tbuckley/cabot-search huggingface dataset:
Patient selection for cetuximab in NSCLC: A systematic review of candidate predictive biomarkers.
Authors: C. Harbison, C. Stroh, T. J. Lynch, D. R. Gandara, K. J. O'Byrne, R. Pirker, S. Maier, I. Celik, M. R. Weber, S. Khambata-Ford
Journal: Journal of Clinical Oncology (2010)

7548 Background: Cetuximab improved overall survival (OS) in first-line advanced NSCLC in a pivotal trial including all histologies (FLEX). Other phase II/III trials have tested cetuximab with several platinum doublets. Putative predictive-marker candidates have been explored retrospectively in some of these trials. Methods: Investigators have evaluated comprehensively the retrospective data available to date from studies of cetuximab plus chemotherapy (CT), analyzing the correlation between biomarker status (K-Ras and EGFR mutations, EGFR protein expression by IHC and EGFR gene copy number [GCN] by FISH) and incremental benefit from cetuximab (phase III and randomized phase II studies), or overall outcome (single arm phase II trials). Results: Tissue collection was not mandatory and tumor-sample ascertainment rates ranged from 20%-30% (except for mandatory tissue collection for EGFR IHC testing in FLEX). Biomarker evaluable populations were representative of ITT populations for baseline factors, although their outcomes differed in some trials. Response rates (RR) in single arm trials were similar regardless of EGFR or K-Ras mutational status. EGFR FISH positivity was associated with better outcomes in the S0342 trial of sequential or concomitant cetuximab plus CT, but this effect was not consistently found in other randomized trials. In randomized phase III trials, benefit from the addition of cetuximab to CT was seen regardless of K-Ras or EGFR mutations, while results for EGFR GCN by FISH have been conflicting. EGFR IHC was a selection criterion in some trials; in the others, only 15% of patients tested negative, data are therefore insufficient to rule out a predictive effect. In randomized studies, the magnitude of benefit from cetuximab seems similar regardless of EGFR IHC expression-based selection. Conclusions: No predictive biomarker for cetuximab benefit in NSCLC has yet been confirmed. Benefit from cetuximab was observed regardless of K- Ras mutations, a strong predictor of lack of cetuximab benefit in CRC, or EGFR mutational status. EGFR FISH is being prospectively evaluated in S0819. Additional studies are ongoing to identify novel predictive biomarkers of cetuximab benefit in NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Infinity Pharmaceuticals, Merck KGaA, Response Genetics Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone Systems, Lilly, Merck, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis Bristol-Myers Squibb, Infinity Pharmaceuticals AstraZeneca, Lilly, Merck KGaA, Merck Serono, None, Roche Abbott Laboratories, Bristol-Myers Squibb, Genentech, ImClone Systems, Lilly, Merck, Merck KGaA, Novartis, Pfizer
Cardiovascular events (CVEs) associated with tyrosine kinase inhibitor (TKI) therapy in patients with metastatic renal cell carcinoma (mRCC) at a regional cancer center
Authors: J. McGhie, M. J. Mackenzie, E. Winquist, S. Ernst, L. Sax, P. O'Brien
Journal: Journal of Clinical Oncology (2009)

e16040 Background: Recent studies suggest the incidence of CVEs associated with TKIs has been underestimated. Phase III trials have reported low incidences of heart failure, cardiac ischemia and hypertension. A recent observational study reported that one third of patients taking sunitinib or sorafenib experienced a cardiovascular event often without symptoms. We assessed the incidence of CVEs in mRCC patients who received TKIs at our centre. Methods: Eligible mRCC patients were identified from a mRCC database between January 2006 and November 2008. Data was retrospectively extracted including age, sex, diagnosis, histology, past cardiac history, cardiac risk factors, number and type of TKI regimens, and CVEs. A CVE was defined as unexplained death, acute coronary syndrome (ACS), heart failure, or arrhythmia requiring intervention. We also identified any new or exacerbated cases of hypertension after the start of TKI therapy, as a CVE. Results: Eighty-five eligible patients were identified. Average age was 61 years (range, 23–78), 72% were male and 80% were clear cell in origin. A total of 31 CVEs occurred in 28 patients (33%). These events occurred at a median of 5 weeks of TKI therapy (range, 1 - 64 weeks). There were 8 cases of ACS, 2 of heart failure, 2 of arrhythmia, and 3 unknown causes of death. Only 2 of these particular CVEs were associated with new or increased hypertension. There were 16 cases of hypertension alone. Those who had CVEs had a higher mean number of cardiac risk factors. They were also more likely to have an echocardiogram during treatment, and less likely to receive sorafenib following sunitinib. Conclusions: Our study suggests a lower rate of CVEs than recent studies, but the true rate may be underestimated, as routine cardiac studies were not performed in all patients. Rational surveillance strategies for patients receiving TKI therapies should be developed. Prospective trials should address predictive and prognostic factors for CVEs. [Table: see text] [Table: see text]
A multicentre, dose finding, phase II study of CP-4055 in combination with sorafenib in patients with metastatic malignant melanoma
Authors: S. Dueland, S. Aamdal, L. Lundgren, G. Wagenius, J. Sarantopoulos, J. M. Kirkwood, U. K. Stierner, J. Gaullier, W. Rasch
Journal: Journal of Clinical Oncology (2008)

