tbuckley/cabot-search huggingface dataset:
Measurement of DKK1 and FRP in breast and prostate cancer patients with bone metastases: Impact of zoledronic acid (ZA)
Authors: T. Helsten, M. Corr, J. E. Mortimer
Journal: Journal of Clinical Oncology (2007)

19659 Background: Bone metastases produce an imbalance in osteoblast and osteoclast activity. While metastases from prostate cancer are osteoblastic, metastases from breast cancer may be osteolytic, osteoblastic or mixed. The wnt/frizzled pathway is involved in maturation of osteoblasts and in adult bone homeostasis. We explored the wnt antagonists dickkopf (DKK1) and frizzled related protein (FRP) as potential biomarkers in bone metastasis after ZA treatment. Methods: This is a pilot cohort study in bisphosphonate naive breast and prostate cancer patients with bone metastases. Cancer therapy was not specified. Patients received 2 monthly doses of ZA 4 mg IV. Pre- and post-treatment (day 60) sera were collected for measurement of FRP and DKK1, along with IL-6, calcium, creatinine and bone-specific alkaline phosphatase (BAP, a marker of osteoblast activity). Primary endpoint: mean change in FRP and DKK1; Secondary endpoints: correlation of biomarkers with each other and comparison of breast vs. prostate cancer patients. Biomarkers were measured using standard ELISA assays. Statistics: comparison of means = student t-test, correlation coefficients = Pearson. Results: Mature data from 14 patients are reported here, 9 with breast and 5 with prostate cancer. Mean age = 61 years (range 42–89). Two breast cancer patients were premenopausal. One prostate and 3 breast cancer patients received chemotherapy; all others were treated hormonally. After ZA, calcium decreased in all patients (p = 0.09). BAP decreased in all but 1 breast and 1 prostate cancer patient (mean decrease 20.0, p = 0.16). IL-6 was undetectable in most patients. FRP decreased in all but 4 patients (mean decrease 6.2, p = 0.13). There was no discernable pattern for DKK1. Pre-treatment DKK1 correlated with FRP (p = 0.01, r 2 = 0.39), but there was no correlation post-treatment. Post-treatment DKK1 correlated with both serum calcium (p = 0.04, r 2 = 0.49) and BAP (p = 0.005, r 2 = 0.65). There was no difference between breast and prostate cancer patients. Conclusions: It is feasible to measure DKK1 and FRP in patients with malignant bone disease. Treatment with ZA has measurable effects upon these and other serum markers. Further studies with more patients are needed to evaluate their potential as biomarkers. No significant financial relationships to disclose.
ERCC1, p16, and Ki-67 immunohistochemichal expression as predictive and prognostic markers in head and neck squamous cell carcinoma treated with platin-based induction chemotherapy: Staining with the two anti-ERCC1 antibodies (8F1 and FL-297) was compared.
Authors: Helene Roussel, Martin Housset, Helene Tournat, Patrice Ravel, Stephane Hans, Patrick Bruneval, Cecile Badoual
Journal: Journal of Clinical Oncology (2012)

e13578 Background: Head and neck squamous cell carcinoma (HNSCC) treatment had undergone important changes, in particular due to the organ preservation and the advent of chemotherapy, particularly using platinum. The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and has been associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1expression with p16 and Ki-67 as predictive markers in the response to platin-based induction chemotherapy and as prognostic markers in patients with HNSCC. Methods: 208 patients treated from 2000 to 2006 by an induction chemotherapy regimen for HNSCC were included retrospectively. ERCC1 (8F1 and FL297 clone), p16 and Ki-67 staining were performed on paraffin-embedded tumor tissue collected before chemotherapy. We assessed response to treatment, progression-free survival (PFS) and overall survival (OS). Results: Respectively, 68% (142/208 patients) and 81.5% (163/200 patients) of HNSCC showed low expression of 8F1 and FL297 ERCC1. No correlation was found between the two clones (p=0.1). There was no correlation between the expression of 8F1 ERCC1, FL297 ERCC1 and Ki-67 and the response to induction chemotherapy, OS or PFS. However, in the subgroup of 129 patients treated with induction cisplatin-5FU chemotherapy, a low expression of 8F1 ERCC1 was significantly associated with a better response (p=0.027). Over expression of p16, found in 34.5% of cancers of the oropharynx was significantly correlated with a better OS (p=0.0007) and a better PFS (p = 0.01). Conclusions: These results suggest that ERCC1 expression might be a useful predictive marker of HNSCC in patients treated by cisplatin-based chemotherapy. The 8F1 ERCC1 clone appears to be the best for immunohistochemical analysis; clone FL297 did not show any association with treatment response and survival. Independently, our study confirms the prognostic value of the over expression of p16 in carcinoma of the oropharynx.
Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors.
Authors: Laurien Aletta Daniëls, Augustinus Krol, Michiel A de Graaf, Arthur JHA Scholte, Hein Putter, Mars B van t Veer, Albert de Roos, Martin J Schalij, Carien L. Creutzberg
Journal: Journal of Clinical Oncology (2013)

8568 Background: Cardiovascular diseases are the most common non-malignant cause of death in Hodgkin Lymphoma (HL) survivors, especially those who had mediastinal irradiation as part of their treatment. We investigated the role of CT coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, related findings to stress testing and subsequent interventions. We also evaluated acceptance of screening. Methods: Patients were eligible if at least 10 years disease-free and treated with mediastinal radiotherapy. All patients were screened with ECG, stress testing and CTA. Primary endpoint was significant CAD (stenosis &gt;50%) on CTA. A sample size of 50 patients would achieve ≥80% power to detect a difference of 13% (≥20% vs a population proportion of 7%) using a two-sided binominal test. Allowing for non-evaluable and false-positive scans, we considered CTA screening to be indicated for testing in a larger population if in ≥six patients revascularization would be necessary. Results: Fifty-two patients were included, 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. Most patients had no risk factors for CAD. There were 45 evaluable scans. Prevalence of significant CAD on CTA was found in 20% (N=9), and significantly increased compared to the 7% expected abnormalities (p=0.01, 95% CI 8.3-31.7%). In 5 of the 8 patients who underwent conventional angiography, significant CAD was confirmed, and revascularization performed. Two patients were started on medication. Stress testing was inaccurate for determining CAD: all participants were asymptomatic and 1 patient with significant CAD had signs of ischemia. Ninety percent of the participants were content with the screening offered in this study, regardless whether the CTA showed abnormalities or not. Conclusions: Prevalence of significant CAD among HL survivors is high. In our participants even the most severe and life-threatening CAD was not preceded by typical symptoms. In symptomatic cardiac patients revascularization improves survival. This might justify both screening by CTA and intervention in this asymptomatic population, but needs to be further evaluated in a larger cohort. Clinical trial information: NCT01271127.
Nasal NK-T cell lymphoma: 10-year experience of a single institute in India.
