tbuckley/cabot-search huggingface dataset:
Determining agreement between immunohistochemistry and RT-qPCR for standard biomarkers in breast cancer: Validation on GEICAM 9906 clinical trial.
Authors: P. S. Bernard, C. Davis, B. Munarriz, I. J. Stijleman, M. Ruiz-Borrego, M. T. W. Ebbert, A. Rodriguez-Lescure, R. R. L. Bastien, C. Crespo, C. M. Perou, C. Rodriguez, F. I. Aranda, V. Furió, I. Alvarez, M. A. Seguí, E. Alba, A. Anton, E. M. Carrasco, R. Caballero, M. Martin
Journal: Journal of Clinical Oncology (2011)

611 Background: Common practice for comparing different technologies measuring the same biomarker is to establish cut-offs using Receiver Operator Characteristic (ROC) curves and maximizing sensitivity/specificity. We introduce a new method for establishing RT-qPCR cut-points using gene expression across biologic subtypes and compare to standard methods. Methods: A RT-qPCR training set was established to identify biologic subtypes of breast cancer using the PAM50 gene expression signature. 155 invasive breast cancers and 16 normal breast samples, procured in formalin-fixed paraffin-embedded tissue blocks, were used to identify prototypic samples for the common biologic subtypes (Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal). Cut-points for ESR1, PGR, and ERBB2 were determined based on their expression across the training set subtypes and used to determine sensitivity/specificity in an independent test set of 793 invasive breast cancers from the GEICAM 9906 study (randomized phase III trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer). Fixed cut-points (low vs intermediate/high) were applied to the continuous RT-qPCR data and compared to IHC scores tested for in a central facility. Results: There was good agreement between RT-qPCR gene expression and immunohistochemistry scoring for clinical markers ESR1/er, PGR/pr, and ERBB2/her2. The accuracy was significantly lower for MKI67/ki67, EGFR/egfr, and KRT5/ck5/6 (Table). Discrepancies between the Herceptest and CISH for 2+ and 3+ samples showed that RT-qPCR agreed better with the Herceptest (AUC: 0.95 vs 0.93). Conclusions: Calling cut-points based on RT-qPCR expression across subtypes is reproducible across datasets and has good agreement with expression by immunohistochemistry for clinically used biomarkers. Agreement between gene and protein expression for common biomarkers in breast cancer. Accuracy Area under curve (AUC) Sensitivity (%) Specificity (%) Gene/protein expression ESR1/er 0.89 96 72 PGR/pr 0.90 83 86 ERBB2/her2 0.95 92 87 ki67/MKI67 0.74 71 62 EGFR/egfr 0.82 80 71 KRT5/ck5/6 0.61 61 53
Hemithoracic radiation therapy and brachytherapy after pleurectomy/decortication for malignant pleural mesothelioma: Results from a 30-year experience
Authors: K. E. Rosenzweig, V. Gupta, B. Mychalczak, L. M. Krug, R. Flores, V. W. Rusch
Journal: Journal of Clinical Oncology (2005)

7180 Background: The role of pleurectomy/decortication (PD) and adjuvant radiotherapy (RT) in the treatment of malignant pleural mesothelioma (MPM) is controversial. We conducted a retrospective review to evaluate the efficacy and toxicity of this treatment. Methods: This study includes MPM patients treated with PD and adjuvant RT at the Memorial Sloan-Kettering Cancer Center from 1974 to 2003. PD consisted of resecting as much gross tumor as possible, typically removing the parietal, mediastinal, and visceral pleura. When indicated, patients received intra-operative brachytherapy to residual tumor. Results: Of the 123 patients in this study, 102 were male, 72 reported asbestos exposure, 86 had a positive smoking history, and 74 had epithelioid histology. All patients received external beam RT (median dose, 42.5 Gy; range, 7.2–67.8 Gy) to the ipsilateral hemithorax after surgery. Fifty four patients underwent brachytherapy with 125I or 192Ir implants to regions of residual disease. The median overall survival for all 123 patients was 13.5 months (range, 1–199 months) and the 2-year and 5-year overall survival were 23% and 5% respectively. Multivariate analysis for overall survival revealed non-epithelioid histology (p=0.002), radiation dose less than 40 Gy (p=0.001), left-sided disease (p=0.01) and the use of an implant (p=0.02) to be unfavorable. CTCAE Grade 3–5 toxicity was seen in 33 (27%) patients including pneumonitis (10%), pericarditis (8%), and esophagitis (4%). Conclusions: Pleurectomy/decortication with adjuvant radiotherapy is not an effective treatment option for patients with malignant pleural mesothelioma. Our results suggest that high external beam radiation therapy doses are needed to control microscopic disease and that residual disease cannot be eradicated, even with brachytherapy. The toxicity of the treatment is significant as suggested by the poor outcome in patients with left-sided disease, presumably from cardiac complications after radiation therapy. No significant financial relationships to disclose.
Reapplication of High-Dose Chemotherapy and Autologous Blood Stem Cell Transplantation as Salvage Treatment for Patients with Relapsed or Refractory Multiple Myeloma – a Single Center Experience.
Authors: Roland Fenk, Vanessa Liese, Ingmar Bruns, Mustafa Kondakci, Sebastian Balleisen, Christian Saure, Thomas Schröder, Rainer Haas, Guido Kobbe
Journal: Blood (2009)
A phase I study of erlotinib, bevacizumab, and external beam radiation therapy (RT) for patients with localized pancreatic carcinoma (PC).
Authors: B. G. Czito, C. Willett, P. Kennedy-Newton, D. S. Tyler, H. Hurwitz, H. E. Uronis
Journal: Journal of Clinical Oncology (2011)