20029 Background: CP-4055 (5’-elaidic acid ester of cytarabine) is a novel chemical entity developed as an antineoplastic agent with observed preclinical cytotoxicity in solid tumors. Promising early phase clinical results with CP-4055 in malignant melanoma (1 PR and several long-lasting SD) have led to the present study. The aim of this study is to evaluate the antitumour effect of CP-4055 given in combination with the oral multi-kinase inhibitor sorafenib in malignant melanoma patients (pts). Methods: CP-4055 is administered at days (d) 1–5 every 4 weeks (q4w) in a 30 min infusion. Starting dose of CP-4055 was 150 mg/m2/d (3 pts) and is continuing at 200 mg/m2/d (15 pts). Sorafenib is given orally every day at 400 mg b.i.d. (800 mg/d). Activity is assessed at the end of each 2nd cycle (cy). If more than 15% response is observed among first 18 pts (step 1), 22 additional pts will be recruited (step 2). Standard hematological, biological and clinical dose limiting toxicity definitions are used. Results: 8 pts enrolled. Among 3 first pts treated with 150 mg/m2/d, 1 is ongoing at cy 5 with SD and 2 withdrew after cy 2 due to PD. The other 5 pts are ongoing in cy 2 with CP-4055 at 200 mg/m2/d. Toxicity (essentially skin rash) did not prevent the escalation of CP-4055 from 150 to 200 mg/m2/d. No significant unexpected AEs have occurred. Conclusions: Infusion of CP-4055 (200 mg/m2/d) in combination with sorafenib 400 b.i.d. is well tolerated by patients with malignant melanoma in a d1–5 q4w schedule. Recruitment is ongoing and updated results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Clavis Pharma ASA Clavis Pharma ASA
Ocular Adnexal Lymphomas (OALs) At Conjunctiva Present a Remarkable Good Prognosis : Oals Study Of 83 Cases At a Single Institution
Authors: Aya Ouchi, Masahiro Yokoyama, Kenji Nakano, Kengo Takeuchi, Hideki Tsuji, Hideaki Nitta, Kyoko Ueda, Noriko Nishimura, Naoko Tsuyama, Yasuhito Terui, Kiyohiko Hatake
Journal: Blood (2013)
Analysis of the prognostic role of regulatory T-lymphocyte-associated marker expression in resectable NSCLC.
Authors: M. Usó, R. Sirera, A. Blasco, E. Jantus, E. Palomares, C. Caballero, R. M. Bremnes, J. Galbis, R. Guijarro, C. Camps
Journal: Journal of Clinical Oncology (2010)