Authors: Prashant Mehta, Vinod Raina, Lalit Kumar, Atul Sharma, Sameer Bakhshi, Ajay Gogia, Tilak Tvsvgk, Bivas Biswas, Siddharth Sahai, Surendra Pal Chaudhary, Vijay Murugan, Mehar C Sharma, Sandeep Mathur, Sanjay Thulkar
Journal: Journal of Clinical Oncology (2014)

e19536 Background: Nasal NK –T cell lymphoma accounts for 5% of all NHLs at our centre. Methods: We reviewed data of 38 patients treated between January 2002 and August 2013. Results: Patients’ median age was 40 yrs (12-75 yrs),M:F = 3.2:1. 8/38 had unilateral loss of vision at presentation, 23/38 (60%) had B symptoms; median duration of symptoms was 3.5 months. Sinuses were involved in 24/38 cases, common being maxillary (42%) and ethmoid (41 %). Palate was perforated in 14 (36 %) cases. Ann Arbor staging revealed; stage I-30/38(79%), II-4/38 (10.5 %) and IV in 4 patients (10.5 %), 4 patients had lung and 1 had both lung and brain involvement. IPI score(n=28) was 1 in 7 patients(25 %), 2 in 13 (46 %) ,3 in 3 patients(10 %) , and 4 -5 in 5 patients (18 %).Patients received CHOP (n= 20) and L-asparaginase based chemotherapy (SMILE, Yamaguchi et al, JCO, 2011;29(33):4410-16, n=11) 2011 onwards. Radiation dose (IFRT) was 45Gy to 50 Gys in 25 fractions (CHOP-10, SMILE-5). Response rates at end of treatment; CHOP-CR -8/20, PR-0, SMILE- CR-7/11, PR-4/11. 4 patients relapsed; CHOP-3, SMILE-1. Among 20 patients in CHOP arm, 5 (25 %) are alive in CR, 6 died of progressive disease, and 9 were lost to follow up, of which 3 were in CR. In the SMILE group 6 of 11 patients are alive in CR and 1 died of progression. In the SMILE cohort (n=11), major toxicities were - neutropenic fever-6, grade 3 thrombocytopenia-3, pancreatitis-1, cortical venous thrombosis-1, coagulopathy-1, liver dysfunction-1, 6 patients required dose reduction, while in the CHOP cohort (n=20) 3 patients had neutropenic fever and 3 required dose reduction. There were no toxic deaths. Patients received prophylactic GCSF in SMILE group. The EFS and OS for 25 pts who completed treatment is 59 % (95% CI=0.29-0.80) and 70 % (95% CI=0.32-0.89), respectively at a median follow up of 15 months. There was no correlation of EFS with B symptoms, stage, IPI score or chemotherapy given (CHOP vs. SMILE), but completion of RT was a significant factor effecting survival. Conclusions: We confirm the higher CR rates and lesser on treatment progression following L-asparaginase based protocol and involved field radiation. SMILE is a feasible protocol; Toxicity with GCSF support is acceptable.
Prognostic value of preoperative lymphocyte-to-monocyte ratio in patients with hepatocellular carcinoma after curative resection.
Authors: Ze-xiao Lin, Dan-yun Ruan, Dong-hao Wu, Xiao-kun Ma, Jing-yun Wen, Xing Li, Zhan-hong Chen, Qu Lin, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2014)

e15118 Background: Previous studies have demonstrated a correlation between immune microenvironment and the biology of hepatocellular carcinoma (HCC). This study aims to evaluate the prognostic value of peripheral blood lymphocyte-to-monocyte ratio (LMR), as a simple surrogate biomarker of the immunological microenvironment, in patients with HCC undergoing curative hepatectomy. Methods: Clinicopathological data from 210 HBV-associated HCC patients treated with hepatic resection from 2003 to 2010 was retrospectively analyzed. Serum complete blood counts before surgery were used to calculate LMR. The best cut-off value of LMR for survival analysis was determined by the receiver operating characteristics (ROC) curve. Univariate and multivariate analyses were performed to assess preoperative variables. Results: ROC curve analysis established 3.2 as the optimal cutoff point of LMR. 66 of 210 patients (31.4%) had LMR of lower than 3.2. Low LMR was associated with larger size of tumor (p = 0.012) and elevated level of total serum bilirubin (p = 0.002). With a median follow-up of 34 months (range, 2-106 months), the median overall survival (OS) for the whole group was not reached and the median recurrence free survival (RFS) was 38.5 months. Patients with low LMR had significantly worse 5-year OS (63.5% vs 82.5%, p = 0.002) and RFS (35.3% vs 45.9%, p = 0.048) than those with high LMR. Multivariate analyses identified low LMR as an independent predictor of shorter OS (hazard ratio = 1.791, 95% confidence interval, 1.011-3.172, p = 0.046) and shorter RFS (hazard ratio = 1.496, 95% confidence interval, 1.009-2.217, p = 0.045). Presence of cirrhosis, high alkaline phosphatase level and poor histological differentiation were also independent risk factors associated with poor prognosis. Conclusions: Our study demonstrates that preoperative LMR, as a simple and economical biomarker combining an estimate of host homeostasis and tumor microenvironment, is an independent prognostic factor for survival in HCC patients after radical liver resection. The combination of LMR and other clinical indices may provide better prognostic stratification for HCC.
Neoadjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00).
Authors: Miklos Pless, Roger Stupp, Hans-Beat Ris, Rolf A. Stahel, Walter Weder, Sandra Thierstein, Alexandros Xyrafas, Martin Frueh, Richard Cathomas, Alfred Zippelius, Arnaud Roth, Milorad Bijelovic, Adrian Ochsenbein, Urs R. Meier, Christoph Mamot, Daniel Rauch, Oliver Gautschi, Daniel C. Betticher, Rene-Olivier Mirimanoff, Solange Peters
Journal: Journal of Clinical Oncology (2013)

7503 Background: For stage III/N2 NSCLC neoadjuvant chemotherapy (NCT) followed by radical surgery is one standard treatment approach. In our previous trial, this strategy led to a median survival of 33 months (Betticher et al. JCO 2003). We now investigated whether the addition of preoperative radiotherapy (RT) would improve outcome. We report the results of a planned interim analysis on data of the first 219 patients (pts). The trial was closed to accrual in December 2012 due to futility after enrollment of 232 of 240 planned pts. Methods: Pts with pathologically proven, resectable stage IIIA/N2 NSCLC, performance status 0-1, adequate heart, kidney, liver and bone marrow function were randomized 1:1 to receive 3 cycles of NCT (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost RT (44 Gy/22 fractions in 3 weeks) or NCT alone, with subsequent surgery for all pts. The primary endpoint was event-free survival (EFS). Results: 23 centers included 219 pts. Median age was 60 years. Pts characteristics were well balanced. Toxicity to CT was substantial, but 91% completed 3 cycles of NCT. RT-induced grade 3 esophagitis was seen in 5 pts, grade 3 skin toxicity in 2 pts. One pt in each treatment arm died during NCT, there was one postoperative death (arm NCT alone). The efficacy results are summarized below, all comparisons are statistically non-significant. Conclusions: This is the first completed phase III trial to investigate the value of the addition of neoadjuvant radiotherapy to CT and surgery. RT did not improve EFS or survival, nor did it reduce the local failure rate. Nevertheless, the overall survival rates of our neoadjuvant chemotherapy strategy confirm our previous report, and are among the best results reported to date in a multicenter setting. Clinical trial information: NCT00030771. [Table: see text]
Phase I/IIa study of therapeutic p16<sup>INK4a</sup> vaccination in patients with HPV-associated cancers.
