aggressive breast tumors.
Building an embedded primary care survivorship model using an implementation science approach.
Authors: Erin Elizabeth Hahn, Corrine E. Munoz-Plaza, Jazmine Garcia Delgadillo, Joanne E. Schottinger, Farah Brasfield, Michael K Gould, Carla Parry
Journal: Journal of Clinical Oncology (2017)

35 Background: There is limited understanding of factors that affect uptake of different models of survivorship care. Few systems have incorporated implementation science into program planning and implementation. Guided by the Consolidated Framework for Implementation Research (CFIR), we conducted an evaluation of stakeholder-perceived acceptability and feasibility of an embedded primary care provider (PCP) survivorship care model as the initial step of an implementation project within an integrated healthcare system. Methods: We identified clinical, operational, and patient stakeholders and conducted semi-structured qualitative interviews. Interviews were recorded, transcribed, coded, and analyzed. Deductive thematic categories were derived a priori from CFIR domains (e.g., acceptability, culture); thematic sub-categories were developed inductively. Results: We interviewed 12 stakeholders; a diverse array of themes was identified. Acceptability: Oncologists and operational leaders perceived the model to be an acceptable solution to issues of capacity and efficiency with the potential to improve quality; however, several oncologists perceived negative consequences including “[loss of] the joy of medicine”. PCPs perceived difficulty in co-managing existing patient panels and new survivors. Patients were less enthusiastic, fearing the loss of a trusted clinician and wary about the introduction of “[someone] who doesn’t know me.” Feasibility: Organizational confidence was high that this model can succeed, although there was concern about finding the right PCP and investment in training and staff support. Culture: Numerous system-level facilitators were identified, including the integrated structure: “We don’t have a fee for service mentality so nobody’s giving up revenue.” Conclusions: Acceptability and feasibility for this model were high among oncologists and operational leaders but patients were ambivalent. Successful implementation requires training and support of engaged PCPs and staff, and a formalized patient transition introduced early in the care trajectory. Operationalization of survivorship models may be improved with integration of implementation science methods.
Lynch syndrome-associated upper tract urothelial cancer: Assessment of clinical screening criteria and tissue-based point of care testing.
Authors: Michael J. Metcalfe, Priya Rao, Maureen E Mork, Firas G. Petros, Lianchun Xiao, Russell Broaddus, Surena F. Matin
Journal: Journal of Clinical Oncology (2017)

371 Background: Lynch syndrome (LS) is an inherited syndrome that places patients at risk for upper tract urothelial carcinoma (UTUC). Our goal was to identify the most reliable means of screening for LS in patients with UTUC at the point of care (POC). Methods: Patient information was retrospectively collected in an IRB-approved protocol on UTUC patients. LS screening was universally performed on all patients presenting from 1/2013-7/2016. We evaluated patient and family history (Amsterdam I and II criteria; AMS1 and AMS2, respectively), tumor immunohistochemistry (IHC) for 4 mismatch repair proteins (MMRP), tumor and normal tissue polymerase-chain reaction for microsatellite instability (MSI), and clinical genetic analysis and counseling (GAC), in those with undiagnosed LS. Patients who were AMS 2 positive, MSI positive, or IHC positive were considered as presumed Lynch syndrome (PLS) and were referred for GAC. Results: 101 UTUC patients without a history of LS were universally screened during clinical follow-up. A total of 15/101 (15%) patients were PLS. 7/101 (7%) patients met AMS2 criteria. 4 patients meeting AMS2 criteria had intact expression of MMRP and no MSI instability. 11 (11%) patients had either loss of one or more MMRP. There were two cases of MSI high instability, both in patients with MMRP loss. There were no cases of MSI-high instability and negative IHC. Insufficient tissue was found in 1/101 (1%) of IHC and 8/88 (9%) of MSI tests (p=0.0164). All patients with any positive screen were referred for GAC, 5 followed-up and all 5 patients had a confirmed germline mutation. The remaining did not follow through with GAC because of financial/insurance barriers. Conclusions: We identified 15% of universally screened UTUC as PLS at the POC using IHC and AMS2 criteria. IHC and AMS2 criteria appear to provide the most reliable screening. MSI is limited by requirement for normal tissue, a greater amount of tumor tissue, and can miss cases of MMRP loss. There are significant barriers to GAC. Our findings of a 15% rate of LS-related UTUC is consistent with prior laboratory tissue studies and has significant implications for universal POC testing of UTUC patients.
Effect of neoadjuvant chemotherapy in patients with resectable colorectal liver metastases.
Authors: Jianmin Xu, Dexiang Zhu, Yunshi Zhong
Journal: Journal of Clinical Oncology (2013)