281 Background: Localized PC is commonly managed with chemoradiotherapy, with or without surgical resection. The optimal combination of agents and doses is the subject of continued investigation. This phase I study examines the combination of two targeted radiosensitizing agents in combination with radiation therapy. Methods: Eligible patients had resectable, borderline resectable or locally advanced adenocarcinoma. Patients received RT (1.8 Gy qd to 50.4 Gy) concurrent with bevacizumab and erlotinib. Dose-level 1 was bevacizumab 10 mg/kg weeks 1, 3 and 5 and erlotinib 100 mg daily, RT days only. Drug doses were escalated depending on encountered toxicity. The primary endpoint was determination of the maximally tolerated dose of this combination. Secondary endpoints included toxicity and activity assessment. Results: Nine patients were enrolled in the phase I study. Maximal EUS/CT stage was T2N0 (n=1), T3N0 (n=1), T3N1 (n=2) or T4N0 (n=5). Of 3 patients in dose-level 1, two had radiographic stable disease (SD) and one partial response (PR). One pt underwent exploratory laparotomy and found to be unresectable, experiencing prolonged postoperative incisional healing. Three patients were then enrolled at dose-level 2 (bevacizumab 10 mg/kg, erlotinib 125 mg). Two had SD and one progressive disease (PD). One pt underwent exploratory laparotomy, aborted due to previously undetected hepatic metastases. Three patients were then enrolled at dose-level 3 (bevacizumab 10 mg/kg, erlotinib 150 mg). One pt had SD and two PR. One pt underwent distal pancreatectomy, experiencing postoperative pancreatic leak and abscess formation. All patients with elevated CA 19-9 at baseline had a decrease, with amedian decrease of 69% (R:13-93%). Dose-limiting toxicity (DLT) was not encountered at any dose-level. Primary non-dose limiting toxicities in all cohorts included NCI CTCAE v3.0 grade 1-2 nausea/vomiting, rash, diarrhea, fatigue, and anorexia. Conclusions: Concurrent chemoradiotherapy utilizing erlotinib and bevacizumab is reasonably well-tolerated. The recommended phase II dose is bevacizumab 10 mg/kg weeks 1, 3, and 5 and erlotinib 150 mg RT days only. Phase II accrual is underway. [Table: see text]
Does the dose of leucovorin (LV) matter with 5-fluorouracil (5FU) in colorectal cancer (CRC)?
Authors: James Joseph Biagi, Nadia Coakley, Craig Earle, Charles Erlichman, Anthony L.A. Fields
Journal: Journal of Clinical Oncology (2016)