Authors: Miriam Reuschenbach, Mohammad-Reza Rafiyan, Julia Karbach, Claudia Pauligk, Franziska Faulstich, Madeleine Sauer, Elena-Sophie Prigge, Matthias Kloor, Salah-Eddin Al-Batran, Andreas M. Kaufmann, Achim Schneider, Elke Jaeger, Magnus von Knebel Doeberitz
Journal: Journal of Clinical Oncology (2014)

3097 Background: Therapeutic strategies specifically targeting HPV-associated cancers are lacking. The cellular protein p16INK4a is strongly overexpressed in HPV-associated cancers, while in normal tissues p16INK4a expression is barely detectable. Therefore targeting of p16INK4a by vaccination could represent an interesting immune therapeutic approach for patients with HPV-associated cancers. We performed a phase I/IIa trial to monitor toxicity and immunogenicity of p16INK4avaccination (Vicoryx). Methods: Patients with advanced p16INK4a-overexpressing, HPV DNA-positive cancer (anogenital region, head and neck) were included after completion of standard treatment. The protocolcomprised a total of 12 subcutaneous injections of a synthetic p16INK4 peptide mixed with Montanide ISA-51 VG in weekly intervals. Objectives of the trial were clinical safety and changes of humoral and cellular immune responses against the p16INK4apeptide. T cell responses were monitored by interferon-gamma ELISpot and antibodies by ELISA from peripheral blood. Results: Phase I is completed with 10 patients, phase IIa is ongoing with 14 patients recruited of 16 planned. No toxicity was observed during and after vaccination that was regarded as related to vaccination with the auto-antigen p16INK4a in any of the patients. While pre-existing baseline T cell and antibody responses against the p16INK4a peptide were rare, p16INK4a-reactive T cells and antibodies were successfully induced in 8 of 16 patients analyzed to date. So far one head and neck cancer patient with lung metastases completed the entire study protocol with stable disease for now 18 months after the last vaccination. The remaining 9 patients of phase I had progressive disease. Conclusions: This is the first study demonstrating that p16INK4a peptide vaccination is safe and well tolerated and that immune responses against p16INK4a can be induced by p16INK4a peptide vaccination and are not accompanied by clinical autoimmune symptoms. Further trials will be designed to assess whether this approach may be an adjuvant therapeutic strategy for patients with HPV-associated cancers. Clinical trial information: NCT01462838.
Initial results of a prospective, multicenter trial to study inherited lung cancer risk associated with germline EGFR T790M: INHERIT EGFR.
Authors: Geoffrey R. Oxnard, Jennifer C. Heng, Elizabeth J. Root, Irene R. Rainville, Alicia L. Sable-Hunt, Kate P Shane-Carson, David Paul Carbone, Georgia L. Wiesner, Judy Ellen Garber
Journal: Journal of Clinical Oncology (2015)

1505 Background: EGFR T790M is most commonly seen as a somatic mutation in NSCLC following resistance to EGFR targeted therapies. Rarely EGFR T790M can be seen as a germline mutation where, in case reports, it has been associated with inherited lung cancer risk. The INHERIT study (INvestigating HEreditary RIsk from T790M, NCT01754025) is designed to prospectively identify and study individuals with this rare germline mutation. Methods: Subjects were eligible if they had EGFR T790M identified on routine cancer genotyping (excluding acquired T790M after therapy), or if they or a relative had already been found to carry a germline EGFR mutation. Subjects could participate in-person at 3 ALCMI sites or remotely via phone & mail. All subjects provided consent, filled out a questionnaire, and submitted a specimen for germline testing in a CLIA lab. Those interested in learning germline results were first provided counseling, and if positive could invite relatives to participate. Results: 46 subjects enrolled between 12/12 and 12/14; 22 in-person and 24 remotely (from 21 US states total); including 16 probands (NSCLC, germline pos), 23 relatives, and 6 germline neg patients with T790M-positive NSCLC (1 pending). Germline T790M prevalence: 16 of 22 patients with T790M-pos NSCLC (72%), 10 of 14 1st-degree relatives (71%). Among 12 total relatives with germline T790M, 1 had previously been diagnosed with NSCLC, 1 was diagnosed with NSCLC since germline testing, 4 have sub-cm lung nodules, 0 have negative CT scans, and 6 have not undergone CT imaging. In 18 germline carriers with NSCLC: median age at diagnosis was 56 (29-76), NSCLC stage was I-II in 2, III in 4, IV in 9. Pedigrees for 14 probands show 1-2 1st-degree relatives with NSCLC in 8, no 1st-degree relatives with NSCLC in 6. Conclusions: Using an innovative trial design including remote participation and germline testing based upon abnormal tumor genotyping, we have assembled the first multi-centered cohort of subjects with germline EGFR mutations. Penetrance is variable, but in some individuals germline T790M is associated with lung nodules or advanced NSCLC at a young age. Clinical trial information: NCT01754025.
