tbuckley/cabot-search huggingface dataset:
Maximizing intravesical therapy options: Is there an advantage to the administration of perioperative mitomycin C prior to an induction course of BCG?
Authors: G. M. Badalato, G. W. Hruby, M. Kates, N. Sadeghi, J. T. Matulay, J. M. McKiernan
Journal: Journal of Clinical Oncology (2011)

e15018 Background: This study sought to evaluate cancer-specific outcomes among patients who received perioperative mitomycin C (MMC) prior to induction BCG versus those who received induction BCG alone. Methods: Between January 2000 and August 2010, 260 patients were identified who underwent a course of induction BCG with or without concomitant perioperative MMC. Specifically, patients who received 40 mg MMC following transurethral resection of all visible tumor followed by an induction course of BCG were compared to a similar cohort of patients who received induction BCG alone. The primary endpoints were overall and recurrence-free survival (RFS). Results: A total of 212 patients were identified who received induction BCG alone, and 48 who received perioperative MMC with induction BCG. The aggregate patient cohort was comprised of those with non-muscle-invasive disease (NMI), and there was no difference between groupings with respect to common demographic and pathologic variables. Over a median follow-up of 34.5 months, there was no difference in overall survival between cohorts. RFS was superior among patients who received combined therapy (5 year survival: 37.5% vs 56.3%, p=0.023). Nevertheless, the regimen of intravesical therapy did not reach significance as an independent predictor (HR 0.61, p= 0.055, CI 0.36-1.01). Conclusions: Although the combination therapy group demonstrated a significant RFS advantage, the intravesical therapy regimen did not independently modulate this benefit. Further investigation is warranted to determine if immediate MMC prior to a course of induction BCG confers a benefit to RFS.
Sorafenib monotherapy in patients with inoperable/recurrent germ cell tumors (GCT) refractory to chemotherapy: Phase II study.
Authors: Iwona Anna Skoneczna, Urszula Natorska, Malgorzata Tacikowska, Ewa Kraszewska, Beata Kotowicz, Malgorzata Fuksiewicz, Wojciech W Rogowski, Irena Federowicz, Grazyna Poniatowska, Agnieszka Chaladaj-Kujawska, Wojciech Michalski
Journal: Journal of Clinical Oncology (2014)

367 Background: The phase II trial was conducted in the population of incurable patients with refractory or relapsed GCT to evaluate the activity of sorafenib, an oral multitarget inhibitor of Raf kinase and the tyrosine kinases VEGFR-2 and PDGFR-alpha. Methods: Patients with progressive metastatic GCT received sorafenib monotherapy continuosly 400mg bid until progression of disease or unacceptable toxicity. Serum tumor markers (STM) were assessed every 4 weeks and imaging was performed every 12 weeks. Responses were assessed using RECIST; STM normalization was required for complete responses and partial responses required at least STM stabilization. STM-only declines were recorded as stable disease. Descriptive analysis of efficacy and tolerance was conducted. Results: 18 male patients with nonseminoma were included between 9/2008 and 6.2010. Pts received median 3 (range 3-4) prior chemotherapy treatments, 2 had received prior high-dose therapy. Median age was 35 (range 26-48), primary site was testicular in 16 and in 2 cases retroperitoneal. All patients had STM elevation before treatment. Median treatment duration was 83 days (31, 617), 12/18 patients were treated more than 2 cycles, 8 pts experienced some degree of STM decline with prolonged SD lasted more than 350 days in 3 pts. No partial or complete responses were observed. Drug related adverse events (AEs) were mainly grade 1 and 2; 55% of patients experienced diarrhea, 44% rash, 55% HFSR, 33% hypertension, 28% fatigue. Some G3 toxicity occurred: diarrhea in one pts, hypertension in one patient, HFSR in 2/18. 31% and 22% of pts required dose interruption and reduction respectively due to AEs. Conclusions: Sorafenib monotherapy was well tolerated but did not demonstrated significant activity in patients with highly refractory GCT, although there were some prolonged SD observed. Clinical trial information: NCT00772694.
Seventh edition (2010) of gastric adenocarcinoma AJCC staging system: Is there room for improvement?
Authors: Manali I. Patel, Kim F Rhoads, Yifei Ma, James M. Ford, Jeffrey A. Norton, George A. Poultsides
Journal: Journal of Clinical Oncology (2012)

