tbuckley/cabot-search huggingface dataset:
Phase I evaluation of troxacitabine administered by continuous infusion in patients with refractory solid tumors
Authors: M. Hidalgo, C. Lee, K. Carducci, J. Jolivet, S. Baker
Journal: Journal of Clinical Oncology (2004)

2071 Background: Troxacitabine (Troxatyl) is a novel L-nucleoside analog different from gemcitabine and cytarabine on its structure, pharmacokinetics (PK), cellular transport and mechanisms of resistance. Phase I and II studies identified a recommended dose of 1.5mg/m2 dailyx5 every 4wk by 30min iv infusion (JCO, 20:96, 2002); significant antitumor activity was observed in patients with advanced pancreatic and renal cell cancer. In human tumor xenografts, the activity of troxacitabine was increased with continuous infusion administration of at least 3 days compared to bolus regimens. This phase I study is evaluating the toxicity, PK, and antitumor activity of continuous infusion troxacitabine in patients with advanced solid tumors. Methods: This is a dose- and infusion length finding study to achieve a minimum steady–state plasma concentration of 21 ng/mL for 72–120h. This target plasma level was based on preclinical efficacy data and the starting dose of 3 mg/m2/d was determined from PK simulation modeling using data obtained from Phase I studies (30min infusion). The starting infusion duration was 48h with escalation to 72, 96 and 120h in cohorts of 3–6 patients. Results: Thus far, 9 adults (6 males, 3 females) with refractory solid tumors have been treated. The first cohort (4 pts) received drug for 48h (total dose 6mg/m2) with no DLT. At the next cohort (72h infusion, total dose 9mg/m2), 2 DLTs were observed in 5 pts, which consisted of prolonged (>7 d) gr 4 neutropenia (2 pts) that was complicated with fever (1 pt) and gr 3 thrombocytopenia (1 pt). The main non-hematological toxicities were skin rash occurring in 3 pts. Enrollment is ongoing at a reduced dose of 2 mg/m2/d for 72h (total 6 mg/m2). At 3mg/m2/d for 48–72h, mean (SD) troxacitabine plasma concentrations at 23.5, 47.5, and 71.5h were 24 (5.6), 28 (8.0), and 31 (7.2) ng/mL, respectively. The 2 pts with DLT had the highest plasma concentrations. Conclusions: Administration of troxacitabine by continuous infusion is feasible. The prospectively defined target plasma concentration has been achieved. Enrollment continues to define the recommended dose and infusion duration for troxacitabine. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Shire Pharmaceuticals Shire Pharmaceuticals
Paclitaxel in relapsed squamous cell carcinoma of head and neck (SSCHN): Retrospective study of a single institution
Authors: J. Fayette, A. Montella, T. Bachelot, P. Pommier, D. Girodet, S. Racadot, X. Montbarbon, B. Favier, P. Zrounba
Journal: Journal of Clinical Oncology (2009)

e17047 Background: For relapse or metastatic SCCHN the standard treatment is the combination of cisplatin and 5FU that showed higher response rate than methotrexate but similar overall survival. Cetuximab demonstrated in a phase III (N Engl J Med. 2008;359:1116) its efficacy and paclitaxel showed efficacy in a phase II study (Cancer. 1998;82:2270). The objective of this study was to evaluate paclitaxel (P) in our institution in various situations. Methods: We retrospectively reviewed 56 pts with relapse or metastatic SSCHN treated with P in a single institution in Lyon (France) between June 2002 and February 2008. P was administered in first line for locally advanced disease, in first line for relapsed or metastatic disease, or in second or more line. P was administered q1w or q3w, alone or in combination with carboplatin or cetuximab. Results: Median age was 59 years (36–84) at the beginning of paclitaxel. Localizations of primitive tumor: oral cavity (14%), oropharynx (30%), hypopharynx (39%) larynx (7%), rhinopharynx (4%), or other (6%). All patients received adequate initial treatment with surgery and/or radiotherapy, 47% had have neoadjuvant chemotherapy (71% with cddp-5fu, but 5 pts received P). Five patients received P as neoadjuvant treatment. Among 52 evaluable patients, 33 received P in first line of treatment after relapse, 12 in second line. Monotherapy was administered to 20 patients and 22 received P combined with carboplatin, and 1 with cetuximab. For all patients, objective response rate (OR) was 30.8% (95% CI 18.7–45.1%). In first line of relapse, OR was 39.4% (95% CI 22.9–57.9%) and 16.7% (95% CI 2.1–18.4%) in second line. In monotherapy OR was 30.0% (95% CI 11.9–54.3%) and 36.4% (95% CI 17.2–59.3%) in combination with carboplatin. The overall survival (OS) of all patients was 6.3 months (95% CI 3.9–7.9 m), and 7.7 m (95% CI 3.9–11 m) and 5.2 m (95% CI 2.8–7.9 m) in first and second line, respectively. There is no difference in OS between monotherapy and combination: 6.1 m (95% CI 3.9–7.9 m) and 5.3 m (95% CI 3.9–7.9 m), respectively. Conclusions: P did not improve overall survival but showed interesting response rate in relapsed patients who are often symptomatic. Recent studies suggest high potentialities in combination with EGFR inhibitors. No significant financial relationships to disclose.
NLG-0304: A phase 2B study of ipilimumab with or without dorgenmeltucel-L (HyperAcute-Melanoma) immunotherapy for patients with stage IV melanoma.
Authors: Adam I Riker, Gabriela R. Rossi, Nicholas N. Vahanian, Charles J. Link
Journal: Journal of Clinical Oncology (2014)

