tbuckley/cabot-search huggingface dataset:
Characterizing the clinical relevance of epithelial mesenchymal transition (EMT) in human tumors.
Authors: K. A. Higgins, K. S. Walters, A. Potti
Journal: Journal of Clinical Oncology (2010)

10507 Background: We propose that the sonic hedge hog pathway (SHH) induces EMT in vitro, resulting in gene expression changes that are clinically relevant. Methods: EMT was induced in lung, breast, and prostate cancer cells in vitro through co-culture with myofibroblasts, a rich source of the SHH ligand. Real-time PCR (QRT-PCR) and immunoflorescence were used to confirm EMT, and invasiveness of the phenotype was assessed with matrigel assays. Microarray analysis was performed on RNA extracted from EMT induced cells and controls and bayesian regression methods were used to generate an EMT signature. Clinically annotated gene expression data from patients with lung (n = 128), breast (n = 286) and prostate (n = 79) cancer was used to ascertain the clinical importance of EMT, using survival as a relevant outcome. Results: QRT-PCR confirmed upregulation of EMT related genes, demonstrating a several fold increase in the expression of Snail, N- cadherin, Gli 2 and SHH genes, respectively (p < 0.0001). Immunoflorescence confirmed the necessary Cadherin switch and the EMT induced cells demonstrated increased invasion (p = 0.001). Cyclopamine inhibited increased expression of Snail, N-cadherin, SHH, and Gli2 (p <0.0001) confirming that SHH was a principal mediator of EMT in human tumors. Using EMT induced cells and control cells, a genomic signature for EMT in adenocarcinoma was characterized, comprised of 200 genes. Upregulated pathways include keratan sulfate biosynthesis and extracellular matrix interaction. Importantly, the EMT signature predicts for 5-yr metastasis-free survival in a large dataset of node negative breast cancer patients (p = 0.004). Similar statistically significant survival differences exist in prostate (p = 0.03) and lung cancer (p = 0.04). In addition, chemosensitivity for over 40 lung cancer cell lines was assessed, with median EC50 values significantly higher in cell lines with a high probability of EMT. Conclusions: Activation of the SHH pathway induces EMT in human cancers and genome-wide changes occurring during EMT can be used to predict clinical outcomes. The SHH pathway represents a unique therapeutic target for suppression of distant metastasis and modulating chemotherapeutic resistance. No significant financial relationships to disclose.
Use of cytokines to predict on-target toxicity in patients with recurrent glioblastoma treated with aflibercept.
Authors: N. A. Shonka, M. R. Gilbert, W. A. Yung, Y. Paio, J. Liu, B. N. Bekele, P. Y. Wen, A. P. Chen, J. Heymach, J. F. De Groot
Journal: Journal of Clinical Oncology (2010)

e12507 Background: On-target toxicity related to antiangiogenic therapy may be severe and limit treatment duration. Treatment-related changes in circulating cytokine and angiogenic proteins may reveal the mechanism of specific toxicities, potentially predict toxicity to antiangiogenic agents and permit tailored therapy. Methods: In a single-arm phase II study (NABTC 0601) we measured circulating cytokine and angiogenic factors in 29 pts with recurrent GBM treated with 4 mg/kg aflibercept iv every two wks. Plasma samples were analyzed at baseline, 24 hrs and at 28 days. 41 circulating factors were measured using suspension bead multiplex assays or ELISA. Grade II and higher toxicities were assessed using CTCAE v3.0 and correlated with cytokine expression. Results: Log-transformed baseline expressions were used and evaluated with Cox proportional hazard regression models to assess the effect of biomarkers on any grade II-IV (GII-IV) toxicity or any GII-IV on-target toxicity (HTN, proteinuria, thrombosis). All tests were two-sided with a statistical significance level of p = 0.05. Among 29 pts, there were 46 GII-IV events. Low baseline levels of IL-7 (HR = 0.30, 95%CI 0.10-0.91, p = 0.033) and elevated levels of CTACK (4.12, 1.14-15. 0, 0.031) and SDF1a (4.02, 1.07-15.0, 0.039) were predictive of any GII-IV toxicity. An increase in IL-13 (2.37, 1.34-4.18, 0.003), G-CSF (5.7, 1.00-32.4, 0.050) and bFGF (1.69, 1.04-2.74, 0.035) from baseline to 24 hrs was significantly associated with the development of any GII-IV toxicity. An increase in IL-13 from baseline to 24 hrs and 28 days trended towards significance in predicting on-target toxicities (1.52, 0.94-2.46, 0.09 at 24 hrs and 4.69, 0.92-23.9, 0.063 at 28 days). Conclusions: Toxicity remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Low baseline levels of proinflammatory cytokines such as IL-7 are associated with a decreased risk of toxicity. Increased IL-13, a profibrotic cytokine, at 24 hrs significantly predicts any toxicity and strongly correlates with on-target toxicity at 24 hrs and 28 days. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize pt risk during antiangiogenic therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genentech, Merck, Novartis, Pfizer, Schering-Plough Merck, Novartis, Schering-Plough Genentech, Novartis, Schering-Plough
Identifying the primary site using gene expression profiling in patients with carcinoma of an unknown primary (CUP): a feasibility study from the GEFCAPI
Authors: Y. Loriot, M. Gross-Goupil, T. Lesimple, E. Blot, Y. Merrouche, M. C. Mathieu, K. Fizazi
Journal: Journal of Clinical Oncology (2009)