77 Background: The gastric cancer AJCC staging system recently underwent significant modifications of the T and N categories as well as stage groupings. The new system has not been validated on a US population database, but studies on Asian patients have reported no difference in survival between stages IB and IIA, as well as IIB and IIIA. Methods: California Cancer Registry data linked to Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (gastroesophageal junction tumors excluded) who underwent curative-intent surgical resection from 2002 to 2006. AJCC stage was reclassified based on the 7 th edition. Disease-specific survival (DSS) probabilities were calculated using the Kaplan-Meier method and compared using the log rank test. Results: Of 4,985 patients identified, 2,262 had complete pathologic data and known cause of death. Median age was 70 years and 60% were males. Median number of examined lymph nodes was 12 and 39% of patients received adjuvant chemotherapy. The 7 th edition AJCC system did not distinguish outcome adequately between stages IB and IIA (P = .25), or IIB and IIIA (P = .33, Table ). By merging stage II into one category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system which showed improved discriminatory ability ( Table ). Conclusions: In this first study validating the new 7 th edition AJCC staging system for gastric cancer on a US population, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC system that better discriminates between outcomes. [Table: see text]
Natural history of untreated patients who had metastatic biliary tract cancer (BTC) with good performance status (PS).
Authors: Jung Hun Kang, Se Hoon Park, Su Jin Lee, Jun Ho Ji, Soon Il Lee, Sung Yong Oh, In Gyu Hwang, Haa-na Song
Journal: Journal of Clinical Oncology (2014)

362 Background: Although chemotherapy is widely recommended to the patients with metastatic biliary tract cancer, the natural course of those group, especially with good PS who are indicated for chemotherapy was rarely known. Methods: We retrospectively reviewed metastatic or distant relapsed BTC patients seen between January 2005 and August 2011 at four cancer centers. Patients were eligible if they had good PS (ECOG 0-2), no history of surgery, chemotherapy, radiotherapy or any treatment for cancer. Results: A total of 1302 patient cohort was identified for metastatic or distantly relapsed BTC and 959 patients were categorized for non-treatment group, 343 patients for treatment group. Of 959 patients, 131 patients were eligible for inclusion criteria and 737 patients were excluded for referral to other hospitals or lost followup, 89 patients for poor PS. The patient demographics were median age of 71 (range:39-89) and male predominant (n=81, 61.8%). Extrahepatic cholangiocarcinoma (n=55, 42.0%) was the most common site of eligible BTC followed by intrahepatic cholangiocarcinoma (n=42,32.1%). Median overall survival was 6.0 months (95% confidence interval [CI];4.9-7.1 months). Univariate analysis showed significant difference of survival depending on the serum level of CA19-9 (CA19-9≥100; 8.2 months vs CA19-9&lt;100;4.4 months, log-rank p-value&lt;0.001). Another potential prognostic factors including age, sex, PS, leucocytosis, serum albumin, CEA level and bile drainage did not have statistical difference in survival. Multivariate analysis showed that elevated 19-9 level was an independent poor prognostic factor(p&lt;0.001, odd ratio, 2.8; 95% CI;1.8-4.8). Conclusions: Metastatic BTC patients with good PS had modest survival. However, patients with normal CA19-9 level showed favorable survival. Further studies comparing chemotherapeutic effect with best supportive care in those group are warranted.
Laparoscopic ventral hernia repair with composite mesh: Analysis of risk factors for recurrence in 185 patients with 5 years follow-up
Authors: Mario Nardi, Paolo Millo, Riccardo Brachet Contul, Riccardo Lorusso, Antonella Usai, Manuela Grivon, Fabio Persico, Elisa Ponte, Paolo Bocchia, Salvatore Razzi
Journal: International Journal of Surgery (2017)
Whole Genome Copy Number Variation Analysis of Chronic Lymphocytic Leukemia (CLL) Cells From Early-Intermediate Stage, High Risk CLL Patients Prior to First Treatment Reveals New Loss of Heterozygosity and Duplication Events in the CLL Genome.
Authors: Steven A. Schichman, Annjanette Stone, Maria Winters, Weleetka Carter, Lori Frederick, Jeanette Eckel-Passow, Timothy G. Call, Tait D. Shanafelt, Neil E. Kay, Clive S. Zent, David S. Viswanatha
Journal: Blood (2009)
Time course of regorafenib-associated adverse events in the phase III CORRECT study.
Authors: Axel Grothey, Eric Van Cutsem, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Heinz-Josef Lenz, Richard M. Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Lisa Cupit
Journal: Journal of Clinical Oncology (2013)

