bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of EGFR mutations in non-small cell lung cancer (NSCLC) smoker patients.
Authors: Izarzugaza Yann , Domine Manuel , Rojo Federico , Casado Victoria , Leon Ana , Fernandez-Acenero Maria Jesus , Rubio Gustavo , Cordova Sharon , Madoz Juan , Martin-Valades Jose Ignacio , Arranz Juan Luis , Serrano Gloria , Carames Cristina , Zazo Sandra , Rincon Raul , Canadas Carmen , Perez-Gonzalez Nuria , Campos Angel , Lobo Francisco , Garcia-Foncillas Jesus ,   Oncology Department Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid
Published: March 2020

e21015

Background: Mutations in the Epidermal Growth Factor Receptor (EGFR) predict a better response to tyrosine kinase inhibitors compared to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Previous studies in caucasian population have reported a frequency of EGFR mutation of 10-15%. The aim of this study is to analyze the prevalence of EGFR mutations in caucasian smoker patients with NSCLC. Methods: Prospective mutation testing in NSCLC patients included in our institution since October 2010 to January 2012 was performed on DNA obtained from available tumor tissue and cytologic samples, using ARMS-scorpion TheraScreen EGFR 29 Mutation Test Kit (Qiagen). Results: From 218 consecutive NSCLC diagnoses, 18 (8.25%) patients showed EGFR mutations: 6 (33.3%) exon 19 deletions, 9 (50%) exon 21 mutations (7 cases L858R and 2 cases L861Q) and 3 (16.6%) exon 20 insertions. In the EGFR-mutated patients, 13 (72.25%) were never-smoker and 5 (27.7%) were smoker (3 current-smoker and 2 former-smoker). The EGFR-mutated smoker population showed the following characteristics: 3 female, 2 male; 4 adenocarcinoma, one squamous cell carcinoma; 3 stage IV, 2 stage IA at diagnosis; 1 (20%) case EGFR deletion exon 19, 1 (20%) case insertion exon 20 and 3 patients (60%) mutation exon 21 (2, L858R and 1, L861Q). Conclusions: The EGFR mutation rate in NSCLC smoking patients in our referral area is superior (27.7%) than previously reported, reinforcing the importance of including EGFR mutation testing in NSCLC smoking population for the correct management of these patients.
Gene expression profiling for prediction of tissue of origin to direct site-specific therapy in patients with CUP: Treatment outcomes by assay predictive probability.
Authors: Rubin Mark S. , Greco Frank A. , Boccia Ralph V. , Scola Michael A. , Spigel David R. , Raby Samuel , Chirwa Thabiso W. , Quinn Raven , Hainsworth John D.
Published: March 2020

e21023

Background: Tumor profiling as a diagnostic technique in CUP depends on the detection of similarities in gene expression between the cancer and the tissue of origin. Assay-directed site-specific therapy may be most effective in tumors with high-confidence molecular predictions, since a) the prediction may be more often correct due to greater similarity between the gene expression profile of the unknown tumor to the assay reference tumor database, and b) the tumor would more likely share biologic characteristics/treatment sensitivity with cancers of known origin. Methods: In a prospective trial performed by the Sarah Cannon Research Institute (SCRI), a 92-gene RT-PCR assay (CancerTYPE ID; bioTheranostics, Inc.) was performed on tumor biopsies from previously untreated CUP pts. Pts were then assigned standard site-specific treatment directed by the assay prediction. Treatment responses were evaluated based on the strength of the assay predictions; probabilities ≥80% were arbitrarily regarded as high confidence results. Results: Between 10/08 and 12/11, 224 pts (26 predicted tumor types) received treatment. Median overall survival (OS) was longer in 113 pts (50%) with high confidence predictions: 11.7 months (mos) vs 9.8 mos; p=.03. 120 pts (59%) had assay predictions of responsive tumor types, known to derive substantial benefit from standard site-specific therapy. Treatment responses, irrespective of predictive probability, were better in these pts vs those with less responsive tumor types (median OS 12.8 vs 7.4 mos; p=.027). Further stratification of high vs lower confidence assay predictions resulted in 4 groups with different OS (p=.03) (Table). Conclusions: Site-specific therapy for CUP pts directed by results of the 92-gene assay was more effective when the probability of the assay prediction was higher, particularly in pts with assay diagnoses of more responsive tumor types. [Table: see text]
Circulating epithelial tumor cells (CETC) during preoperative chemotherapy (CTX) of patients with gastric cancer.
Authors: Schmalenberg Harald , Pachmann Katharina , Pauligk Claudia , Hochhaus Andreas , Al-Batran Salah-Eddin
Published: March 2020