10643 Background: Regulatory T-lymphocytes (Tregs) play a critical role in immune tolerance to tumor cells. Several molecules, including CD4, CD25, CD127, CTLA-4, IL-10 and TGFβ1 have been reported markers of Tregs. Another highly specific marker for Tregs is FoxP3, a transcription factor which appears to be a master control gene for their development and function. The aim of this study was to determine the expression of Treg-associated markers by RT-PCR and to correlate them with clinicopathological and prognostic variables in NSCLC. Methods: RNA was obtained from frozen lung specimens (tumor and normal lung) from resectable NSCLC patients (n = 135). RT-PCR was performed to analyze the expression of: CD4, CTLA-4, FoxP3, IL10, CD25, CD127 and TGFβ1. Relative expression was normalized by an endogenous gene (GUS) using the Pfaffl formulae. Statistical analyses were considered significant at p < 0.05. Results: Compared to normal lung tissue, tumor samples had significantly higher expression of CD25 (x2.1) and lower expression of CD127 (x0.42), reflecting a Treg phenotype infiltrating the tumor. In concordance, those patients that relapsed presented significantly higher CD25 and lower CD127 level in the tumor (p = 0.05 and p = 0.006, respectively). Additionally, patients that did not relapse presented higher levels of CD4 and CD8 (p = 0.004 and p = 0.037, respectively), markers of infiltrating helper and cytotoxic lymphocytes respectively. Survival analyses revealed that patients with high FoxP3 expression had reduced OS (p = 0.028) whereas those with high CD4 expression had improved PFS (p = 0.007) and OS (p = 0.047). Conclusions: Based on gene expression analysis, it seems that the presence of a Treg profile is associated with an increased risk of relapse. We also observed that FoxP3 or CD4 can be used as prognostic marker in resectable NSCLC patients. Supported by ISCIII grant. No significant financial relationships to disclose.
Phase 1 dose escalation and expansion safety study of BLZ-100 in subjects with skin cancer.
Authors: Dennis Michael Miller, Miko Yamada, Melinda Lowe, Casey Rowe, Dominic Wood, Kelly Byrnes-Blake, Tarl Prow, Lynda Spelman
Journal: Journal of Clinical Oncology (2015)

TPS9084 Background: BLZ-100 is an intraoperative, fluorescent imaging agent designed to specifically label malignant tissue and enable more complete surgical resection of tumor tissue. BLZ-100 achieves tumor targeting through the peptide portion of the molecule, a modified chlorotoxin (CTX) peptide, and its imaging properties from the coupled near-infrared fluorescent dye, indocyanine green. Tumor-specific uptake of BLZ-100 has been shown in multiple mouse tumor models and in dogs with spontaneous cancers. Methods: In order to characterize the safety of BLZ-100, a first-in-human, phase 1 dose escalation and expansion study in subjects with suspected skin cancer is being conducted. BLZ-100 is administered via a 15-minute IV infusion to subjects approximately 2 days before planned excision of their skin tumor. Subjects with known or suspected non-melanotic skin cancer (e.g., basal cell carcinoma) are included in the dose escalation. Subjects with known or suspected melanoma are included in the dose expansion. Subjects must have adequate bone marrow, liver and kidney function to participate. Dose escalation is being conducted according to a traditional “3+3” design. Dose limiting toxicity is defined as any related adverse event (AE) of ≥ Grade 3 severity occurring within 7 days of BLZ-100 administration. Measures of safety include patient or physician reported adverse events, laboratory measures of hematology, liver and kidney function, and coagulation parameters and changes in vital signs and electrocardiograms (ECG). Blood samples are collected over the 7-day DLT period to measure BLZ-100 serum concentrations via a LC/MS method. Serial fluorescence imaging of suspected skin tumors in situ is conducted over 48 hours using the Fluobeam 800 device. Portions of the excised skin specimens from the dose escalation were also subjected to fluorescent image analysis using an Odyssey scanner and immunohistochemistry analysis for the presence of Annexin A2 (presumed target of BLZ-100). Dose escalation in the 5 pre-specified dose levels has been completed without DLT. Enrollment of the expansion cohorts is on-going as of December 16, 2014. Clinical trial information: NCT02097875.
Palliative embolization of metastases from kidney cancer
Authors: E. C. Kent, A. Forauer, P. Esper, B. Redman
Journal: Journal of Clinical Oncology (2004)

4663 Background: Treatment options for symptomatic patients with advanced kidney cancer are limited. Catheter-based embolization of metastatic lesions from kidney cancer has been used in the pre-operative setting to manage operative blood loss. Palliative benefit from the embolization procedure itself has been reported in several small case series. We performed a retrospective review of patients who had undergone catheter-based embolization of metastases from kidney cancer at our institution purely for palliative purposes. Methods: Records from 22 patients who had undergone palliative embolization were reviewed. Data collected included indication, prior local or systemic therapies, complications, symptom relief, and any local therapy required subsequently. Relief from pain was rated complete (CR) if patients were able to discontinue narcotics and partial (PR) if narcotic use was decreased by ≥ 50%. Results: 39 procedures were performed in 22 patients (34 for pain alone, 3 for hemorrhage, 1 for airway compromise, 1 for spinal cord compression and pain). Pain relief was CR in 20 (57%) and PR in 12 (34%) in the 35 procedures performed for pain control. In all 3 cases performed for bleeding, bleeding stopped (transfusion independence) for a duration of 1–8 months. The patient with airway compromise achieved a complete radiographic response with patency of airway. In the case of the spinal cord compression, the patient appreciated partial improvement in leg strength. Complications included one pulmonary embolus and one incomplete T12 paraparesis. Conclusions: Catheter-based arterial embolization can provide a safe and effective palliative option for patients with metastatic kidney cancer. No significant financial relationships to disclose.
Expression of fatty acid synthase in gestational trophoblastic neoplasms with potential targeted therapy using its inhibitor
Authors: S. Ueda, R. E. Bristow, F. Kuhajda, I. Shih
Journal: Journal of Clinical Oncology (2008)