467 Background: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Methods: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Results: The safety population comprised 753 patients (pts): REG n=500; placebo n=253. The mean treatment duration was 12.1 ± 9.7 weeks in the REG group and 7.8 ± 5.2 weeks in the placebo group. Treatment-emergent AEs occurred at any grade in 99.6% of REG pts and 96.8% of placebo pts, at grade 1/2 in 21.6% and 47.8%, respectively, at grade 3 in 56.0% and 26.5%, respectively, and at grade 4/5 in 22.0% and 22.5%, respectively. AEs occurring in ≥10% more REG than placebo pts were fatigue, hand–foot skin reaction (HFSR), anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, low platelet count. The most frequent AEs deemed to be regorafenib related were HFSR, fatigue, diarrhea, hypertension, and rash/desquamation. The frequency of these AEs over time is shown in the Table. The incidence of HFSR, fatigue, hypertension, and rash/desquamation peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles. The incidence of diarrhea remained relatively constant throughout treatment. AEs led to dose modification in 66.6% of pts in the REG group and 22.5% in the placebo group. Data on dose intensity across treatment cycles will be presented. Conclusions: In the CORRECT trial, the incidences of the most common AEs in the REG group peaked early during treatment. There appeared to be no evidence for cumulative toxicity of REG. Clinical trial information: NCT01103323. [Table: see text]
The role of adjuvant radiation therapy in T4 nonrectal colon cancers.
Authors: Orrin Pail, Benjamin Spieler, Benzion Samueli, Einat Shacham-Shmueli, Mordechai Gutman, Oded Zmora, Moris Venturero, Talia Golan, Jeffrey Goldstein, Zvi Symon, Yaacov Richard Lawrence
Journal: Journal of Clinical Oncology (2014)

553 Background: The standard treatment for non-metastatic locally advanced (T4M0) non-rectal colon cancer is surgical resection followed by adjuvant chemotherapy. There is strong rational for the use of post-operative radiation therapy (RT) in T4 tumors since negative margins are difficult to obtain. Despite promising single institutional studies, a phase III clinical trial closed early due to poor accrual. The efficacy of adjuvant RT in these patients remains unknown. We hypothesized that patients at lower risk of micro-metastases would benefit most from aggressive local treatment. Methods: Cases were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Inclusion criteria: T4-anyN-M0 non-rectal colon cancers, diagnosed between 1988 and 2010. Exclusion criteria: rectal tumors and cases lacking staging information. Endpoints: overall survival (OS) and cancer-specific survival. Analyses were based on the Kaplan-Meier method and Cox proportional hazard model. Results: A total of 36,260 patients with T4 colon cancer were identified. Due to changes in the use of systemic adjuvant therapies, an initial analysis was performed to determine effect of adjuvant RT by year of diagnosis. Prior to 2003, adjuvant RT provided no significant improvement in OS. However, between 2003 and 2010, adjuvant RT improved OS by 8 months, from 48 to 56 months (HR: 0.83, p = 0.001). Within this latter period, adjuvant RT improved OS in three subsets of the population: in patients without nodal involvement (N0) (HR: 0.79, p = 0.009); in patients with primary tumor in the sigmoid colon (HR: 0.79, p=0.007); in patients with primary tumor size of 6cm or greater (HR: 0.74, p &lt; 0.001). On multivariate analysis, the following categories remained significant: N stage, tumor grade, year of diagnosis, gender, primary site, and radiation therapy. Conclusions: Some patients with T4 non-rectal colon cancer appear to benefit from adjuvant RT after surgical resection of the primary tumor, especially node-negative tumors located within the sigmoid colon, larger than 6cm in diameter. This benefit has become more evident since the introduction of more effective adjuvant chemotherapy. Our conclusions require verification in a prospective study.
Phase 2 trial of imatinib mesylate (IM) for treatment of recurrent or refractory pediatric solid tumors: A Children’s Oncology Group study
Authors: M. Bond, M. L. Bernstein, A. Pappo, K. R. Schultz, M. Krailo, M. Fouladi, D. A. Hill, M. Heinrich, S. Blaney, P. C. Adamson
Journal: Journal of Clinical Oncology (2005)