e22168 Background: CUP are an heterogeneous family of neoplasms with a dismal prognosis, with empiric chemotherapy as the recommended treatment. The aim of this study was to evaluate the feasibility of a 500-mRNA microarray to identify the tissue of origin in patients with CUP. Methods: Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 22 patients with CUP were prospectively collected. Gene expression profiling was performed using oligonucleotide microarray that contains 495 genes selected as highly differentially expressed between 49 tumor types (CupPrint). Results: The assay was successfully performed on specimens from 18 of the 22 patients (82%). It could not be performed because of a low RNA preservation in the remaining 4 cases. The median age was 57 years (range: 29–70 years). The median delay from tissue shipping to receipt of CupPrint result was 11 days (range: 1–26 days). The most common tissues of origin identified were lung cancer (22%) and colorectal cancer (17%). Of note, a primary cancer which would not be adequately treated by an empiric chemotherapy regimen currently recommended in CUP (like cisplatin-gemcitabine or carboplatin-paclitaxel) was identified in about half patients: kidney cancer (1), hepatocarcinoma (1), colorectal cancer (3), head and neck cancer (2) and cholangiocarcinoma (1). Conclusions: Gene expression profiling of FFPE biopsy specimens from patients with CUP is feasible in a reasonable delay, making it feasible in clinical practice. A phase III randomized trial is planned to compare therapy based on gene expression-suspected primary cancer versus empiric chemotherapy. No significant financial relationships to disclose.
A phase II trial of gemcitabine and celecoxib for metastatic pancreatic cancer
Authors: H. Q. Xiong, K. R. Hess, O. R. Kayaleh, J. W. Goodwin, T. Banerjee, S. S. Sinclair, M. J. Fisch, R. A. Wolff, J. L. Abbruzzese
Journal: Journal of Clinical Oncology (2005)

4174 Background: Overexpression of cyclooxygenase-2 (COX2) is detected in 75% of resected pancreatic cancer and correlates with aggressive tumor biology. COX 2 promotes tumor growth by upregulating angiogenesis and invasiveness, and inhibiting apoptosis. Celecoxib, a COX 2 specific inhibitor, has demonstrated anti-tumor activity against a variety of human cancers in animal models, including pancreatic cancer xenografts. The primary objective of this study is to determine the overall survival at 6 months for patients with metastatic pancreatic cancer. Methods: The study is being conducted through the community clinical oncology research base affiliated with M. D. Anderson Cancer Center, and the target accrual is 40 patients. Eligible patients have biopsy proven metastatic pancreatic cancer (locally advanced disease was excluded), ECOG performance status 0–2, radiographic evidence of disease, adequate organ and marrow functions, and no prior treatment for metastatic disease. Gemcitabine is administered at 650 mg/m2 over a 65-minute infusion days 1, 8, and 15 every 4 weeks and celecoxib 400 mg administered orally twice a day continuously. Results: Twenty-eight (13 female and 15 male) patients have enrolled into the study so far. Median age is 67 years old, ranging from 40 to 83. The Kaplan-Meier median survival duration is 6.2 months for 20 patients with complete follow-up data. The 3-months survival rate is 72%. Grade 3 or 4 thrombocytopenia and neutropenia developed in two patients each. Clinically relevant treatment related grade 3 or 4 non-hematological toxicities include nausea/vomiting (3 patients), supraventricular arrhythmia (1), dyspnea (1), pleural effusion (1), gastrointestinal bleeding (1), and hyponatremia (1). Conclusions: The combination of gemcitabine and celecoxib is active and can be delivered with acceptable toxicity to patients with metastatic pancreatic cancer. No significant financial relationships to disclose.
The use of CA15.3 in breast cancer: A single institution experience
Authors: R. Sheikh, A. T. Behbehani, M. Peader, J. McCaffrey
Journal: Journal of Clinical Oncology (2007)