16510 Background: To determine if fatty acid synthase (FAS), an enzyme overexpressed and conferring poorer prognosis in certain epithelial cancers involving the breast, colon, and prostate, is upregulated in gestational trophoblastic neoplasms (GTN) and to study the possible anti- tumoral effects in vitro of selective FAS inhibition. Methods: Immunohistochemical analysis was performed on paraffin-embedded tumor specimens obtained at the Johns Hopkins Hospital from 1994–2006. Cases of GTN (n= 62) were compared to normal early placentas (n= 8). Monoclonal mouse antibody against FAS was utilized at 1:3000 dilution, and scoring intensity ranged from 0–3+. Cell cycle analyses and characterization of apoptotic response to the FAS inhibitor, C93, were then carried out in vitro on JEG3 and JAR choriocarcinoma as well as IST- 2 placental site trophoblastic tumor cell lines. Results: FAS immunoreactivity was demonstrated in both the cytotrophoblasts and intermediate (extravillous) trophoblasts of normal placentas and also in all types of GTN. All choriocarcinomas (n= 33), 90% of epithelioid trophoblastic tumors (n= 20) and 56% of placental site trophoblastic tumors (n= 9) exhibited FAS positivity. Treatment of JEG3, JAR, and IST-2 cell lines with C93 at concentrations of 5–10 micromoles induced dramatic apoptosis within 24 hours without affecting the cell cycle. Conclusion: FAS inhibitors like C93 may potentially serve a role in treating GTN refractory to conventional therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration FASgen
Prognostic index for safety and compliance of docetaxel/ciplatin/5-fluorouracil (TPF) induction followed by radiochemotherapy (RT-CT) in 203 patients (pts) with unresectable squamous cell carcinoma of the head and neck (USCCHN).
Authors: F. Peyrade, C. Mercier, E. Chamorey, B. Lallemant, M. Alfonsi, C. Righini, B. Guelfucci, M. Beltran, M. Zanaret, O. Dassonville
Journal: Journal of Clinical Oncology (2010)

e16001 Background: Although TPF is the standard induction regimen for USCCHN, frequent comorbidities in USCCHN pts limit its use. TPF may improve cure rate providing better patient screening. Study aim: identify easy to use prognostic factors for safety and compliance of TPF induction regimen followed by RT- CT. Methods: This retrospective study was conducted in 203 USCCHN pts having received 1 to 3 induction TPF cycles in 7 institutions. Besides usual data, parameters to be recorded were determined by 12 experts according to Delfy method. This study has been approved by ethic comities. Materials: 517 TPF cycles were administered in 172 men and 31 women. Mean age was 56.8 years (±6.7), PS was < 2 (WHO) in 97% of pts, 52% of them had ongoing chronic alcoholism. Disease was stage III or IV in 70% of cases. Grade III/IV toxicities occurred in 9.8 % and 18% of pts during TPF and RDT-CT respectively. At least 2 TPF cycles were administered as planned in 84% of pts. Full treatment sequence (TPF followed by RT-CT) could be given in 73.84% of pts. Following TPF induction, complete response, partial response, stable disease and progression rates were 21.67%, 58.62%, 5.42% and 6.9% respectively. Results: In multivariate analysis, age > 60 significantly predicts for an increased risk of grade 3-4 TPF toxicity (p 0.05) and subsequent RT-CT toxicity (p 0.001), and also for a higher chance of early TPF discontinuation (p 0.002) and lack of full treatment sequence compliance (p 0.002). Haemoglobin < 12g/dl and albumin < 40g/l predict for early TPF discontinuation (p 0.007) and lack of full treatment sequence compliance (p 0.006). Conclusions: in this 203 pts series, age < 60, albumin > 40g/l and haemoglobin > 12 g/l seem to predict for better compliance of 2 to 3 TPF cycles followed by RT-CT. This needs to be confirmed by prospective studies. No significant financial relationships to disclose.
Novel mechanism linking noncanonical Wnt ligand induction to suppression of colorectal cancer cell proliferation.
Authors: Donald Peter Braun, Bani M Fagla, Irshad Ali
Journal: Journal of Clinical Oncology (2015)