708 Background: In June 2015 Cancer Care Ontario convened an expert panel to determine if there is an optimum LV dose in 5FU-LV combinations for the treatment of CRC. This request arose out of observed variation in LV dosages between some cancer centers. The research question was effect of LV dose on overall survival (OS), progression free survival (PFS), disease free survival (DFS), response rate (RR) and adverse events/toxicity, given a constant dose of 5FU. Methods: A systematic search was conducted for guidelines (GL) and comparative trials; eligibility included English language, with &gt; 30 patients, that examined different doses of LV where dose of 5FU was not varied. Assessment of studies for inclusion was completed by 4 reviewers. Results: We identified 5 GL, 0 systematic reviews and 12 trials that defined a LV dose in combination with 5FU. None of the GL informed an optimal dose of LV. RR was assessed in 10 trials; 4 showed trends to higher RR with higher LV dose, but differences were not statistically significant (SS) between arms. PFS or DFS was reported in 6 trials and was similar between arms. Time to recurrence reported in one trial that included bevacizumab (BV) was longer in the high dose LV group that was SS. OS was addressed in 10 studies: no difference found in 7 studies; in one RCT OS was longer with the higher dose LV 55 vs. 45 months (p not reported); in one retrospective study OS was 23 vs. 20 months in favor of high dose LV (p not reported); one study of LV and BV had longer OS vs. lower dose LV at 26 vs. 21 months (SS). Toxicity: higher dose LV was associated with greater toxicity in 3 of 4 studies that reported stomatis, and increased rates of diarrhea in 9 of 11 trials. Meta-analysis was not appropriate as studies were too heterogeneous. Conclusions: There is no convincing evidence to identify an optimum dose of LV to be used in 5-FU/LV combinations. Amongst studies that did show a difference the trend was improved survival in favor of the higher dose. Similarly, differences in toxicities when identified were consistently greater with the higher dose LV. The expert panel concludes that the existing literature provides insufficient data to suggest that chemotherapy protocols should deviate from standard protocol doses.
From Anthrax to Zika: memoirs of a disease detective
Authors: James W Rudge
Journal: The Lancet Infectious Diseases (2017)

Swine flu, Middle East respiratory syndrome coronavirus, Ebola virus disease, Zika virus disease: in the past decade alone we have certainly not been bereft of headline-grabbing viral disease outbreaks. As soon as the media frenzy around the prevailing disease of the day begins to die down, it never takes long for a new contagion to step into the limelight. But as the world's attention and resources shift reactively from one high-profile outbreak to the next, is there sufficient emphasis on reflecting on these events and addressing the structural weaknesses that compromise our ability to prevent or mitigate the impact of future threats? Indeed, are there commonalities in the challenges faced and lessons that can be learned from such seemingly disparate events as an anthrax attack in Washington DC, and an Ebola virus disease outbreak in west Africa?
The effect of pathologic T-stage and Gleason score on cancer-specific survival in patients with positive surgical margins after surgery for high-risk prostate cancer.
Authors: Lorenzo Tosco, Hendrik Van Poppel, Thomas Van den Broeck, Patrick Bastian, Alberto Briganti, Felix K. Chun, Paolo Gontero, Chien Yeh Hsu, R. Jeffrey Karnes, Giansilvio Marchioro, Rafael Sanchez-Salas, Martin Spahn, Bertrand Tombal, Henk Van Der Poel, Steven Joniau
Journal: Journal of Clinical Oncology (2014)

140 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach but patients with positive section margins (R1) disease have not always the same cancer-specific survival (CSS). The current study aims to analyze current postoperative pathological features in order to predict CSS of HRPC patients with R1, but with negative lymph nodes (pN0), treated with surgery. Methods: From a multi-institutional retrospective cohort of 5,876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1541 patients with pN0 and R1 were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT&lt;3) and p-Gleason score (pGS≥8 and pGS&lt;8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age at surgery was 66 years (42-89). Of all patients, 399 (25.9%) had GS≥8 and 999 (64.8%) had pT≥3 at definitive histopathology. Patients were classified as COMBO groups: C1 (423; 27.4%; GS&lt;8,pT&lt;3), C2 (674; 43.7%; GS&lt;8, pT≥3), C3 (83; 5.4%; GS≥8, pT&lt;3), C4 (362; 23.5%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 3%/5%, C2 15%/21%, C3 21%/20%, C4 28%/40%. Kaplan-Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97%, C2 93.8%, C3 85.1% and C4 77.3% (p&lt;0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide margin-positive, pN0 HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]
Prophylactic use of antidiarrheal agents to control diarrhea associated with lapatinib therapy in breast cancer patients.
Authors: Muhammad Omer Jamil, Maira Rizwan, John T. Carpenter
Journal: Journal of Clinical Oncology (2015)