21017 Background: Breast cancer is a significant cause of morbidity and mortality worldwide. Recent advanced its treatment are promising. Gathering prognostic information may optimise treatment delivery. In addition to clinical parameters, the use of tumour markers may aid this process. CA 15.3, is a transmembrane glycoprotein.. Its clinical application varies from detecting disease recurrence in asymptomatic patients, assessing response in metastatic setting and monitoring the clinical course of the disease. Methods: A retrospective analysis was conducted evaluating medical record data of all the patients treated for breast cancer in our institution between 1999- 2005. CA15.3 was carried out using Roche 2010 (Elecsys system). Results: A total of 176 patients were identified. Table (1) Group A, one hundred patients remained disease free at follows up (58%). 95 patients had their CA15.3 within normal range, a diagnostic specificity of 95%. Group B, 61 patients developed metastatic/recurrent disease at follow up. 39 patients (64%) developed metastatic disease later. Group C, 15 patients had metastatic disease at diagnosis. We found that CA15.3 has a sensitivity value of 64% and a specificity of 95% in our institution.. This correlates well with ASCO review 67% and 92% respectively. In patients with no evidence of metastatic disease at diagnosis, a postive CA15.3 during follow up is strongly suggestive of disease recurrence. Giving a positive predictive value of 89%. In Two patients (5%) CA15.3 was the first predictor of recurrence. Radiology was the first indicator of recurrence in six cases (15%), while both radiological and serological correlation was noted in 31 patients (80%). Conclusions: We found CA15.3 a reliable marker in assessing response for therapy. In clinical practice, raised CA15.3 can be incorporated in decision making to change current chemotherapeutic regimen whenever there is a delay in obtaining prompt radiological evaluation. [Table: see text] No significant financial relationships to disclose.
Control of cancer-associated inflammation and survival: Results from a prospective randomized phase II trial in gastric cancer
Authors: A. Reichle, A. Lugner, C. Ott, F. Klebl, M. Vogelhuber, A. Berand, R. Andreesen
Journal: Journal of Clinical Oncology (2009)

e15584 Background: An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. Methods: A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: capecitabine 1 g orally twice daily for 14 days with one week break until tumor progression) or combined anti-inflammatory/angiostatic treatment (arm B: capecitabine as mentioned above plus etoricoxib 60 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. Patients with refractory or progressive disease following any first-line therapy except capecitabine or frail were eligible. According to the one stage design, a sample size of 64 patients was calculated for the primary objective, improvement of response rate. Results: As similar response rates were observed (arm A/B 15/14%) after the accrual of 42 patients, the study was closed (n=20 (A), n=22 (B); median age 69 years (range 46 to 86ys); frail A/B n=9/11). Median progression- free survival for arm A/B was 3.0/2.9 months (P=0.878), and overall survival 5.0/6.1 months (P=0.778). In both treatment arms a significant decline of serum C-reactive protein (CRP) levels was observed within the first 4 to 6 weeks on treatment, A/B P= 0.01/0.04, respectively. CRP response &gt; 50% from baseline was associated with a significantly improved overall survival in arm A/B (3.1 versus 11.0 months, P= 0.023/ 3.3 versus 7.1 months, P= 0.078) indicating an impact of inflammation-control on survival. WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 20% and 23%, respectively, mostly due to hand-foot-syndrome. Conclusions: Metronomic low- dose chemotherapy in gastric cancer may induce anti-inflammatory response, but the chosen additional anti-inflammatory approach neither has impact on tumor-associated inflammation nor on response or survival rate. In a historical comparison, CRP-responder have similar outcome as patients treated with combination chemotherapy in first-line. No significant financial relationships to disclose.
Pegylated lyposomal doxorubicin (PLD) and oxaliplatin (LOH) as salvage chemotherapy in patients with previously treated metastatic gastric cancer (MGC).
Authors: F. Recchia, G. Candeloro, S. Necozione, S. Rea
Journal: Journal of Clinical Oncology (2010)