e21063

Background: we investigated CETC in blood samples accompanying a German multicenter phase II/III trial comparing perioperative CTX with epirubicin, cisplatin, 5-FU, leucovorin (ECF) every 3 weeks or 5-FU, leucovorin, oxaliplatin, docetaxel (FLOT) every 2 weeks. Methods: 7.5ml of anti-coagulated blood was drawn before the first and before the second course of CTX and after the end of preoperative CTX before surgery. After red blood cell lysis the white blood cells including the CETC were stained with a fluorescent labelled anti-epithelial antibody, positive events counted using an automated image analysis microscope and calculated per volume blood. Results: CETC were evaluable from 98 patients (FLOT: n=41; ECF: n=57). Characteristic response pattern to treatment were observed: Most patients (n=33 (81.5 %) from the FLOT arm and n=45 (79%) from the ECF arm) showed a decrease in CETC numbers during the first treatment course. Of these patients 11/33 (33%) in the FLOT arm and 24/45 (53%) in the ECF arm had a re-increase in cell numbers after chemotherapy (chi-square test p=.079). 11/11 (100% of patients with an initial increase in CETC in the FLOT arm subsequently showed decreasing CETC numbers whereas this was true only for 8/12 (66%) of the patients from the ECF arm (chi-square test p=.035). Conclusions: this is the first report on CETC during neoadjuvant CTX of gastric cancer. We have observed a rapid decrease in the number of CETC during CTX in the majority of patients in both arms. A re-increase under ongoing CTX was seen more frequently in patients receiving ECF. Whether the initial decrease of CETC correlates with tumor size reduction and subsequent difference in behaviour of CETC numbers during CTX translates into clinical outcome needs to be investigated in the frame of the ongoing German multicenter study.
Prognostic and predictive value of hedgehog (Hh) signaling in advanced non-small cell lung cancer (NSCLC).
Authors: Berardi Rossana , Santinelli Alfredo , Onofri Azzurra , Caramanti Miriam , Savini Agnese , Chiorrini Silvia , Biscotti Tommasina , Ballatore Zelmira , De Lisa Maria Grazia , Mandolesi Alessandra , Biagetti Simona , Alfonsi Simona , Pompili Cecilia , Salati Michele , Brunelli Alessandro , Mazzanti Paola , Pierantoni Chiara , Sabbatini Armando , Bearzi Italo , Cascinu Stefano
Published: March 2020

e21070

Background: Advanced NSCLC still represents a medical challenge in cancer therapy. The Hh pathway is critical for cell growth and differentiation. The aim of our study is to evaluate the role of the Hh signaling pathway in determining the clinical outcome of NSCLC patients. Methods: The expressions of Hh-related molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) were determined by immunohistochemistry in 35 histologic samples (biopsies and surgical specimens) of advanced NSCLC patients. All the neoplastic area presents in the slides was considered and both cytoplasmic and nuclear stainings were evaluated, according to the positive neoplastic cells. The intensity of the staining was considered and scored as 0 (absent), 1+ (low), 2+ (medium) and 3+ (high). Results: 18 adenocarcinomas and 17 squamous cell carcinomas were analysed. Positivity of Gli1-cytoplasmic expression and Gli1-nuclear expression were expressed in adenocarcinoma at a significantly higher level and more frequently than compared to squamous cell carcinoma (p<0.05), while Ptch1 did not differ significantly in the two histotypes. Overall survival was higher in Gli1 and Ptch1 negative tumor samples compared to the positive group (p=0.02). The 18 patients with adenocarcinoma received erlotinib as second line therapy and those presenting a lower Gli1 and Ptch1 expression experienced a significantly better progression free survival. Conclusions: These results suggest that the Hh pathway might play a major prognostic role in NSCLC with significant differences between the histotype. Furthermore it might predict the efficacy of erlotinib as second-line treatment in patients with advanced lung adenocarcinoma.
The chemoattractant chemerin as a natural tumor suppressive cytokine.
Authors: Pachynski Russell Kent , Zabel Brian , Tejeda Nicole , Monnier Justin , Holzer Alison K , Gentles Andrew , Kohrt Holbrook Edwin , Hadeiba Husein , Alizadeh Arash A. , Butcher Eugene
Published: March 2020

e21071

Background: Infiltration of specialized immune cells regulates the growth and survival of neoplasia. In a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is downregulated in melanoma as well as other human cancers. Moreover, high chemerin mRNA expression predicted improved outcomes in human melanoma. Methods: Forced re-expression of chemerin by tumor cells was achieved by transfection. An alternate strategy involved direct intratumoral injection of recombinant chemerin into tumors. Tumor line expression of chemerin was confirmed by ELISA and functionality of expressed, secreted chemerin confirmed by chemotaxis of CMKLR1 (the main receptor for chemerin) positive cells. Tumors were evaluated by FACS and immunofluorescence for presence of recruited leukocytes. Results: In studies of the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor infiltrating cells with an increase in natural killers (NK cells), and a relative reduction in myeloid derived suppressor cells and putative immune inhibitory plasmacytoid DC. Tumor inhibition required host expression of CMKLR1, the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumors, suggesting the potential for therapeutic application. Conclusions: We therefore conclude that chemerin recruits anti-tumor immune effector cells, and that it may act as an endogenous tumor suppressor, whose downregulation in melanoma and potentially other neoplasia contributes to immune evasion and tumor growth.
Triple probe FISH approach for detecting EML4-ALK gene rearrangement in Chinese patients with NSCLC.
Authors: Mao Weimin , Han Mark , Ling Zhiqiang , Sun Wenyong , Zhang Gu , Dong Hongshan , Zhang Yingzi
Published: March 2020

