tbuckley/cabot-search huggingface dataset:
Is non-HD–MTX based, dose-dense, combination chemotherapy a valid choice in osteosarcoma in developing world?
Authors: Jyoti Bajpai, Chandrakanth MV, Nishitha Shetty, Jaya Ghosh, Bharat Rekhi, Tushar Shailesh Vora, N. A. Jambhekar, Nehal Rishi Khanna, Shripad Dinanath Banavali, Sudeep Gupta
Journal: Journal of Clinical Oncology (2014)

10537 Background: Recent meta-analysis in osteosarcoma (OGS) revealed superiority of high-dose-methotrexate (HD-MTX) containing 3-drug combination chemotherapy (CTh) compared to 2-drug regimens with 5y-EFS of 54% and 46%, respectively (p = 0.03). The use of HD-MTX requires in-patient treatment with stringent monitoring. Non HD-MTX based CTh regimens merit evaluation especially in resource constrained scenarios. Methods: This prospective study evaluated the efficacy & toxicity of dose-dense CTh regimen comprising doxorubicin, ifosfamide, and cisplatin. Response to CTh was graded based on histological necrosis (HN). Good responders (GR) were defined as those with ≥ 90% HN. Survival analysis was performed using the Kaplan-Meier method and compared the log-rank test. Baseline disease status and nutritional parameters were correlated with outcomes. Results: Majority were males (61%) with a median age of 18 yrs. Thirteen (36 %) had metastatic disease. The mean lesion size was 11.5cm. Seventeen (47%) were malnourished, 9 (25%) anemic, 12 (33%) iron deficient and 15 (41%) were B12 deficient at presentation. Post CTh 21(91%) with non-metastatic and 6 (46%) with metastatic disease underwent surgery. For either group GR was 67%. At the median follow-up of 2.2yrs, 30 (84%) were surviving and 21 (59%) remained progression free. Patients with non-metastatic disease had an OS and PFS of 95% and 70% while patients with metastatic disease have an OS & PFS of 61% and 40% respectively. Survival difference between the two groups was statistically significant. Other prognostic factors like ECOG score of ≥ 2 & Hb levels ≤ 10.6 gm% had a significant impact on PFS (p=0.01 & 0.03) and OS (p =0.01& 0.05). On multivariate analysis presence of metastasis was an independent prognostic factor. During CTh 41% patients had febrile neutropenia after the first cycle and were managed successfully. Conclusions: Non-HD-MTX based dose-dense CTh results in acceptable disease control and toxicity in patients with non-metastatic OGS. Patients with metastatic disease probably warrant more aggressive regimens.
Modularly engineered injectable hybrid hydrogels based on protein-polymer network as potent immunologic adjuvant in vivo
Authors: V.H. Giang Phan, Huu Thuy Trang Duong, Thavasyappan Thambi, Thanh Loc Nguyen, Md. Hasan Turabee, Yue Yin, Seong Han Kim, Jaeyun Kim, Ji Hoon Jeong, Doo Sung Lee
Journal: Biomaterials (2019)
Phase lb study of BEZ235 plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC).
Authors: Jordi Rodon Ahnert, Martin H. Schuler, Jean-Pascal H. Machiels, Dagmar Hess, Luis Paz-Ares, Ahmad Awada, Roger von Moos, Neeltje Steeghs, Cristina Cruz Zambrano, Peggy De Mesmaeker, Heike Richly, Catherine Herremans, Markus Joerger, Jesus Corral Jaime, Maria Alsina, Fabienne Baffert, David Demanse, Vincent Duval, Alex Morozov, Luc Dirix
Journal: Journal of Clinical Oncology (2014)