205 Background: Lapatinib causes diarrhea in about 40-50% of patients treated with it for HER-2 positive breast cancer. It is the major dose and treatment limiting toxicity of lapatinib. Methods: This is a retrospective review of a cohort of patients treated with lapatinib for HER2 positive breast cancer at the Kirklin clinic at the University of Alabama at Birmingham from January 1, 2009 through September 30, 2013. Loperamide 2-8mg before lapatinib dose was recommended for prophylaxis in patients who developed clinically significant diarrhea. Additional doses of loperamide were used if needed. Results: 44 eligible patients were identified, 7 had stage IA, 10 had IIA, 7 had IIB, 5 had IIIA, 5 had IIIB and 6 had stage IV disease. Median age was 52 years (28-72 years) with 75% Caucasians. Starting dose of lapatinib was 1000mg oral daily. Overall 33 patients experienced diarrhea. 14 had NCI grade I, 5 had grade II, 10 had grade III and 3 had grade IV diarrhea. Other side effects encountered included rash, nausea, vomiting, LFT elevation, fatigue and allergic reaction. 17/33 patients received prophylactic loperamide. Median treatment duration with lapatinib for all patients was 6 months, range 1-60 months for patients receiving prophylactic loperamide and 1-22 months for others. 12/17 patients who received prophylactic loperamide had early improvement in diarrhea to NCI grade I or less vs. 4/16 for others. 5/17 patients who received prophylactic antidiarrheals required dose reduction due to diarrhea vs. 8/16 for others. Grade III and IV diarrhea was more common in standard treatment patients (8 vs. 5). 14 patients did not complete expected treatment duration, 5 due to diarrhea, all of whom had not received prophylactic antidiarrheals. Conclusions: Our study suggests that the use of prophylactic antidiarrheal treatment with lapatinib is possibly an effective strategy in getting patient to their therapy goals without interruptions or dose adjustments. The discontinuation rate and dose reduction rate in our population is lower than previously reported. Larger prospective studies will be of interest to evaluate this strategy further. Similar strategy could be applied to other agents causing diarrhea.
Effect of upregulation of ANGPT2 by DARPP-32 on angioenesis in gastric cancer.
Authors: Zheng Chen, Shoumin Zhu, Jun Hong, Abbes Belkhiri, Wael El-Rifai
Journal: Journal of Clinical Oncology (2013)

34 Background: Gastric cancer is the second most frequent cause of cancer-related death worldwide. We have previously shown that Dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) and its truncated form (t-DARPP) are overexpressed in two-thirds of gastric adenocarcinomas. Angiopoietin 2 (ANGPT2) -TIE2 signaling is a secreted protein that acts as a key regulator of adult vascular homeostasis and blood vessel formation. Methods: The expression of DARPP-32 in the multi-step carcinogenesis cascade was examined using IHC analysis on 533 samples. ANGPT2 mRNA level was detected by real-time quantitative polymerase chain reaction (PCR) in 30 gastric cancer tissue samples and 30 normal gastric tissues. DARPP-32 and t-DARPP were over expressed using stable and transient expression in AGS and MKN-28 gastric cancer cell lines, lacking endogenous DARPP-32 to investigate the induction of ANGPT2 by DARPP-32 and t-DARPP. Results: We found that ANGPT2 was higher expressed in cancer samples than normal tissues from RT-PCR. We also found gastric cancer tissue samples expressed higher DARPP-32 and t-DARPP mRNA than normal gastric tissues. Over expression of DARPP-32 and t-DARPP led to a significant increase of the mRNA and protein levels of ANGPT2 as compared to empty vector control. Consistent with these findings, the condition media from DARPP-32 and t-DARRP expressing cells showed high levels of secreted ANGPT-2. TNF-α treatment induced the levels of ANGPT2 further in DARPP-32 and t-DARPP expressing cells as compared to control. Of note, this increase in NF-κB activity was significantly higher in DARPP-32 and t-DARPP expressing cells as compared to control. To confirm the angiogenic potential, we used condition media from DARPP-32 and t-DARPP expressing AGS cells and demonstrated its ability to stimulate tube formation on human umbilical vein endothelial cells (HUVEC) models than the condition medium from control cells. Conclusions: Our results suggest that DARPP-32 and t-DARPP over expression may participate in the angiogenesis of gastric cancer. The in vitro studies indicate that DARPP-32 and t-DARPP play a role in up regulation of ANGPT2 in gastric cancer cells by enhancing the TNF-α induced activation of NF-κB signaling pathway.
Analysis of the methylation profile of 49 cancer-related regions in human breast cancer.
Authors: D. M. Marzese, F. Gago, J. I. Orozco, O. M. Tello, M. Roqué, L. M. Vargas-Roig
Journal: Journal of Clinical Oncology (2010)