e21080

Background: The echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion represents a novel target for the therapy of a subset of non-small cell lung cancer (NSCLC). ALK rearrangement has been found in approximately 1.6–11.6% of NSCLC in unselected patient populations, but the frequency also varied when different diagnostic approach was used. We, for the first time, investigated frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC using recent developed fluorescence in situ hybridization (FISH) triple color break-apart probe. Methods: One hundred-thirty one FFPE specimens from NSCLC patients were collected for the investigation. Fusion between 3’ portion of ALK gene and the 5’ portion of EML4 gene was detected using FISH tri-check probe (ZytoVision, Germany). Positive cells were defined as having any signal A ( distance more than two-time the ALK signal size) or signal B ( distance between one- and two-time the ALK signal size plus EML4 translocation signal) or any isolated ALK 3’ signal. Total 100 nuclei for each specimen were counted. Specimen was as classified as EML4-ALK rearrangement when the proportion of positive cells was over 15%. ALK/EML4 signals over 6 in over 10% nuclei were classified as gene amplification. Results: Of 131 specimens, frequency of ALK rearrangement was 10.7% (14/131) when positive cells were counted by signal A and isolated ALK 3’ signal (dual color). Frequency of EML4-ALK rearrangement was 13.0% (17/131) when positive cells were counted by signal A, B and isolated ALK 3’ signal (triple color), in which 21% (17/14) more cases were classified as EML4-ALK rearrangement comparing dual color enumeration. ALK and EML4 amplification were observed in 2.3% (3/131) specimens, respectively, in which two were co-amplified and none of them had EML4-ALK rearrangement. Conclusions: Present result showed that frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC was 13.0% determined by FISH tri-check probe. This study suggested that counting both ALK inversion and EML4 translocation may contribute to defining EML4-ALK positive cells.
Local infiltration of lymphocytes in large bowel tissue cancer and chronic colitis.
Authors: Nikipelova Elena A , Kit Oleg I
Published: March 2020

e21101

Background: comparative analysis of concentrations of lymphocyte subpopulations in tissue of various intestinal zones in cancer of large bowel and chronic atrophic colitis. Methods: subpopulation composition of T- (CD3, CD4, CD8) and B- (CD19) lymphocytes, natural killers NK (CD16CD56), and T-lymphocytes with antigen-recognizing receptors TCRαβ and TCRγδ were examined in bowel adenocarcinoma tissue, peritumoural zone (1-3 cm away from tumour) and in resection line (10 cm away from tumour edge) and in chronic colitis tissue. Flow cytofluorimetry was used for immunophenotyping of the lymphocytes Results: 52 cases of adenocarcinoma and 24 cases of chronic colitis were examined. CD3 level in tumour tissue (64.2±3.6%) didn’t differ from this in colitis samples (65.6±3.5%); CD3 level was significantly lower in peritumoural zone and resection line (54.9±4.0% and 51.9±3.6%, correspondingly, p<0.05) than in colitis samples. The quantaty of lymphocytes with TCRαβ receptor in all tissue samples with cancer was significantly higher in comparison with one in chronic colitis samples. The level of lymphocytes with TCRαβ receptor in all tissue samples with cancer was 49.8±7.25, in peritumoural zone – 39.3±5.9%, in resection line 46.5±6.0%, compared to chronic colitis – 20.7±5.7%, p<0.05. Concentration of lymphocytes with TCRγδ receptor in cancer samples was 3-5 times less (tumour – 14.2±4.8%, peritumoural zone – 9.5±1.5%, resection line – 11.3+2.1%) than in samples colitis ones (42.9±9.9%) p<0.05. It was found that tumour tissue, in contrast to peritumoural tissue, accumulated T-lymphocytes (64.2±3.6% and 51.9±3.6%, correspondingly) due to CD4 cells (35.5±2.3% and 24.3±2.1%, correspondingly, p<0.05). Lower level of B-cells was found in tumour (18.0±2.8% and 30.1±3.7%, correspondingly, p<0.05). Conclusions: abnormalities of local cellular immunity at diseases of large bowel are probably related not only to imbalance of lymphocyte subpopulations, but also to change of local correlation of levels of αβ-T-lymphocytes capable of recirculation, and tissue γδ-T-lymphocytes. This may cause inadequacy of immune protection at cancer of large bowel.
Blood and tumor inflammation markers in non-small cell lung cancer (NSCLC): Blood leukocytosis as an independent risk factor in early stage.
Authors: Carus Andreas , Ladekarl Morten , Hager Henrik , Pilegaard Hans , Nielsen Patricia Switten , Donskov Frede
Published: March 2020

e21110

Background: Cancer inflammation is associated with impaired survival in a range of cancers. We reviewed blood and intratumoral inflammatory markers in NSCLC. Methods: At the Departmentof Thoracic Surgery, Skejby Hospital, Aarhus, Denmark, consecutive patients with resected NSCLC from 2000 to 2008 were reviewed, and 906 patients with complete clinical data were identified. A subset of 341 consecutive patients, resected between 2003 and 2006, also had intratumoral CD66b+ neutrophils and CD163+ macrophages measured by immunohistochemistry and evaluated by stereological assessment. Results: A total of 526, 197, and 183 patients had stage I, II, and III, respectively. Multivariate analysis stratified for tumor stage revealed elevated blood leukocytes above upper limit of normal as a significant prognostic factor for recurrence-free survival (RFS)(hazard ratio [HR] 1.9; 95% CI 1.4-2.6; p<0.0001), cancer specific survival (CSS)(HR 1.9; 95% CI 1.4-2.7; p<0.0001), and overall survival (OS)(HR 1.5; 95% CI 1.1-1.9; p<0.006) in stage I NSCLC, but not in stage II and III. No prognostic impact of intratumoral neutrophils or macrophages was seen on CSS, RFS, or OS, neither in the entire cohort, nor limited to stage I patients with elevated blood leukocytes or with normal counts. Controlling intratumoral neutrophils and macrophages for localization restricted to tumor tissue, stromal tissue, or blood vessels, respectively, were also with no statistically significant difference. Conclusions: Blood leukocytosis is an independent prognostic factor for short recurrence free survival, cancer specific survival, and overall survival in stage I NSCLC, but not in stage II and III. However, intratumoral neutrophils or macrophages did not impact prognosis. Further studies are needed to elucidate the role of cancer inflammation in NSCLC.
Routine detection of EGFR gene mutations in lung carcinomas: A 2-year single-center experience.
Authors: Vallee Audrey , Sagan Christine , Le Loupp Anne-Gaelle , Theoleyre Sandrine , Dejoie Thomas , Hiret Sandrine , Denis Marc G.
Published: March 2020