TPS9115 Background: Dorgenmeltucel-L immunotherapy consists of allogeneic melanoma cells that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity. It is αGal that is primarily responsible for the hyperacute rejection of foreign tissue via this potent immune defense mechanism in humans. Dorgenmeltucel-L leverages this mechanism to educate the immune system towards components of the patients’ own tumor cells. In prior Phase 1 and 2 studies of dorgenmeltucel-L, there have been no grade 3 or higher immunotherapy related adverse events. In the Phase 2 study in combination with pegylated interferon, all evaluable patients developed autoimmune antibodies and 4 developed vitiligo which correlated with either CR or durable post resection NED state. Ipilimumab has now become standard therapy for advanced melanoma patients, particularly those that are BRAF negative. Preclinical data has demonstrated synergy between therapeutic vaccination and anti-CTLA-4 therapy. This study is designed to determine if there is benefit to adding dorgenmeltucel-L to standard ipilimumab therapy. Methods: This is a randomized Phase 2B study for patients with stage 4 metastatic melanoma. 100 patients will be randomized to receive either standard ipilimumab therapy (3mg/kg q 3 weeks x 4) or standard ipilimumab plus dorgenmeltucel-L 300 million cells per each immunization, given weekly x 4, then biweekly for 5 months, monthly for 6 months, and every 3 months for an additional year. Patients receiving dorgenmeltucel-L and ipilimumab will start ipilimumab with the 4th dose of dorgenmeltucel-L. Primary endpoint is the overall clinical response rate. Secondary endpoints include Disease free survival (DFS), Progression-free survival (PFS), and Overall survival (OS), Duration of Complete Response (CR), Duration of Stable Disease (SD), and immunologic correlates. Clinical trial information: NCT02054520.
Analysis of somatic mutation in miRNAs and miRNA regulation-related genes in gynecological cancers: New frameshift mutation of TNRC6A found in endometrial cancer.
Authors: Qi Mei, Yang Yang, Ellen Honisch, Shi Ying Yu, Johann Wolfgang Janni, Dieter Niederacher
Journal: Journal of Clinical Oncology (2012)