10543 Background: Aberrant methylation of CpG islands is a common mechanism for suppressing gene expression in breast cancer. The methylation profile of primary tumor could serve to detect circulating tumor-specific DNA (ctDNA) in peripheral blood of cancer patients. Methods: The methylation status of 49 cancer-related regions was studied using methyl specific-multiplex ligation probe amplification (MS-MLPA) assay in invasive breast tumors (n=68), axillary lymph nodes (n= 21), and normal breast tissue (n=7). A double round of MS-MLPA (drMS-MLPA) was set up to identify ctDNA in pre-surgical peripheral blood samples. Blood samples from healthy individuals were used as control. Results: We observed methylation of at least 5 of the 49 studied gene regions in all the breast cancer samples. The profile was specific for each tumor and we found that the frequency of methylation of some genes was significant different according to the molecular classification, the tumor grade, and the involvement of lymph nodes. For example, the methylation of p73 appeared in 37% of Luminal A tumors vs. 100% of HER2 tumors (p=0.0006), and in 73% of Triple Negative tumors (p=0.045). The methylation of CDH13 was present in 21% of Luminal A vs. 70% of HER2 (p=0.006). p73 was methylated in 17%, 38%, and 87% of tumor grade 1, 2 and 3, respectively (p=0.0025, grade 1 vs. 3, and p=0.001, grade 2 vs. 3). The methylation of RARβ appeared in 48% of primary tumors with positive lymph nodes and in 14% of tumors with negative nodes (p=0.03). Using drMS-MLPA approach we were able to detect ctDNA in pre-surgical blood samples based on the epigenetic signature of primary tumors and we also could establish its sensitivity. Conclusions: The methylation of some genes correlates with pathological characteristics of breast cancer. This methylation is related to prognostic parameters like tumor grade or lymph nodes metastasis. The drMS-MLPA approach could be useful for the follow up of breast cancer patients. No significant financial relationships to disclose.
The impact of HCV co-infection on the outcome and the clinical features of HIV-related non-Hodgkin lymphoma (NHL)
Authors: C. Simonelli, M. Spina, R. Talamini, R. Tedeschi, A. Bearz, M. Berretta, U. Tirelli
Journal: Journal of Clinical Oncology (2008)

19504 Background: Epidemiological studies show an association between HCV and B NHL. Treatment and outcome of patients with NHL and HCV infection in the general population and in HIV-infected population are still debated. Methods: HIV-infected individuals with NHL diagnosed and treated at the National Cancer Institute of Aviano (Italy) from April 1991 to October 2006, whose serology for HCV- infection was known at NHL diagnosis, were enrolled in the study. The aim of the study was to describe and compare clinical features and outcome of NHL in HIV patients with or without HCV co-infection. Co-infected and mono-infected patients were treated with the same therapeutical protocols. Results: 301 HIV-infected patients with NHL were included in the study: 123 (40.2%) HCV co-infected and 178 mono-infected. As regards HIV disease’s characteristics the co-infected patients had a significantly higher percentage of intravenous drug users (IDUs) in comparison with mono-infected patients, whereas no significant differences were seen in CD4, CD8 count, HIV viral load, AIDS-defining condition at NHL diagnosis and antiretroviral therapy. As regards NHL’s characteristics at the onset, co- infected patients showed a significantly lower percentage of Burkitt histotype, whereas no significant differences were seen in Performance Status, stage and International Prognostic Index. Co-infected patients showed a significant higher NHL involvement of the spleen. No differences were observed in response rate (RR), complete response rate (CRR) and overall survival (OS) at 5 years. Co-infected patients had a significantly higher percentage of G3-G4 liver toxicity during chemotherapy (4.5% vs 0%; p=0.0083) although it was not life threatening. Conclusion: Co-infected patients had a significantly higher rate of IDUs as risk factor for HIV infection, of Burkitt lymphoma among lymphoma histotypes, and of spleen involvement as NHL site. No other differences were observed in the characteristics of HIV and NHL disease. No differences in RR, CRR and OS were observed between co- and mono-infected patients, although a higher rate of liver toxicity was observed in co-infected patients. No significant financial relationships to disclose.