e21117

Background: Activating mutations in the tyrosine kinase domain of the EGFR gene in lung carcinoma has been associated with a dramatic response to tyrosine kinase inhibitors. Therefore, routine analysis of pathological specimens is mandatory in clinical practice to predict patient response. We have analyzed the results of the tests we performed during years 2010 and 2011. Methods: DNA was extracted from formalin-fixed paraffin-embedded tissues, following macrodisection, using an iPrep robot (Invitrogen). The p.L858R and p.L861Q substitutions (exon 21) were assessed by allele-specific PCR and exon 19 deletions by PCR amplification followed by DNA fragment analysis (polyacrylamide gel electrophoresis). These techniques allowed us to detect these mutations when present in at least 2% of the cells. Results: During these 2 years, we analyzed samples from 1,041 patients (including 907 adenocarcinomas, 71 large cell carcinomas and 28 squamous cell carcinomas). The EGFR mutational status could not be determined in 51 cases : DNA could not be amplified in 23 cases (2.2%), and 28 samples (2.7%) contained a limited percentage (<10%) of cancer cells. The EGFR status could thus be successfully determined in 990 (95.1%) samples. EGFR mutations were detected in 142 (14.3%) patients : 74 exon 19 deletions, and 68 p.L858R mutation. The mutation rate was, as expected, higher in women (24.0%) than in men (7.2%), and mutated patients were significantly older than non mutated patients (median age : 71 y vs 63 y). Furthermore, the mutation rate was much higher in tumors expressing the TTF-1 antigen (117/638; 18.3%) than in TTF-1 negative tumors (5/228; 2.2%). Similar mutation rates were obtained with primary tumors (89/661; 13.5%) and metastases (40/274; 14.6%), and with surgical specimen (43/325; 13.2%), fiberoptic bronchial biopsies (36/250; 14.4%), CT-guided needle biopsies (25/181; 13.8%) and transbronchial needle aspirates (5/38; 13.2%). Conclusions: The results obtained through routine analysis of more than 1000 samples indicated that our procedure is very efficient. All types of samples can be analyzed without any significant bias. TTF-1 immunostaining might be used to predict for negative EGFR mutation status.
Efficacy of treatment of vulva cancer patients and analysis of their hormonal status.
Authors: Nerodo Galina A. , Nerodo Ekaterina
Published: March 2020

e21127

Background: hormonodependency of vulva is wellknown. This broughtusto study hormonal status of vulva cancer patients depending on treatment efficacy Methods: we present comparative analysis of hormonal status of vulva cancer patients in two groups: group 1 (50 patients) without relapse of the disease in 5-year period, and group 2 (35 patients) with relapse developed within the first year. Blood concentrations of testosterone, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone were determined in all patients under study by means of radiometric methods. Estrone, estradiol, estriol with subsequent calculation of their sum were determined in daily urine by Brown method. Results: In the presence of effect (group 1) initial total amount of estrogens was twice as large than in its absence. In group 1 estradiol concentration exceeded the corresponding parameter of group 2 by three times(7.6±0.6 & 1,4±0.3,p<0.001). The amount of secreting estriol at positive result was almost twice higher than in cases of absence of the effect(10.02±1.7 & 4.6±0.49, p<0.001). The groups differed by secretion levels of follicle-stimulating and luteinizing hormones. Blood concentration of these hormones was lower in negative results that in positive. Distinct differences were also observed in progesterone and prolactin levels. In the group with positive result of treatment progesterone concentration was much higher than in the group without treatment effect. On the contrary, prolactin concentration in group 1 was significantly less than in group 2. The highest degree of reliability of quantitative indices related to treatment efficacy was observed for progesterone. Positive result of corresponding treatment may be predicted at normal initial progesterone level, and negative result at its low level (3-4 times lower than the norm). Another parameter - blood concentration of prolactin - can be used almost with the same degree of reliability. Conclusions: results of the study allow to suggest an existence of interrelation between treatment efficacy of vulva cancer patients and functional activity of hypophysis-gonadal system. Some of its parameters may be used to predict results of complex treatment of vulva cancer patients.
Is serum tryptase level a novel biomarker in colorectal cancer patients?
Authors: Brandi Mario , Gadaleta-Caldarola Gennaro , Ruggieri Eustachio , Ammendola Michele , Patruno Rosa , Goffredo Veronica , Misino Andrea , Montemurro Severino , Gadaleta Cosmo Damiano , Ranieri Girolamo
Published: March 2020