New var reconstruction algorithm exposes high var sequence diversity in a single geographic location in Mali
Authors: Antoine Dara, Elliott F. Drábek, Mark A. Travassos, Kara A. Moser, Arthur L. Delcher, Qi Su, Timothy Hostelley, Drissa Coulibaly, Modibo Daou, Ahmadou Dembele, Issa Diarra, Abdoulaye K. Kone, Bourema Kouriba, Matthew B. Laurens, Amadou Niangaly, Karim Traore, Youssouf Tolo, Claire M. Fraser, Mahamadou A. Thera, Abdoulaye A. Djimde, Ogobara K. Doumbo, Christopher V. Plowe, Joana C. Silva
Journal: Genome Medicine (2017)

Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) proteins mediate tissue-specific cytoadherence of infected erythrocytes, resulting in immune evasion and severe malaria disease. Sequencing and assembling the 40–60 var gene complement for individual infections has been notoriously difficult, impeding molecular epidemiological studies and the assessment of particular var elements as subunit vaccine candidates. We developed and validated a novel algorithm, Exon-Targeted Hybrid Assembly (ETHA), to perform targeted assembly of var gene sequences, based on a combination of Pacific Biosciences and Illumina data. Using ETHA, we characterized the repertoire of var genes in 12 samples from uncomplicated malaria infections in children from a single Malian village and showed them to be as genetically diverse as vars from isolates from around the globe. The gene var2csa, a member of the var family associated with placental malaria pathogenesis, was present in each genome, as were vars previously associated with severe malaria. ETHA, a tool to discover novel var sequences from clinical samples, will aid the understanding of malaria pathogenesis and inform the design of malaria vaccines based on PfEMP1. ETHA is available at: https://sourceforge.net/projects/etha/ .
Influence of cytotoxic tumor-infiltrating T lymphocytes on outcome in resectable pancreatic cancer: Results from the CONKO 001 trial.
Authors: Jana Kaethe Striefler, Marianne Sinn, Korinna Jöhrens, Uwe Pelzer, Hendrik Blaeker, Anja Jühling, Bruno Valentin Sinn, Helmut Oettle, Lilianna Wislocka, Sven Bischoff, Carsten Denkert, Hanno Riess, Philipp Lohneis
Journal: Journal of Clinical Oncology (2017)

281 Background: The role of T lymphocytes, frequently found in the tumor microenvironment, on development and behavior of several solid tumors is well recognized. Studies on breast cancer and colon carcinoma showed the prognostic and predictive impact of tumor infiltrating T lymphocytes (TILs) while there are no similar studies on pancreatic cancer (PC) until now. Methods: We evaluated the prognostic effect of CD8 and CD103 positive TILs in a cohort of PC patients in the CONKO-001 study treated with adjuvant Gemcitabine or observed only. In 165 formalin-fixed paraffin-embedded (FFPE) tissue samples suitable for tissue microarray construction, CD 8 und CD 103 positive TILs were identified by immunohistochemical staining and counted manually; a ratio of intraepithelial to total CD 103 positive TILs was calculated. Results: The mean number of CD8 positive TILs was 69, a high number ( &gt; 42 TILs) of CD8 positive lymphocytes was significantly associated with longer disease-free (DFS) and overall survival (OS) in the overall study population (high vs low median DFS 12.8 vs 7.4 months; p = 0.007, median OS 26.7 vs 18.1 months; p = 0.018). Furthermore, a ratio of intraepithelial to total CD103 positive lymphocytes &lt; 0.3 was associated with significantly improved DFS and OS in the overall study population (high vs low median DFS 6.5 vs 11.8 months; p = 0.031, median OS 16.6 vs 24.7 months; p = 0.009). Conclusions: Our results suggest that the presence of TILs is important for prognosis in resected PC. We showed for the first time a prognostic effect of CD 8 and CD 103 expressing lymphocytes in PC. Therefore, we suggest further analysis of lymphocyte populations in this dismal entity.