e13051 Background: Aim of this study was to evaluate the activity and safety of a combination of pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) as salvage chemotherapy in patients with metastatic gastric cancer (MGC) who had been previously treated with docetaxel, capecitabine, 5-fluorouracil, and leucovorin. Methods: Thirty-six patients, with pretreated MGC, were recruited for the study. The treatment consisted of 40 mg/m2 PLD and 120 mg/m2 LOHP, administered over 2 days, every 3 weeks. Primary endpoint was response rate, secondary endpoints were toxicity, progression-free survival, and overall survival. Response to therapy was assessed using the RECIST criteria, toxicity was evaluated by NCI-CTC (version 2.0). Results: Characteristics of patients: median age 68 years, performance status was good in 30 patients. Visceral metastasis was present in 26 instances. All patients were previously treated with at least one line of chemotherapy. After a median follow-up of 11 months and 202 courses of chemotherapy administered (median 5 courses per patient), the overall response rate in the 36 evaluable patients was estimated to be 28%. Grade 3 and 4 hematological toxicities were neutropenia in 44% of patients, grade 2-3 diarrhea in 16% of patients, and grade 2 neuropathy in 12 patients. Median progression-free survival and overall survival were 5.8 months and 9.2 months, respectively. Median survival time from the diagnosis of metastatic disease was 31.5 months. Seventy-five percent of patients (95% c.i. 58-88%) obtained a clinical benefit from this chemotherapy regimen. Conclusions: PLD and LOHP is an active regimen, with a low toxicity rate, able to give palliation in a substantial number of patients with MGC pretreated with taxanes. No significant financial relationships to disclose.
The information needs of young women (YW) undergoing adjuvant chemotherapy (AC) for early-stage breast cancer (ESBC) regarding fertility and menopause issues.
Authors: E. M. Wilson, J. Ballot, D. Mc Donnell, J. Crown
Journal: Journal of Clinical Oncology (2010)

e19539 Background: Approximately 30% of ESBC is diagnosed in women aged <51. YM form a unique cohort of ESBC pts, whose specific psycho-social needs are under-researched. There is a need to assess the adequacy of current strategies of imparting knowledge concerning age-specific side effects of AC in YM with ESBC Methods: Eligible pts were women under the age of 51 with stages I-III BC, who were undergoing adjuvant AC. Study pts took part in 2 in-depth thematic interviews, at 6 mth intervals, conducted by the same facilitator. Themes systematically explored included: how the diagnosis and prognosis were communicated, effects on relationships, including those with family and friends, and concerns regarding fertility, sexuality and body-image. Pts were encouraged to explore any other themes of concern to them. Results: A total of 33 pts were offered enrolment between Apr and Oct 2009 (approximately 65% of eligible pts seen in our institution, a large University Hospital). Eight pts declined, and of the 25 who were recruited, 24 were on AC, and 1 had completed AC. A total of 21 had children. Five were considering having another child prior to the diagnosis of BC. One of these was distressed that treatment induced menopause and its potential impact on her fertility had never been discussed. Two had no children and accepted that they would not. Two pts had hoped to have children and expressed significant distress at treatment related infertility. Both had sought information from sources outside the hospital. All women interviewed expressed a level of confusion regarding their menopause status. It ranged from having no knowledge about premature menopause to recognising menopausal symptoms but being unsure of the significance of them. All women expressed a desire for more information about treatment induced menopause. Some women commented that they were uncomfortable discussing concerns about their menopausal status because they felt there was an expectation that they should be grateful to have been cured of cancer. Conclusions: Young women with ESBC have unique information needs. Miscommunication/misunderstanding regarding fertility and menopause issues is common. No significant financial relationships to disclose.
Biweekly combination chemotherapy with paclitaxel and carboplatin for advanced non-small cell lung cancer
Authors: K. Takayama, M. Ichiki, M. Kawasaki, K. Ninomiya, N. Miyazaki, M. Kuba, F. Iwami, Y. Nakanishi
Journal: Journal of Clinical Oncology (2004)