648 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation. A central pathway in the control of proliferation and differentiation is the Wnt pathway. Wnt function is mediated by a canonical pathway (CP) which utilizes β-catenin and stimulates cell proliferation, and a non-canonical pathway (NCP) independent of β-catenin involved with differentiation. Studies suggest that dysfunctional Wnt signaling results from imbalance of CP components. The possibility that modulation of NCP components are involved in this process has not been studied comprehensively. Given their importance in constraining CP signaling and proliferation, the purpose of this study was to determine the capacity of NCP components to suppress human colorectal cancer (CRC) proliferation. Methods: Short term, primary CRC lines were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of the CP, Dkk1, an inhibitor of the CP, and IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion. CRC proliferation and Wnt pathway gene expression were determined by MTS assays and quantitative gene expression respectively. Results: Unexpectedly, CRC proliferation was inhibited significantly (p&lt;0.01) by LiCl and stimulated modestly (ns) by Dkk1. This was associated with a 20 fold increase in gene expression for the NCP ligand, Wnt9A. LiCl treated cells incubated with IWP-2 reversed the unexpected LiCl-mediated suppression of CRC proliferation. Conclusions: The unexpected finding that LiCl suppresses proliferation and Dkk1 has the opposite effect indicate dysregulation of the Wnt pathway in CRC. Further support for this hypothesis is the fact that Wnt 9A, an NCP ligand is increased by LiCl in CRC, an effect that is not expected in non-malignant cells. That IWP-2, a pan Wnt ligand secretion inhibitor reverses these effects is consistent with these observations. This study is the first to demonstrate a correlation between NCP ligand induction and suppression of CRC proliferation and suggests that control of CRC proliferation may be achieved in patients by modalities that activate the NCP Wnt pathway.
Structural abnormalities in vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve aneurysm
Authors: Hong Lien Do, Maria Nataatmadja, Deborah Stenzel, Christina Theodoropoulos, Malcolm West
Journal: Circulation (2006)

Thoracic aortic aneurysm (TAA) associated with Marfan syndrome (MFS) and bicuspid aortic valve (BAV) is characterized histologically by vascular smooth muscle cell (VSMC) loss, areas of cystic medial necrosis and patchy elastic tissue destruction in the tunica media. In this study we identified the relationship between morphological changes in VSMC and disorganization of aortic wall structure using light microscopy (LM) and transmission electron microscopy (TEM). No TEM study of MFS or BAV VSMC has been previously reported. Aortic tissue was collected from normal aorta (1M; 4F; age 39 ± 14 yr), MFS (5M; 3F; age 35 ± 11 yr) and BAV (6M; 5F; age 57 ± 16 yr). Aortic tissue and cultured VSMC derived from tissue were processed and embedded in resin. Semi thin sections were cut and stained with toluidine blue for LM and viewed at a magnification of 1000x and ultra thin sections were cut for TEM analysis at a magnification of 25000x. Organelles including the mitochondria, endoplasmic reticulum and Golgi apparatus appeared normal in each group. Apart from the presence of cystic medial necrosis reported previously in MFS and BAV aneurysm, LM study revealed generalized severe structural abnormalities of VSMC that were independent of areas of cystic medial necrosis. VSMC contained numerous vacuoles and structural masses occupying most of the cytoplasmic region (normal=10.1±0.1 %; MFS=34.0±0.1%; BAV=29.1±0.1%). Many VSMC were partly disintegrated lying between intact elastic lamellae (normal=1.4±0.1%; MFS=5.3±0.1%; BAV=10.0±0.1%). TEM study showed a loss of interdigitation between VSMC and elastic lamellae. Calcification of VSMC and extracellular matrix components were common findings in BAV. Cultured VSMC showed bulging intracellular masses, tearing of the cytoplasmic membrane, cellular indentations and disintegration. The findings suggest that morphological VSMC changes were present prior to recognizable alterations of elastic lamellae, and that the primary defect in the pathogenesis of TAA arises within the VSMC.