5097 Background: Micro RNAs (miRNAs) are small non-coding RNAs which plays an important role in tumorigenesis and mutation of a miRNA gene or miRNA regulation-related gene may cause butterfly effect on alteration of global gene expression.In order to investigate this hypothesis,high resolution melting analysis (HRM) and denaturing high-performance liquid chromatography (DHPLC) were used to screen 20 miRNA genes and 6 miRNA regulation-related genes for mutations in gynecologic cancers. Methods: In this study,182 DNA samples from breast cancer tumors,42 from ovrian cancers and 28 from endometrial cancers were obtained.18 human cancer cell lines were also included.We used HRM and/or DHPLC to screen mutations of these genes in human cancer cell lines and tumor tissues. All samples with curves that differed in shape compared to wild-type were directly sequenced for confirmation.Secondary structures for the wild-type and variant primary precursor of miRNA sequences obtained from sequencing were predicted using RNAfold software.Western blot and immunohistochemistry were used to evaluate the related protein change in cancer cell line and tumor tissues. Results: Polymorphisms of these genes were very frequently observed in gynecologic cancers.Two rare variants were found in the primary precursor sequences of mir-200c and mir-142 gene.Moreover,a novel frameshift mutation( c.3547_3548insA) in TNRC6A gene was found in two endometrial cacner cell lines (RL95-2 and Hec-1A) and endometrial cancers (1/28).Western blot and immunohistochemistry showed loss of expression of TNRC6A protein in the endometrial cacner cell lines and endometrial cancers with this mutation. Conclusions: Two rare novel variants in 20 miRNA genes and a novel frameshift mutation in TNRC6A gene were identified in gynecologic cancers.Oue data indicate that mutations in TNRC6A gene may contribute to the cancer development and might be a potential new therapeutic target in endometrial cacner.
Molecular characteristics in breast cancer tumors treated with neoadjuvant chemotherapy with and without bevacizumab: Results from NeoAva— Randomized phase II study.
Authors: Olav Engebraaten, Laxmi Silwal-Pandit, Elen Kristine Moller, Silje Nord, Marit Krohn, Hans Kristian Moen Vollan, Hedda von der Lippe Gythfeldt, Elin Borgen, Oystein Garred, Anne Fangberget, Marit Muri Holmen, Steinar Lundgren, Erik Andreas Wist, Ole Christian Lingjaerde, Bjorn Naume, Anne-Lise Borresen-Dale
Journal: Journal of Clinical Oncology (2015)

2523 Background: The molecular characteristics of responding and non-responding breast cancers when treated with antiangiogenic therapy are largely unknown. Methods: To investigate molecular alterations in tumors treated with antiangiogenic therapy, the NeoAva study included patients with HER2 negative primary tumors of ≥ 25 mm that were randomized (1:1) to receive chemotherapy (4 x FEC100 + 12 weeks of taxane-based therapy) with or without bevacizumab. Tumor material was obtained at screening, 12 weeks into treatment and at surgical removal at 25 weeks. mRNA expression profiling was performed (Agilent). In this study, 131 patients were evaluable for tumor response. Results: pCR in breast and axilla were obtained in 14 (21.1%) patients in the chemo+bev arm, and in 7 (10.6%) patients in the chemo-only arm. The overall pCR rates were higher in the ER negative tumors compared to ER positive tumors ((9 of 23) vs (12 of 108)). Addition of bevacizumab seemed to improve pCR in the ER positive patient group (9 vs 3) and not in ER negative patient group (5 vs 4). Tumors that achieved pCR showed a significant higher expression of genes (n = 362) enriched for immune response related pathways, compared to the tumors that did not achieve pCR in the ER positive group. The identified immune gene signature predicted response independent of the PAM50 proliferation signature and VEGF pathway signature, particularly in the bevacizumab treated group (p < 0.001). Proliferation scores regressed across time-points in response to therapy (p < 0.001), and bevacizumab treatment accelerated the reduction of the proliferation score in the ER positive tumors. In response to therapy, tumors achieved a better prognosis profile, i.e. Luminal A or Normal-like profile. ER positive tumors, particularly Luminal B showed significant differences in gene expression and associated pathways between two treatment arms (chemo only and chemo+bev), while minimal change was observed for ER negative/Basal-like tumors. Conclusions: The immune signature was found to be a strong predictor of response in ER positive tumors, particularly in tumors treated with chemotherapy combined with bevacizumab. Clinical trial information: NCT00773695.
Questionnaire to evaluate prostate cancer multidisciplinary committees in Spain.
Authors: Javier Cassinello, Iván Henríquez López, Aranzazu Gonzalez del Alba, Carmen González San Segundo, José López Torrecilla, Enrique Gallardo Díaz, Alfredo Rodríguez Antolín, Álvaro Juárez, Miguel Unda, Jose Angel Arranz Arija
Journal: Journal of Clinical Oncology (2017)