621^ Background: Preclinical data suggest BEZ235 (BEZ; dual PI3K/mTOR inhibitor) may enhance the activity of PTX ± TZ in pts with advanced cancers. In this 4-arm study (NCT01285466), BEZ or buparlisib (pan-PI3K inhibitor) were investigated in combination with PTX in pts with aST or with PTX + TZ in pts with HER2+ BC. Here, we report the BEZ arms only. Methods: Pts with aST or HER2+ BC who were candidates for PTX ± TZ were eligible. The primary objective was to define the MTD in each arm by assessing dose-limiting toxicities (DLT) in Cycle 1. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Pts with PI3K-pathway alterations were enrolled in a BEZ + PTX safety expansion cohort. Results: (2 Apr 2013): BEZ + PTX: 35 pts received BEZ at 400–800 mg/d and PTX at 70–80 mg/m2/wk. Median number of prior regimens was 3 (range: 1–10). DLT occurred in 5 pts: in 1 out of 4 pts at 600/80 and in 4 out of 26 pts at 800/80. The MTD was declared as BEZ 800 mg/d + PTX 80 mg/m2/wk. Median exposure was 11 wks. Study drug-related Grade 3/4 AEs (>10%) included diarrhea (17%), fatigue (20%), and asthenia (11%). 29% of pts discontinued due to AEs and 63% due to progressive disease. The median AUC0–24of BEZ at the MTD on C1D8 was 11000 (range: 1730–39000) h*ng/ml. The PK of PTX were unaffected by BEZ. Per RECIST, there were 3 PRs (ORR = 9%) and 18 SD. BEZ + PTX + TZ: 11 pts received BEZ + PTX (80 mg/m2) + TZ (2 mg/kg/wk) at 2 BEZ doses: initially at 600 mg/d (5 pts) and then at 400 mg/d (6 pts). Median number of prior regimens was 4 (range: 1–10). DLT occurred in 2 pts (600 mg/d). The MTD was declared as BEZ 400 mg/d + PTX 80 mg/m2/wk + TZ 2 mg/kg/wk. Median exposure was 19 wks. Study drug-related Grade 3/4 AEs (>10%) included neutropenia (27%), neurotoxicity (18%), and lymphopenia (18%). The median AUC0–24of BEZ at the MTD on C1D8 was 3590 (range: 2190–12200) h*ng/ml. Per RECIST, there were 2 CR, 4 PR (2 with prior PTX/TZ in metastatic setting; ORR = 55%) and 3 SD. Conclusions: BEZ + PTX ± TZ has a challenging safety profile and substantial interpatient variability in PK parameters. However, encouraging signs of clinical activity suggest that PI3K-pathway inhibition in combination with PTX ± TZ is a promising approach for treating pts with aST. Clinical trial information: NCT01285466.
Phase II trial of oral S-1 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard chemotherapies (CCOG-1105 study).
Authors: Kazuhiro Ezaka, Goro Nakayama, Hiroyuki Yokoyama, Takanori Matsui, Shinichi Umeda, Yuki Sunagawa, Kenta Murotani, Yuichi Ando, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2018)

841 Background: The aim of this multicenter, single-arm phase II trial was to investigate the efficacy and safety of S-1 plus bevacizumab (BEV) as a salvage treatment for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies. Methods: Patients who had unresectable mCRC with mutant-type KRAS; were refractory to fluoropyrimidine, irinotecan, oxaliplatin; and had previous treatment with BEV were enrolled and received S-1 plus BEV therapy (bevacizumab 7.5 mg/kg on day 1 and S-1 40-60 mg bid on day 1-14, every 3 weeks). The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), tumor response, and safety. Results: A total of 27 patients were enrolled. After a median follow-up period of 12.3 months, the events of disease progression and death occurred in 26 patients (96%) and 20patients (74%), respectively. The median number of treatment cycles was 3 (range, 1-17 cycles). Median PFS was 2.3 months (95% confidence interval [CI], 2.2-2.4 months), and the median OS was 7.7 months (95% CI, 4.3-10.1 months). The overall response and disease control rates were 0% and 33%, respectively. The median tumor shrinkage rate (DpR) was -15% (range, -59 to 15%). The frequencies of hematological and non-hematological adverse events above grade three were 25% and 8%, respectively. Conclusions: S-1 plus BEV therapy could be feasible salvage line treatment for Japanese patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000006476.
Aprepitant versus metoclopramide, both combined with dexamethasone, for preventing cisplatin-induced delayed emesis: A randomized, double-blind study.
Authors: Fausto Roila, Enzo Ballatori, Benedetta Ruggeri, Sonia Fatigoni, Aurora Mirabile, Barbara Frau, Luigi Cavanna, Sergio Fava, Ida Colantonio, Lucia Angelelli, Libero Ciuffreda, Stefania Eufemia Lutrino, Filippo Zerilli
Journal: Journal of Clinical Oncology (2014)