e21134

Background: Tryptase is a serin protease stored in mast cell granules that plays a role in tumour angiogenesis. Mast cells (MCs) can release tryptase following c-Kit receptor activation. On the other hand colo-rectal cancer (CRC) is a well-established angiogenesis dependent tumour and anti-angiogenic based therapy is a standard treatment in metastatic CRC. This preliminary study aims to assess tryptase serum levels in 51 CRC patients before and after radical surgery. Methods: In this study patients with stage B and C CRC (according to Astler e Coller staging system) were selected. Samples of blood were taken from CRC patients between 7 and 9 a.m.1 day before and 1 day after curative surgery. Venous blood was dispensed into a tube for serum (Becton Dickinson Hemogard Vacutainer Systems, Plymouth, UK). Tryptase levels were measured using the UniCAP Tryptase Fluoroenzymeimmunoassay (Pharmacia,Uppsala, Sweden). Primary tumour tissue were also evaluated in terms of MCs positive to tryptase by immunohistochemistry utilizing an anti-tryptase primary antibody (clone AA1; Dako, Glostrup, Denmark). Results: Mean ± s.d. tryptase level pre-tumour surgical resection was 6.37 ± 4.57 μg/L, and mean ± s.d. tryptase level post tumour surgical resection was 5.15 ± 3.82 μg/L. A statistically significant difference between pre-tumour surgical resection and post-tumour surgical resection tryptase level concentrations was found: p=0.000 by t-test. A statistically significant correlation between MCs positive to trypase and serum tryptase levels pre-surgical resection was also found (r=086; p=0.000) by Pearson’s analysis. Conclusions: This pilot report analyzes the possible significance of serum tryptase levels changes in CRC patients who underwent curative surgery. Our results demonstrated higher serum tryptase levels CRC patients suggesting the release of tryptase from MCs of primary CRC tissue. As expected, after radical surgical resection, serum tryptase levels had decreased. We suggest that tryptase may play a role as a new predictive biomarker in CRC patients. In this context several tryptase inhibitors such as gabexate mesilate and nafamostat mesilate might be evaluated as adjuvant treatment in clinical trials.
The level of FSHR expression in the primary kidney tumors to predict the response to subsequent antiangiogenic therapy with sunitinib.
Authors: Siraj Muhammad Ahsan , Pichon Christophe , Radu Aurelian , Ghinea Nicolae
Published: March 2020

e21138

Background: Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used to treat advanced metastatic renal cell carcinoma and other types of cancer. Sunitinib is effective in only approx. 70% of clear cell renal cell carcinoma (CCRCC) patients, has significant adverse side effects, and no method is available to predict which patients will not respond. Our purpose was to explore the possibility of introducing an effective prediction method based on a marker of the tumor vasculature, the Follicle Stimulating Hormone Receptor (FSHR). Methods: Using immunohistochemistry on paraffin sections with anti-FSHR monoclonal antibodies we studied by photonic and fluorescence microscopy the expression of FSHR in 50 patients diagnosed with advanced metastatic CCRCC. All patients were subjected to surgery for removal of the primary tumor and were subsequently treated with sunitinib orally for ≥ 3 months with a dose of 50 mg/day for 4 weeks followed by 2 weeks off. After therapy the patients were categorized as “responsive”, “stable”, or “non-responsive” based on the RECIST guidelines. The blood vessel density and the percentage of FSHR-positive vessels were determined by immunofluorescence on sections from the primary tumors removed by surgery, prior to the sunitinib treatment. Von Willebrand factor (vWF) was used as specific endothelial marker. Results: There were no significant differences in the total density of vessels (detected with anti-vWF antibody) among the responsive, stable and non-responsive patients. The percentage of FSHR-stained vessels was on average five fold higher for the patients that responded to the treatment in comparison with the stable group and almost eight fold higher than in the non-responsive group. The percentage allowed the detection of responders with 87-100% sensitivity and specificity. Conclusions: The data suggest that FSHR expression levels in the blood vessels of CCRCC primary tumors can be used to predict, with high sensitivity and specificity, the patients that will respond to sunitinib therapy.
Thromboembolic complications in cancer patients.
Authors: Yenidunya Gulsah , Turna Hande , Ozturk Mehmet Akif , Tural Deniz , Selcukbiricik Fatih , Yildiz Ozcan , Ozguroglu Mustafa , Demirelli Fuat , Buyukunal Evin , Serdengecti Suheyla
Published: March 2020

e21143

Background: Thromboembolic events are frequent and important complications causing mortality and morbidity in cancer patients.To determine the charecteristics of these events can help us to determine the patients who have higher risks for thromboembolism. Methods: Characteristics of clinically or radiologically determined thromboembolic events were retrospectively analayzed from files of cancer patients followed up in the outpatient oncology clinic of Cerrahpasa Medical Faculty of Istanbul University. Results: A total of 267 thromboembolic events were analyzed.Events were encountered mostly in the venous system, only 3% were in the form of arterial embolism.Venous events were in the form of deep vein thrombosis (67%), pulmonary embolism (16.5%), vena cava superior thrombosis (2.6%), superficial migratory thrombophlebitis (0.4%) or two different forms occuring concomitantly(10.5%). Thromboembolism was determined most frequently in patients with gastrointestinal tumors (41.9%), lung cancer (22.1%) and gynecological tumors (12.1%). The most frequent histopathology was adenocarcinoma (72.4%).Thromboembolic complications were mostly in the form of lower extremity deep venous thrombosis in patients with gastointestinal, gynecological and urogenital tumors where as in the form of pulmonary embolism and vena cava superior thrombosis in patients with lung cancer. Nearly half of the patients with pulmonary embolism (%48.%) were asymptomatic and were diagnosed incidentally with radiological imaging. Upper extremity thrombosis were frequently encountered in patients with venous port a-cath system Most of the patients (87.7%) had metastatic cancer and were receiving chemotherapy (65.5% ) when the event occured. Cisplatin, 5–FU and gemcitabine were the most frequently used chemotherapy agents.Thromboembolic events related to cancer surgery occured usually (59%) in the first month after surgery.Recurrent thromboembolic events were determined in 8.9% of patients mostly whom had gastrointestnal primary tumors (54%). Conclusions: Characteristics of thromboembolic events can help to determine the patients who have higher risk for thromboembolism and predict types and time of the event and provide anticoagulation without delay.
Effect of obinutuzumab (GA101), a type II glycoengineered monoclonal antibody targeting CD20, against rituximab resistant and sensitive cell lines in B-cell non-Hodgkin lymphoma.
Authors: Tiwari Aradhana , Ayello Janet , Van de ven Carmella , Cairo Mitchell S.
Published: March 2020