8520 Background: In in vitro studies, IM inhibits KIT and PDGF receptor tyrosine kinases. Clinical activity has been demonstrated against gastrointestinal stromal tumors (KIT mutations) and dermatofibrosarcoma protuberans (PDGFR rearrangements). On immunohistochemistal staining, Ewing sarcoma (EWS), osteogenic sarcoma (OS), neuroblastoma (NBL), desmoplastic small round cell (DSRCT) and synovial sarcomas (SS) often over express KIT or PDGF receptor. A pediatric phase 2 study using a 2-stage design was performed. Methods: Patients less than age 30 years of age with refractory or recurrent EWS, OS, NBL, DSRCT, SS or GIST were eligible. IM (440 mg/m2/day) was administered daily for 28 day courses. Doses larger than 600 mg were divided bid. Responses were assessed using RECIST criteria. A minimum of one response in the first 10 patients was required to proceed to the second stage of accrual. The study sought to identify diseases with at least a 25% response rate with a probability of 0.92; three or more responses were considered evidence of activity. Results: Seventy eligible pts were enrolled and 59 were evaluable (EWS 24, OS 10, NBL 10, GIST 1, DSRCT 10, SS 4). One partial response (PR) occurred among the 24 patients with EWS (95% confidence interval - 0.11%–21%). No other responses occurred. Hemorrhagic pleural effusions occurred in 4 patients with progressive pulmonary disease (PD) and in 3 others in whom PD was not confirmed. Intratumoral bleeding was reported in 3 patients. Two patients discontinued treatment due to unacceptable GI symptoms. Grade 3/4 hematologic toxicity occurred in <10% of courses. Other grade 3/4 toxicities were uncommon (< 5% of courses). Conclusion: IM as a single agent at a dose of 440 mg/m2/day is inactive in pediatric EWS, OS, NBL and DSRCT. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis
BMS-354825 (BMS) inhibits the kinase activity of mutant KIT proteins associated with seminomas (S) and has synergistic effects with cisplatin (CDDP)
Authors: M. M. Schittenhelm, S. H. Shiraga, D. J. Griffith, A. J. Schroeder, F. Y. Lee, C. Bokemeyer, M. C. Heinrich
Journal: Journal of Clinical Oncology (2005)

4685 Background: KIT is expressed by 90% of S and activating mutations of KIT are found in 25% of cases of S. Imatinib mesylate (IM) potently inhibits wild type (WT) KIT and certain mutant KIT isoforms and is the standard of care for patients with metastatic GI stromal tumors. However, mutations of the KIT activation loop (AL) such as D816V/H, which are the most commonly found mutations in S, are insensitive to IM (IC50 > 5000 nM). BMS is a synthetic small-molecule ATP-competitive inhibitor of SRC and ABL tyrosine kinases that has potency in the low nanomoloar dose range. Notably, BMS binds to the ATP-binding site of ABL regardless of the conformation of the AL and is therefore able to inhibit the kinase activity of AL-mutants of BCR-ABL associated with IM-resistant CML. BMS is currently being tested in phase I/II studies for safety and efficacy in the treatment of IM-resistant CML and various solid tumors. We have evaluated if BMS has activity against IM-resistant AL KIT mutations associated with S. Methods: The effects of BMS on the kinase activity of WT or mutant KIT stably expressed in BaF3, p815 or HMC-1 cells was assessed by immunoblotting. Cell proliferation and induction of apoptosis (Annexin V binding) was measured using an XTT-based assay and a flow cytometric based assay, respectively. Results: BMS potently inhibited KIT-WT kinase activity with an IC50 of 1–10 nM for autophosphorylation and KIT-ligand-dependent cellular proliferation. In contrast, the IC50 for inhibition of GM-CSF-dependent proliferation of these same cells was > 5000 nM. BMS inhibited KIT autophosphorylation as well as cellular proliferation of cell lines expressing human KIT D816V/H mutations, and the homologous murine D816Y mutation (IC50 50–100 nM). Apoptosis was induced in the same dose range that inhibited kinase activity (IC50 50–100 nM). In addition, we found that BMS was strongly synergistic with CDDP (CI 0.3–0.6) in reducing proliferation and inducing apoptosis of cells expressing KIT D816V/H. Conclusions: BMS not only inhibits the kinase activity of WT KIT and IM-resistant KIT AL-mutant kinases associated with S but also exhibits a strong synergistic anti-tumor activity in combination with CDDP. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Meyers Squibb Bristol-Meyers Squibb Novartis
Cytologic and molecular characterizations of CTC detected in patients with metastatic colorectal carcinomas.
Authors: Julien Coget, France Blanchard, Aude Lamy, Emmanuel Toure, Frédéric Di Fiore, Isabelle iwanicki-Caron, Pierre Michel, Francis Michot, Jean-Christophe Sabourin
Journal: Journal of Clinical Oncology (2012)