e568 Background: Prostate Cancer (PC) management through Multidisciplinary Committees (MDC) has demonstrated some benefits that could be relevant in patient's outcomes. In Spain MDC are widely implemented although they are not homogeneous among hospitals. The aim of the study was to design a questionnaire to evaluate the functionality/effectiveness of PC MDC in Spain. Methods: The questionnaire was developed from a literature review (22 articles included) and validated by 9 opinion leaders (3 medical oncologists, 3 urologists and 3 radiation oncologists). Experts scored each questionnaire item regarding its ability to assess MDC functionality/effectiveness to obtain a final score of each hospital (from 0-minimum to 100-best functionality/effectiveness) used to classify them according to the cluster analysis (high/intermediate/low level of functionality/effectiveness). The questionnaire was distributed to different specialties by the Spanish Societies of Urological Cancer (URONCOR, GUO and SOGUG). Results: 218 physicians answered the questionnaire, 90 medical oncologists, 86 urologists and 42 radiation oncologists, from 109 hospitals with national representativeness. 91% of hospitals had a Urological MDC, 5% a PC MDC and 4% a General Tumour Committee. Core medical specialities (Urology, Medical Oncology, Radiation Oncology, Pathology, Radiology) were represented in &gt; 80% of MDC. Only 9% MDC discussed the treatment of all patients with PC whereas in 60% of MDC less than 50% of the whole population of PC patients were evaluated. According to 95% of physicians, agreement in therapeutic strategies were reached in &gt; 80% of cases discussed. A score was established that allowed the classification of MDC in each center according to its functionality into 3 clusters: 43% of centers fell in cluster 3 (high), 36% in cluster 2 (intermediate) and 21% in cluster 1 (low). Conclusions: Urological Cancer MDC is a widespread practice in Spain, which comprises a wide range of medical specialists that meet regularly to agree on therapeutic strategies for PC patients. Less than 50% of total PC patients are evaluated in Urological MDC. It is still necessary to improve some aspects allowing more hospitals to reach a higher level of functionality.
Detection of EGFR and KRAS somatic mutations in tumor tissue and peripheral blood by a liquidchip technology for patients with advanced non-small cell lung cancer.
Authors: Shucai Zhang, Hui Zhang, Xinjie Yang, Xi Li, Na Qin, Jiasen Xu, Huiyi Yang, Yong-Qing Zheng, Gang Yu
Journal: Journal of Clinical Oncology (2012)

e18142 Background: Responsiveness of non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors has been confirmed to relate to mutations in the epidermal growth factor receptor (EGFR) signaling pathway genes. This study’s aim is to detect mutations in two important components of the EGFR signaling pathway, EGFR and KRAS, using a novel liquidchip technology, and to evaluate the correspondence between tumor and plasma DNA in the same patient. Methods: 58 advanced primary NSCLC ( IIIB or ‡W) tumor tissues and matched peripheral blood samples (MPBS) were obtained. The procedures for multiplex PCR, allele specific primer extension (ASPE) and hybridization were performed after DNA extraction. A novel liquidchip platform for simultaneous detection multiple alleles of DNA somatic mutations was applied to detect the EGFR and KRAS status in matched samples. Results: EGFR exon 19 and exon 21 mutation rate was detected to be 29.3% (17/58) and 17.2% (10/58) respectively in tumor tissues, while 20.7% (12/58) and 12.1% (7/58) in MPBS. Among those 27 patients who harbor either EGFR exon 19 or exon 21 mutations in tissues, 19 (70.4%) of them were detected to have the same mutations in their peripheral blood samples. EGFR exon 20 T790M mutations were found in one of the paired samples. All the patients who were detected to have wild-type EGFR in tissues were detected to have wild-type in MPBS as well. In 50 of 58 (86.2%) of the paired samples, the EGFR mutation status in the tumors was consistent with those in the MPBS. The KRAS exon 2 mutation was also found in both blood and tumor samples in one patient; however only in the blood of another patient, not in his tumor. Conclusions: The liquidchip technology may serve as an effective method for detecting multiple gene mutations. EGFR and KRAS gene mutations in blood DNA were highly consistent with the corresponding tissue samples, and therefore, peripheral blood could be used as an alternative sample to predict patients’ response to the anti-EGFR targeted therapy. Further studies to evaluate the clinical application are suggested.
Effect of dose of melphalan used in conditioning regimen on outcomes of autologous stem cell transplantation in overweight/obese patients with multiple myeloma.
Authors: Elizabeth Ellent, Sachin Gopalkrishn Pai, Ashley Chasick, Qingyang Luo, Charles V. Wendling, Robert Emmons
Journal: Journal of Clinical Oncology (2015)