e21150

Background: : Relapse or insufficient response or resistance to Rituximab (RTX) has evolved as a challenge in therapy of B-cell NHL. RTX in combination with FAB chemotherapy is a safe, well tolerated and associated with > 90% EFS in children with advanced mature B-Cell NHL (Cairo M.S. et al, ASCO 2010). Obinutuzumab (GA101), a novel type II glyco-engineered CD20 antibody of the IgG1 isotype, demonstrates superior cell death induction and its glycoengineered Fc region has shown to cause significantly enhanced ADCC (Mössner et al, Bld 2010; Niederfellner G. et al, Bld 2011). We evaluated the efficacy of GA101 against Raji (Burkitt Lymphoma), a RTX sensitive cell line (RSCL) and RTX resistant cell lines(RRCL), Raji-2R and Raji-4RH, respectively (generously supplied by M. Barth, MD, Roswell Park Cancer Center, Buffalo, NY. Barth M. et al, ASH 2010). Methods: All cell lines were cultured in RPMI with 10% FBS and incubated with escalating doses of GA101 (1-1000 µg/ml) for 24 hrs (n=10), 48 and 72 hrs (n=6). Cell death was evaluated by staining with AnnexinV/7AAD and flow-cytometry. B-Cell Lymphoblastic Lymphoma (BLL) U-698-M cells (CD20+) were used as the positive and Loucy cells (CD20-) (T-ALL) were used as the negative controls. Results: At 48 hrs 100 µg/ml of GA101, Raji and U-698-M demonstrated highest cell death of 33.62±5.7% and 37.8± 3.9%, respectively; while Raji-2R and Raji-4RH cell death was 22.8±1.8% and 10.31±0.81% (p<0.02) and (p<0.001) respectively. At 1000 µg/ml of GA101 at 24 hrs, Raji demonstrated increased cell death 40.27±9.1% compared with Raji2R 14.1±0.07 and Raji4RH 20.3± 3.2 (p<0.001) and (p<0.001) respectively. Conclusions: GA101 represents a promising candidate for treating RTX resistant B-Cell Lymphomas and related CD20+B-Cell malignancies. Further studies should aim to identify novel approaches such as combination with activated NK Cells or chemotherapeutic agents that may enhance or synergize with the efficacy of GA101. Further investigations aim to elucidate the mechanisms responsible for minimal cell death induction on the U698M and Raji cell lines.
Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.
Authors: Demetri George D. , Reichardt Peter , Kang Yoon-Koo , Blay Jean-Yves , Joensuu Heikki , Maki Robert G. , Rutkowski Piotr , Hohenberger Peter , Gelderblom Hans , Leahy Michael Gordon , von Mehren Margaret , Schoffski Patrick , Blackstein Martin E. , Le Cesne Axel , Badalamenti Giuseppe , Xu Jian-Ming , Nishida Toshirou , Laurent Dirk , Kuss Iris , Casali Paolo Giovanni ,   on behalf of GRID Investigators
Published: March 2020

LBA10008

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Results of the X-PECT study: A phase III randomized double-blind placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Ervin Thomas J. , Senzer Neil N. , Richards Donald A. , Firdaus Irfan , Lockhart A. Craig , Cohn Allen Lee , Saleh Mansoor N. , Gardner Lesa R. , Sportelli Peter , Eng Cathy
Published: March 2020

LBA3501

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ryan Charles J. , Smith Matthew Raymond , De Bono Johann Sebastian , Molina Arturo , Logothetis Christopher , De Souza Paul L. , Fizazi Karim , Mainwaring Paul N. , Piulats Rodriguez Jose Maria , Ng Siobhan , Carles Joan , Mulders Peter , Kheoh Thian San , Griffin Thomas W. , Small Eric Jay , Scher Howard I. , Rathkopf Dana E. ,   on behalf of the COU-AA-302 Investigators
Published: March 2020

LBA4518

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Axitinib versus sorafenib as second‑line therapy in Asian patients with metastatic renal cell carcinoma (mRCC): Results from a registrational study.
Authors: Qin Shukui , Bi Feng , Cheng Ying , Guo Jun , Ren Xiu Bao , Huang Yiran , Wang Jinwan , Ben Yong , Kim Sinil , Tang Jie , Ye Dingwei
Published: March 2020