e14523 Background: Whether patients with resectable colorectal liver metastases (CRLM) receive a survival benefit from neoadjuvant chemotherapy prior to hepatectomy remains controversial. Methods: We retrospectively analyzed 466 consecutive patients with resectable CRLM between 2000 and 2010. Patient and tumor characteristics, surgical procedure and survival data were recorded. Results: The patients were divided into two groups: one group with neoadjuvant chemotherapy (group NC, n=121) and one group without (group WN, n=345). There was no significant difference in the median survival (60.0 m vs. 53.9 m) or 5-year survival (52% vs. 48%) between the two groups. No significant differences were identified between the two groups in terms of 30-day mortality (1.7% vs. 1.2%) or morbidity (33.9% vs. 25.8%). A primary tumor at stage T4, ≥ 4 liver metastases, the largest liver metastasis ≥ 5 cm in diameter, and a serum CEA level ≥ 5 ng/ml were independent prognostic factors for the surgical patients. By assigning one point to each of above factors, all of the patients were divided into a low-risk group (0-2) and a high-risk (3-4). The patients in the low-risk group received no survival benefit from neoadjuvant chemotherapy, whereas those in the high-risk group received a survival benefit (median survival, 38.9 m vs. 28.4 m; 5-year survival, 39% vs. 33%, P=0.028). Conclusions: Preoperative neoadjuvant chemotherapy did not significantly increase mortality or complications. Not all resectable patients (only those with more than 2 independent risk factors) receive a survival benefit from neoadjuvant chemotherapy.
Assessment of off-label use for oncology drugs: A fair option for all?
Authors: Beat Seiler, Robert Fries, Hanspeter Honegger
Journal: Journal of Clinical Oncology (2014)

e17601 Background: Therapeutic benefits of off-label use are often unclear. Swiss Government regulates insurance coverage. Prerequisite for reimbursement is a substantial clinical benefit (CB) for patients with no alternative. The costs are covered proportionally to the expected benefit. Medical officers of Helsana Group, the largest Swiss health insurer, evaluate the benefits of off- label drugs before starting therapy. Methods: The examiners use MediScore (MS). This model was developed 2011 by Helsana in cooperation with swiss pharma groups and integrates evidence based medicine. It scores within the frame of ”Clinically Meaningful Outcomes” (L. Ellis, ASCO 2013). MS allows high expected individual benefit also with inferior evidence/outcome data, therefore respecting ethical principles. The assessment shows the expected patient benefit with four categories (cat). A and B for good CB; C for doubtful CB in studies, but possible CB in individual case and D shows no proven CB. The requests are rated with MS based on literature research. The rating enables an appropriate coverage in A and B. C gets covered, when an attempt of therapy shows signs of therapeutic benefit. We examined the processing of the off- label requests using MS for 2012 and 2013. Results: 1,294 requests (100%), not on the national list of drugs for approved indications, were included in the sample. In 81% of the requests insurance coverage was granted. In total 4o% (522) belonged to cat A and 36% (463) to cat B. 18% (237) of the cases are assessed to cat C. 25% (60) of the C-cases responded to therapy and so the costs of therapy were covered. Around 1% (10) were cat D and 5% (62) cases were refused because of alternative therapies available. Allocation of categories and percents of responding therapy in C remained identical in 2012 and 2013; thus the model is stable. Conclusions: Our model offers seriously ill patients access to coverage for innovative drugs with high therapeutic benefit. The system allows rapid appraisal and is transparent and ethical It is a dynamic assessment tool which allows up or downgrading of the rating if new evidence appears. It facilitates balance between costs and benefits in off-label drug and is widely accepted in Switzerland.
Actual total hospital costs of primary localized prostate cancer treatments analyzed by risk group.
Authors: Hugh J. Lavery, Adam W. Levinson, Adrien Phalen, Nelson Stone, Richard Stock, Dov Sebrow, Adele Hobbs, David B. Samadi
Journal: Journal of Clinical Oncology (2012)