7335 Objective: To evaluate the efficacy and safety of chemotherapy with a biweekly use of paclitaxel and carboplatin plus for advanced NSCLC. Methods:The study is a phase II multi-institutional trial. Eligible patients had inoperable stage IIIB or IV disease, ECOG performance status 0–2, and no previous treatment. Patients were treated with the following regimen: paclitaxel (140 mg/m2) and carboplatin (AUC = 3) were administered every 14 days for 6 cycles. Results:Registration has finished by October 2003, and so far, 64 patients were analyzed for the toxicity, efficacy and survival. There were 10 patients with stage IIIB and 54 with stage IV disease. The median age was 62 years (47–74). There were 49 patients with adenocarcinoma, 11 with squamous cell carcinoma, and 4 with large cell carcinoma. The hematologic toxicities ≥ grade 3; 21% leukopenia, 53% neutropenia, 3% anemia. no thrombocytopenia. The response rate was 33% with 21 PR. Median survival time was 362 days, and 1 year survival was 50%. As of Dec 22nd, 2003, the median follow up time is 411days. Treatment completion rate was 52.7% and the dose intensity was 60.5 mg/m2/week. Conclusions:Biweekly combination chemotherapy with paclitaxel and carboplatin appeared to be safe and useful regimen to stage IIIB or IV NSCLC. However, careful clinical follow-up is required to confirm the safety and efficacy of this regimen. Updated data is to be presented. No significant financial relationships to disclose.
Factors affecting the risk of brain metastases after chemoradiotherapy for locally advanced non-small-cell lung cancer (LA-NSCLC)
Authors: M. Fujii, Y. Segawa, N. Nogami, Y. Hamamoto, M. Kataoka, E. Komori, S. Sawada, M. Yamashita, T. Shinkai, S. Takashima
Journal: Journal of Clinical Oncology (2006)

17019 Background: With an improvement in treatment outcome in patients with LA-NSCLC undergoing radical chemoradiotherapy, brain metastasis has become a greater problem. We assessed the cumulative incidence of brain metastases and its risk factors in such patients with LA-NSCLC. Methods: Between 1993 and 2003, 85 consecutive patients with stage IIIA or IIIB NSCLC underwent chemoradiotherapy in our institution. The characteristics of these patients were as follows: median age, 64 years (range, 39 to 74 years); stage IIIA/IIIB, 30/55 patients; squamous-cell/nonsquamous-cell histologies, 39/46 patients. Concurrent and sequential chemoradiotherapy were administered for 78 and 7 patients, respectively. Only two patients underwent surgical resection after chemoradiotherapy. Fifty-seven patients received conventional thoracic radiotherapy with a total dose of 59.5 ± 1.4 Gy (range, 40 to 70 Gy), and 28 received twice-daily radiotherapy with a total dose of 71.5 ± 6.5 Gy (range, 43 to 86 Gy). Thirty-eight patients received a combination chemotherapy consisting of cisplatin and docetaxel, and the remaining 47 received the other platinum-based regimens. Results: At a median follow-up time of 51 months (range, 9 to 131 months), median survival time was 25 months, with a 3-year survival rate of 36.9%. The median disease-free survival time was 13 months. During treatment and observation periods, 21 (24.7%) patients had developed brain metastases. Thirteen (15.3%) patients experienced brain metastases as the first site of relapse, and in nine (10.6%), brain was the sole site of relapse. The cumulative risk of brain metastases was 15.4% at 1-year, 21.1% at 2-year, and 25.7% at 3-year, respectively. In a multivariate analysis using Cox proportional hazard model, T-factor (T4 vs. T1–3) was the most predictive of brain failure (hazard ratio, 3.51; 95% confidence interval, 1.35 to 9.13; p = 0.01). Conclusions: In patients with LA-NSCLC undergoing chemoradiotherapy, brain was one of the most common sites of failure when locoregional control was achieved. Although efficacy of prophylactic cranial irradiation (PCI) on survival remains unclear for such patients with NSCLC, identification of patients more likely to have a benefit from PCI would be useful. No significant financial relationships to disclose.
Monoclonal antibody imaging in the management of patients with colorectal cancer.
Authors: D G Haller
Journal: Journal of Clinical Oncology (1988)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1988.6.8.1213 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3411338 Monoclonal antibody imaging in the management of patients with colorectal cancer. D G HallerxD G HallerSearch for articles by this author https://doi.org/10.1200/JCO.1988.6.8.1213 First Page PDF © 1988 by American Society of Clinical Oncology