LBA4537

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Highly sensitive determination of PIK3CA exon 9 and 20 hotspot mutations in breast tumors.
Authors: Harle Alexandre , Lozano Nicolas , Nicolaizeau Cyrielle , Lion Maeva , Husson Marie , Rouyer Marie , Ramacci Carole , Genin Pascal , Merlin Jean-Louis
Published: March 2020

TPS10634

Background: Hotspot mutations in exons 9 (E542K and E545K) and 20 (H1047L and H1047R) of PIK3CA gene encoding for the p110α catalytic subunit of Phosphatidylinositol 3-kinases (PI3K) are found in approximately 25% of breast carcinomas. PIK3CA mutations cause the overactivation of PI3K/AKT/mTOR pathway and lead to resistance to anti-HER2 targeted therapies in breast cancers, are involved in response to anti-mTOR agents and are proposed as molecular diagnosis marker for PI3K inhibitors. A highly sensitive method is required to detect PIK3CA mutations in paraffin-embedded tumor tissues. Methods: We developed a real-time PCR assay using allele-specific scorpion primers and amplification refractory mutation system (PCR-ARMS) to detect hotspot mutations in exons 9 (E542K and E545K) and 20 (H1047L and H1047R) of PIK3CA of PI3K. Results: PIK3CA mutations were analyzed in 102 paraffin embedded breast tumors (88 invasive ductal carcinomas and 14 lobular ductal carcinomas). All specimens were validated by pathologist examination and processed for DNA extraction and PCR. PIK3CA exon 9 and 20 mutations were found in 22.5% of the specimens, 39.1% in exon 9 (26.1% for E542K, 13.0% for E545K) and 60.9% in exon 20 (17.4% for H1047L and 43.5% for H1047R). These results were comparable to the literature data (χ²=0.327 ; p<0.05). PCR ARMS was found to be highly sensitive, able to detect 0.5 % mutated DNA. Conclusion: PCR ARMS assay is highly sensitive for PIK3CA exon 9 and exon 20 hotspot mutations analysis in breast carcinomas as molecular marker for anti-HER2 and PI3K inhibitors response prediction.
Phase III open-label, randomized, multicenter study of NKTR-102 versus treatment of physician's choice (TPC) in patients (pts) with locally recurrent or metastatic breast cancer (MBC) previously treated with an anthracycline, a taxane, and capecitabine (ATC).
Authors: Perez Edith A. , Awada Ahmad , O'Shaughnessy Joyce , Rugo Hope S. , Twelves Christopher , Cortes Javier ,   BEACON Study Group, Nektar Therapeutics, San Francisco, California
Published: March 2020

TPS1140^

Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate that hydrolyzes to provide continuous exposure to SN-38. A phase 2 trial of single-agent NKTR-102 was conducted in pts with 3rd-line MBC; 2 schedules (q14d; q21d) investigated a dose of 145 mg/m2. ORR was 29% (including 3% CR) with the prior ATC subset demonstrating an ORR of 31%. Dosing q21d was better tolerated; in this arm, median PFS and OS equaled 5.3m and 13.1m, respectively. Trial Design: Pts will be randomized 1:1 to receive single-agent NKTR-102 or TPC in an open-label, randomized, multicenter phase 3 study in pts with advanced breast cancer. Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, kidney and marrow function. All pts must have received prior therapy with ATC (these drugs can be administered in the neo/adjuvant or locally advanced/metastatic setting). Prior A is not mandated if contraindicated. Prior toxicities must have resolved to ≤ Grade 1 (except sensory neuropathy ≤ Grade 2; complete resolution of prior diarrhea). Pts with brain metastases may be eligible, if lesions are stable for prior 3 weeks without steroids. Methods: Primary efficacy endpoint is OS. Secondary endpoints include: ORR by RECIST v1.1, clinical benefit rate (ORR+SD > 6 months), PFS and QoL. NKTR-102 is given IV at 145 mg/m2 over 90-min every 21 days without premedications. Pts randomized to TPC receive 1 of the following: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel (the agent must be available at the treating institution). Pts are stratified by region, prior eribulin and receptor status (TNBC, Her2+ or Other). Target Accrual: ~840 pts will be required for sufficient events to occur in the planned follow-up time; OS will be compared using a two-sided log-rank test; 1 interim analysis will occur when 50% of the deaths are reported. PK sampling is performed in a subset of pts. CTCs (isolated by Apocell ApoStream technology) are serially assessed for potential predictive markers of response and toxicity. Enrollment is expected to remain open until late 2013.
Statin polyp prevention trial in patients with resected colon cancer: NSABP protocol P-5.
Authors: Boman Bruce M. , Bandos Hanna , Wickerham D. Lawrence , Petrelli Nicholas J. , O'Connell Michael J. , Wolmark Norman
Published: March 2020