e15164 Background: Radical prostatectomy (RP) and radiotherapy (RT) provide comparable HRQOL and oncologic outcomes of localized prostate cancer (PCa), yet no studies have evaluated their relative costs when investigated by risk group. We evaluated hospital costs associated with modern PCa therapies at a multidisciplinary program. Methods: Institutional billing data was queried for hospital patients from 2005 to 2009 with a primary admission for prostate cancer and primary procedure codes for RP, brachytherapy (BT), intensity modulated RT (IMRT) or combination treatment. All hospital costs related to the primary procedure were analyzed as assigned by the hospital. Costs were adjusted to 2009 USD and analyzed per patient and pretreatment D’Amico risk group. Results: 1969 localized PCa patients with a median age of 62 were identified with complete clinical information. There was a marked increase in the use of robotic-assisted laparoscopic prostatectomy (RALP) starting in 2007. The median total hospital costs for IMRT monotherapy ($16,673), BT+IMRT ($22,145) and RP+ adjuvant IMRT ($24,380) combination therapies were significantly higher than any other treatment type, although these patients had worse pathologic features. BT was the least expensive treatment with a total cost of $7,506, but was not routinely used as monotherapy for high-risk patients. The total cost of RALP ($7,676) was lower than open radical prostatectomy (RRP) ($8,991, p&lt;0.001) and similar to laparoscopic radical prostatectomy (LRP) ($7,769).These trendsremained consistent when stratified by risk group (Table). Conclusions: In a high volume setting, RALP and BT are the least expensive modalities for treating low and intermediate risk PCa. For high risk patients, all forms of RP and IMRT alone were less expensive than combination therapy. [Table: see text]
Venous thromboembolism in patients with glioblastoma multiforme.
Authors: Natasha Edwin, Alok A. Khorana, Michael Khoury, Gene H. Barnett, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2014)