e18014 Background: Melphalan at 200 mg/m2 has been an established conditioning regimen in patients undergoing autologous hematopoietic stem cell transplant (ASCT) with Multiple Myeloma (MM). There are no clear guidelines on dosing melphalan in obese patients. Consequently, ideal body weight (IBW) or adjusted body weight (ABW) rather than dose based on actual body surface area has often been used in an attempt to minimize toxicity. The impact of such a dosing algorithm is not clear. We did a retrospective analysis comparing the differently dosed overweight/obese MM patients for short and long term outcomes. Methods: We conducted a retrospective chart review of overweight and obese (BMI ≥ 25 kg/m2) MM patients treated from January 1, 2011 through March 31, 2014 at Bone marrow transplant program at Ochsner Cancer Institute in New Orleans, Louisiana. Ratio of administered dose (IBW or ABW based dose) to the actual body surface area based dose was calculated. We subdivided the cohort in 2 groups based on this ratio; group 1 (ratio ≤ 0.95) and group 2 (ratio > 0.95). We compared short term outcomes with respect to days to engraftment, immediate toxicity and long term outcomes using International Myeloma Working Group criteria at day 100 and Year 1. Results: Twenty-six patients were studied with mean duration of follow up of 1053 days in group 1(n = 10) and 446 days in group 2 (n = 16). Results are summarized in table below. Conclusions: We did not detect statistically significant difference in short or long term outcomes when melphalan was dosed differently in obese MM patients undergoing ASCT in our short case series. Group 1 2 P value Class of obesity (%) (%) 0.34 Overweight 40 68.8 Class I obesity 10 31.2 Class II obesity 50 0 Short Term Outcomes Length of stay (days) 18.9 17.6 Nausea/vomiting (%) 80 62.5 0.61 Diarrhea (%) 50 81.3 0.21 Mucositis (%) 50 37.5 0.83 Mean days to ANC engraftment 11.8 11.1 0.60 Mean days to platelet engraftment 16.3 18.6 0.16 Long Term Outcomes Time to Relapse (D) 679 592 0.71 Day 100 assessment (%) (%) sCR 10 12.5 0.026 Cr 80 50 VGPR 0 37.5 PD 10 0 Year 1 assessment (%) (%) sCr 20 7.1 0.84 Cr 20 21.4 VGPR 20 35.7 SD 0 7.1 PD 40 28.6
Mutant <i>BRAF</i> upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.
Authors: Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Debabrata Mukhopadhyay, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2017)

603 Background: Oncogenic BRAF V600E mutations activate MAP kinase signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer (CRC). In BRAF V600E mutant CRCs, treatment failure may be related to BRAF V600E -mediated apoptosis resistance that occurs by an as yet undefined mechanism. Methods: BRAF isogenic RKO CRC cells and RKO, HT29, WiDr cell lines were treated with cobimetinib ± the small molecule MCL-1 inhibitor, A-1210477. Apoptosis was measured by Annexin V staining and caspase cleavage. Gene knockdown or overexpression was achieved by lentivirus; ERK siRNA was utilized. Competitive RT-PCR was performed for MCL-1 mRNA expression. HT-29 cells with control or MCL-1 shRNA were xenografted into SCID mice, treated with cobimetinib or vehicle, and tumor volume was measured. Results: We found that BRAF V600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using CRC cell lines isogenic for BRAF. BRAF V600E -induced MCL-1 upregulation was confirmed by ectopic BRAF V600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1 Thr163 ) and stabilize MCL-1. Upregulation of MCL-1 was mediated by MEK/ERK shown by ERK siRNA that suppressed MCL-1. Stabilization of MCL-1 by phosphorylation was shown by a phosphorylation-mimicking mutant and an unphosphorylated MCL-1 mutant that decreased or increased MCL-1 protein turnover, respectively.MEK /ERK inhibition by cobimetinib suppressed MCL-1 expression/phosphorylation and induced pro-apoptotic BIM to a greater extent than did vemurafenib in BRAF V600E cell lines. MCL-1 knockdown vs control shRNA significantly enhanced cobimetinib-induced apoptosis in vitro and in HT29 colon cancer xenografts. A-1210477 also enhanced cobimetinib-induced apoptosis in vitrothat was due to disruption of the interaction of MCL-1 with pro-apoptotic BAK and BIM. Knockdown of BIM attenuated BAX, but not BAK, activation by cobimetinib plus A-1210477. Conclusions: BRAF V600E -mediated MEK/ERK activation can upregulate MCL-1 by phosphorylation/stabilization to confer apoptosis resistance that can be reversed by MCL-1 antagonism.
Sensitive and cost-effective detection of epidermal growth factor receptor mutations in small biopsies by denaturing high performance liquid chromatography.
Authors: T.M. Chin, D. Anuar, R. Soo, Manuel Salto-Tellez, W.Q. Li, B. Ahmad, S.C. Lee, B.C. Goh, K. Kawakami, B. Iacopetta, R. Soong
Journal: Clinical Cancer Research (2005)