485 Background: Circulating tumor cells (CTC) appear to be associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). ScreenCell technology, which is based on the separation of CTCs from other circulating cells by blood filtration, could allow clinical use of this new biomarker. The aim of our study was to demonstrate the feasibility of CTC filtration in a clinical situation and to compare CTC cytological/molecular characterizations. Methods: Sampling of venous blood was performed in 39 patients with mCRC before starting chemotherapy regimen. For cytology, blood were filtered using ScreenCell Cyto devices. After staining with hematoxylin, each filter was analyzed by a cytopathologist. Cells visualized on the filter were considered as tumoral if they met the following morphological criteria: nuclear diameter &gt;7micron, anisocytosis, membrane irregularities, presence of large nucleolus. For molecular biology, blood were filtered using ScreenCell MB columns: DNA was then extracted for KRAS genotyping. Prior to the clinical study, HCT116 cells were used in order to establish biological procedures. Results: 3 samples were not analysed due to blood coagulation. The presence of CTC was identified in 23/36 patients with mCRC (64%). KRAS mutation was present in 40% of tumor patients. In those patients, no mutation was observed on CTC specimens even when using whole gene amplification and PNA selective PCR, whereas KRAS mutation was detected in 10 HCT116 cells diluted in 3ml of normal blood using this same procedure. Conclusions: ScreenCell Technology allows cytological studies which appear to be fast and efficient for the detection of CTC in mCRC patients. Detection of CTC molecular abnormalities is a major challenge: implementation of molecular tests such as KRAS genotyping, allowing tumor characterization directly from minimally invasive blood sampling, could have tremendous clinical applications. Our first in vitro results highlight the fact that detection of somatic molecular alterations is feasible, from just a few tumoral cells diluted in blood, which encourages further developments using other molecular approaches.
Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumor cells in patients with early breast cancer.
Authors: N. Xenidis, M. Perraki, S. Apostolaki, S. Agelaki, K. Kalbakis, N. K. Vardakis, A. Kalykaki, A. Xyrafas, S. Kakolyris, D. Mavroudis, V. Georgoulias
Journal: Journal of Clinical Oncology (2011)

10554 Background: To investigate the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumor cells (CTCs) in patients with early breast cancer. Methods: The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated both before and after chemotherapy, using a real-time RT-PCR assay, in 545 women with stage I-III breast cancer who received adjuvant taxane-free (FE75C and E75C) or taxane-based (sequential docetaxel followed by epirubicin/cyclophosphamide or docetaxel/epirubicin) chemotherapy. Results: Taxane-based regimens were more effective than taxane-free regimens in the elimination of CTCs since 49.7% and 33.0% of patients with detectable CTCs before chemotherapy, respectively, became CK19 mRNA-negative after completion of chemotherapy (p=0.015). The incidence of clinical relapses was higher in patients treated with taxane-free than in those treated with taxane-based (33.2% and 16.6%, respectively, p=0.00001). Patients treated with a taxane-free regimen had a significantly lower DFS compared to patients treated with a taxane-based chemotherapy (p=0.035); this difference was observed in patients with but not without detectable CTCs before chemotherapy (p=0.018 and p=0.481, respectively). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with a prolonged DFS (HR: 2.00; 95% CI: 1.20-3.34) in patients with detectable CTCs. Conclusions: Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy may be an indicator of the efficacy of the chemotherapy regimen and this is associated with a favorable clinical outcome in patients with detectable CTCs