2068 Background: Patients with glioblastoma (GBM) are at increased risk of venous thromboembolism (VTE) as well as intracranial bleeding and clinicians are reluctant to use anticoagulants. The natural history of VTE in GBM in the post-bevacizumab era is not well understood. We conducted a cohort study to evaluate the risk of recurrent VTE and bleeding Methods: We studied consecutive Cleveland Clinic patients with GBM presenting with objectively diagnosed deep vein thrombosis (DVT) or pulmonary embolism (PE) from 2008 to 2013 with at least 6-month follow-up. We collected information on patient demographics, VTE, treatment, recurrence and bleeding. Results: The study population comprised 450 patients of whom 129 (28.7%) developed 229 VTE events. Of these, 24 (10.4%) were PE and 205 (89.5%) were DVT. Sixty (46.5%) VTE occurred in the first 30 days post-operatively, 45 (34.9%) on chemotherapy and 70 (54.3%) in the outpatient setting. Inpatient thromboprophylaxis rates were low in eligible patients (N=10/59, 16.9%). Treatment of VTE included enoxaparin monotherapy (N=32, 24.8%), warfarin (N=11, 8.5%) or vena caval filters either alone (N=39, 30.2%) or in combination with anticoagulation (N=18, 13.9%)Recurrent VTE occurred in 24% (N=31)at a median of 39 days (range, 2-375 days). Forty percent occurred in the immediate postoperative period (N=13, 41.9%). There were 20(15.5%) episodes of major bleeding after index VTE; a majority were intracranial (N=15, 75%).Two(10%) bleeds occurred in the absence of anticoagulation, 10 (50%) on enoxaparin and 4(5%) on warfarin. Conclusions: GBM patients with VTE are at high risk for both recurrent VTE (24%) and major bleeding (15.5%), seemingly confirming clinicians’ concerns regarding anticoagulation. However, bleeding is common both with and without anticoagulation. Both primary and recurrent VTE are common in the post-operative period and improved adherence to thromboprophylaxis in this setting could reduce the risk. A prediction tool to individualize risk of VTE and bleeding could optimize use of anticoagulation in prophylaxis and treatment.
A limited access phase I trial of paclitaxel, cisplatin and ABT-888 in the treatment of advanced, persistent, or recurrent carcinoma of the cervix: An NRG/GOG study.
Authors: Premal H. Thaker, William E Brady, Heather A. Lankes, David E. Cohn, Carol Aghajanian, David Gardner Mutch, Robert S. Mannel, Katherine M. Bell-McGuinn, Paul DiSilvestro, Danijela Jelovac, Jori S. Carter, Ritu Salani
Journal: Journal of Clinical Oncology (2015)

5600 Background: The poly (ADP-ribose) polymerase (PARP) family of proteins is a family of nuclear enzymes required for the repair of single-stranded DNA damage. Preclinical studies demonstrate that PARP inhibition (PARPi) not only augments the apoptotic response in cervical cancer cell lines, but also sensitizes cells to the effects of alkylating agents like cisplatin. Given the use of cisplatin and paclitaxel as primary treatment for advanced, recurrent or metastatic cervical cancer before the findings of the benefit of adding bevacizumab in GOG 240, we aimed to evaluate whether PARPi can enhance the chemotherapy effectiveness in the treatment of cervical cancer. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent squamous or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy). Patients were not required to have measurable disease; have had concurrent chemotherapy and radiation for management of their disease; and have adequate organ function. The trial is a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175mg/m2 on day 1, cisplatin 50mg/m2 on day 2, and ABT-888 50mg po bid days 1-7 at dose level 1 and escalating by 50mg every dose level until dose level 8 at 400mg po bid days 1-7. Results: Thirty-seven patients were enrolled from 6/1/11-1/8/14, but only 34 are evaluable. Dose limiting toxicities (DLTs) were assessed during cycle on 1 of each dose level of ABT-888 and the three DLTs were as follows: grade 4 dyspnea which was possibly related to the ABT-888 in dose level 2, grade 3 neutropenia > 3 weeks in dose level 4, and febrile neutropenia in dose level 8. Cycles were repeated every 21 days until disease progression. At all dose levels the response rate [complete and partial] (RR) was 34% (95%CI: 20-53%); at the maximum dose level the RR was 60% (95%CI: 23-88%). Translational studies evaluating defects in the Fanconi Anemia pathway are ongoing. Conclusions: PARPi plus chemotherapy appears to have significant clinical benefit in cervical cancer therapy and warrants further investigation with bevacizumab in a clinical trial. Clinical trial information: NCT#01281852.
Association of human neurotropic JC virus with pediatric gangliogliomas.
Authors: Jennifer Rose Mullinax, Amanda Parker Struckhoff, Jimena Trillo-Tinoco, Michael Ripple, Randall Craver, Luis Del Valle
Journal: Journal of Clinical Oncology (2013)