TPS1615

Background: HMG-CoA reductase inhibitors (statins) are effective lipid-lowering agents that are used for treating hyperlipidemia. Results from cell culture, animal experiments, and epidemiologic studies indicate that statins may be active chemopreventive agents against colorectal cancer (CRC). However, the clinical studies come largely from retrospective, observational studies originally designed to investigate lipid-lowering or cardiovascular endpoints rather than tumor endpoints. Methods: NSABP P-5 is a randomized, prospective placebo-controlled, double-blind study of rosuvastatin (10 mg per day x 5 years) or placebo for the prevention of adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, and colon cancer recurrence. Additional secondary endpoints include the size, number and features of the colorectal adenomas as well as health-related quality of life and self-reported symptoms. Selected Eligibility: (1) Patients who have undergone complete resection of AJCC Stage I or II colon cancer within 1 year before randomization. (2) Colonoscopy within 180 days before randomization. Selected Ineligibility: (1) Hyperlipidemia, (2) Familial Adenomatous Polyposis, (3) Lynch Syndrome. Sample Size:1,740 patients will be entered, and as of January 23, 2012, 163 (9.37%) have been randomized. The study is open at NSABP and CTSU sites in North America. Funded by NCI PHS grants U10-CA-37377 and U10-CA-6974, with additional funding from AstraZeneca Pharmaceuticals, LP.
O6-benzylguanine (BG) and temozolomide (TMZ) therapy of glioblastoma multiforme (GBM) with infusion of autologous lentiviral transduced P140KMGMT+ hematopoietic progenitors to protect hematopoiesis: A phase I study.
Authors: Sloan Andrew E. , Reese Jane , Rogers Lisa R. , Lo Simon S. , Nock Charles John , Lazarus Hillard M. , Machtay Mitchell , Fu PingFu , Fung Hua , Embree Heather , Dropulic Boro , Gerson Stanton ,   UO1 CA62502
Published: March 2020

TPS1616

Background: The administration of radiation therapy (RT) and concomitant and adjuvant temozolomide (TMZ) for the treatment of newly-diagnosed glioblastoma (GBM) is associated with modestly prolonged survival. However, the benefit of concurrent therapy is restricted to a subgroup of patients whose tumor exhibits methylation of the promoter for methylguanine-DNA-methyltransferase (MGMT). Promoter methylation silences the expression of DNA alkyltransferase (AGT), the product of the MGMT gene which functions to repair alkylated DNA. Unfortunately, the majority of GBMs have non-methylated MGMT promoters and do not appear to benefit from adding TMZ to radiotherapy. Two potential strategies for targeting MGMT-induced chemoprotection in gliomas include depletion of tumor MGMT, and dose escalation of TMZ accomplished by minimizing TMZ-induced bone marrow toxicity. In this study, we propose to combine the irreversible MGMT inhibitor O6-benzylguanine (BG) with infusion of autologous hematopoetic stem cells (HSCs) transduced with lentiviral P140K-MGMT, an MGMT mutant which is highly resistant to inactivation by BG, with the intent to reduce or prevent the myelosuppressive effects of TMZ. The primary objective is to assess the safety and feasibility of combining these two strategies in patients with newly-diagnosed GBM. Methods: This is a three cohort, Phase I study for patients with newly resected supratentorial GBM. There will be at least four evaluable patients per cohort. Cohort 1 will receive standard RT and concomitant TMZ prior to infusion of autologous lentiviral P140K-MGMT transduced HSCs, followed by adjuvant TMZ. Cohort 2 will receive an induction dose of TMZ+BG followed by infusion of autologous LV-P140K-MGMT HSCs prior to concomitant RT +TMZ and adjuvant TMZ. Cohort 3 will include intra-patient dose escalation of TMZ in patients who exhibit detectable levels of P140K-MGMT marked cells in vivo, using the design (i.e. cohort 1 or 2) proven to be safest and most effective. The study is open and has accrued the first patient.
A phase I study of BMS-936558 plus sunitinib or pazopanib in patients with metastatic renal cell carcinoma.
Authors: Hammers Hans J. , Rini Brian I. , Hudes Gary R. , Ernstoff Marc S. , Kollmannsberger Christian K. , Shen Yun , Waxman Ian , Dhar Arindam
Published: March 2020

TPS2614

Background: Standard treatments for metastatic renal cell carcinoma (mRCC) block the vascular endothelial growth factor pathway (eg, sunitinib, pazopanib) or mammalian target of rapamycin pathway (e.g., temsirolimus, everolimus). However, most patients (pts) develop resistance and complete responses are rare. Upregulation of programmed death-1 (PD-1) in tumor infiltrating lymphoctyes, and its ligand PD-L1 in tumors, is associated with more aggressive disease and poor prognosis. Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for mRCC. In preliminary results of a phase I trial, the anti-PD-1 monoclonal antibody BMS-936558 had antitumor activity in pts with advanced tumors, including objective responses (ORs) in 6 of 18 pts with mRCC. Here we describe a phase I study planned to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of BMS-936558, when combined with sunitinib or pazopanib in pts with mRCC. Methods: This open-label study will have two parallel treatment arms (BMS-936558 plus sunitinib and BMS-936558 plus pazopanib) conducted in two parts (dose escalation and dose expansion). Pts must have received ≥1 prior systemic therapy to be eligible for dose escalation. Only treatment-naïve pts will be eligible for dose expansion. Up to 36 pts (18 per arm) will be treated in the dose-escalation phase. After determining the MTD of BMS-936558, treatment-naïve pts will be enrolled to expansion cohorts allowing 24 pts to be treated at the MTD of each arm. Each treatment cycle will be 6 weeks, with BMS-936558 dosed on Days 1 and 22 and sunitinib or pazopanib given according to product label. Adverse events will be graded according to NCI CTCAE v4.0. Disease will be assessed every 6 weeks for the first four assessments and then every 12 weeks until disease progression. Pts will be treated until unacceptable toxicity, disease progression, or withdrawal of consent. The safety profile in pts treated at the MTD will be used to determine the recommended phase II study dose of BMS-936558 in each combination arm. Secondary objectives will include OR rate and duration of response based on RECIST 1.1. Exploratory analyses will investigate predictive biomarkers of BMS-936558.