2085 Background: JC virus (JCV), a member of the Polyomaviridaefamily, is a widespread ubiquitous human pathogen found in greater than 80% of the adult population, where it persists in a latent state, most likely in the kidneys and bone marrow. JCV is tumorogenic in animals and is associated with a variety of human malignancies, including brain tumors where it infects glial cells. JCV exerts its oncogenic effects through the oncoprotein T-Antigen, which binds and inactivates tumor suppressor proteins p53 and Rb. In addition, T-Antigen can translocate IRS-1 to the nucleus, where it impedes faithful DNA repair. In this study, we will investigate the presence of JC virus and the oncoprotein T-Antigen and explore their role in pediatric gangliogliomas. Methods: Formalin-fixed paraffin-embedded tissue samples of pediatric gangliogliomas were obtained from the archives of the Pathology Department at Children’s Hospital in New Orleans. PCR amplification was performed with specific primers for the T-Antigen coding region of JCV. Immunohistochemistry for T-Antigen, p53, Rb, and IRS-1, the docking molecule of the IGF-1 pathway, was also performed. Results: Our study included 15 samples of pediatric gangliogliomas. JCV genomic sequences were amplified in 12 of the 15 samples (80%). T-Antigen expression was found in the nuclei of tumor cells in 7 of the 15 samples (47%) by immunohistochemistry. T-Antigen was present in both the glial and neuronal components of the tumors. Of the seven samples positive for T-Antigen, five were positive for both p53 and Rb, one was positive for p53, and one was negative for both p53 and Rb, but positive for nuclear IRS-1. Conclusions: The presence of JCV genomic sequences in pediatric tumors suggests that primary infection occurs early in life. The expression of T-Antigen in both the glial and neuronal components of gangliogliomas suggests that these mixed tumors most likely originate in a common primitive cell, which then differentiates into two different phenotypes. The co-localization of T-Antigen with p53 and Rb suggests that cell cycle deregulation is one oncogenic pathway in gangliogliomas. Nuclear IRS-1 suggests alterations on faithful DNA repair mechanisms. These findings warrant further investigation.
Cost-effectiveness analysis of magnetic resonance imaging-ultrasound fusion biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer.
Authors: Matthew Ingham, Matthew Mossanen, Ye Wang, Steven Lee Chang
Journal: Journal of Clinical Oncology (2017)

25 Background: We sought to determine if the reported improved performance of magnetic resonance imaging-ultrasound (MRI-US) fusion biopsy over systematic transrectal ultrasound-guided biopsy (TRUS) in the detection of prostate cancer justifies the added cost of the MR imaging. Methods: A decision-analytic Markov model with a lifetime horizon of 10 years was developed to evaluate diagnostic accuracy, long-term health outcomes, costs, and quality-of-life of two strategies (i.e., TRUS versus MRI-US fusion biopsy [prostate MRI followed potentially by MRI-US fusion biopsy]) as the initial diagnostic test in men with elevated prostate-specific antigen ( &gt; 4 ng/ml) without prior evaluation. Probabilities of clinical events were obtained from published literature. Direct medical costs, including diagnostic and treatment-related costs, were derived from the Premier Hospital Database. Costs were inflated to 2015 US dollars and discounted at an annual rate of 3%. Health outcomes were measured in quality-adjusted life years (QALYs), which were determined based on published literature and expert opinion. We calculated the incremental cost-effectiveness ratio and performed sensitivity analyses to assess uncertainty. Results: The MRI-US fusion biopsy strategy yielded a lower average discounted cost ($5,358 versus $6,372) and higher total QALYs-gained (7.21 versus 7.19) than TRUS. The reduced expenditures associated with MRI-US fusion biopsy was primarily due to avoiding intervention for clinically insignificant prostate cancer. The results were robust with the sensitivity analyses. Conclusions: For men in the United States with an elevated PSA, the use of MRI-US fusion biopsy in the evaluation for prostate cancer represents a greater value than TRUS, the standard of care option. Widespread adoption of MRI-US fusion biopsy may serve to reduce the economic burden of prostate cancer.