9503 Background: A combination of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in acute phase, and aprepitant+dexamethasone (A+D) in delayed phase. Aim of this study was to verify if A+D is superior to metoclopramide plus dexamethasone (M+D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. Methods: A randomized double-blind study comparing A+D versus M+D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg, dexamethasone 8 mg, and oral aprepitant 125 mg. On day 2-4 patients randomly received oral dexamethasone 8 mg qd plus aprepitant 80 mg qd (days 2-3) or metoclopramide 20 mg qid plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. Results: Of 303 enrolled patients 288 were evaluable, 147 receiving A+D, 137 M+D. Day 1 results were similar inboth arms. On day 2-5, complete response rate was not significantly different (80.3% with A+D versus 82.5% with M+D, p<0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, score of Functional Living Index-Emesis; p<0.24). Adverse events incidence was not significantly different between the two treatments. Conclusions: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis foracute emesis, A+D is not superior to M+D in preventing delayed emesis, and both treatments present similar toxicity. Clinical trial information: NCT00869310.
Treatment outcome of genitourinary rhabdomyosarcoma: 10 years experience.
Authors: Shady Fadel, Mohamed Yousef, Ahmed Hanoo, Amr Kamal
Journal: Journal of Clinical Oncology (2014)

e21019 Background: Genitourinary rhabdomyosarcoma is a special entity that needs complex treatment algorithm with chemotherapy, surgery and radiotherapy, which impacts the disease control and long term outcome. We aim to retrospectively review genitourinary rhabdomyosarcoma outcome in our limited resources country. Methods: A retrospective review was made of the clinical records of all patients younger than the age of 18 years diagnosed with Genitourinary RMS and treated at Alexandria University Hospital, over a period of 10 years (2002 – 2012).The primary outcome examined was Overall survival. A secondary outcome, local recurrence, and progression free survival rates were calculated. Toxicities and adverse effects following treatment were evaluated by the National Cancer Institute–Common Toxicity Criteria version 4.0. Results: 20 patients histologically confirmed GU – RMS. The age at presentation varied between 9 months to 18 years with a median of 9 years. There were 11 males (55%) and 9 females (45%). Median follow up for the entire group was approximately 2.6 years ( range 0.8 to 8.3 ) from initiation of therapy. The most common primary tumor site was the Bladder / Prostate 9 patients (45 %), paratesticular in 4 (20%), retroperotineum in 2 (10%), uterus in 3 (15%) , cervix in 1 (5%) and vagina in 1 (5%). All patients presented with IRS group III disease. 16 patients were treated according to SIOP MMT protocol, while the remaining 4 patients were treated according to IRSG protocol IV. At the end of our study, 15 patients (75%) showed no evidence of disease. 4 cases showed recurrence (22%). Grade 3/4 toxicities were 20% diarrhea and 19% febrile neutropenia .2 cases died, one case died due to severe febrile neutropenia, the other died from advanced disease. Conclusions: Our results in a limited resource country, is close to published data, when multimodal treatment was applied.
Abstract A08: TGFβb inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma
Authors: Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Swain M. Hayley, Julia Love, Joe Conner, Louis Boon, Timothy P. Cripe
Journal: Cancer Research (2018)

Abstract Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an antitumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the TGFβR1 inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy/survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved antitumor T-cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4+ or CD8+ cells. These data suggest that TGFβ inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy. Citation Format: Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Swain M. Hayley, Julia Love, Joe Conner, Louis Boon, Timothy P. Cripe. TGFβb inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A08.
AB0534 Proportion of sjogren’s syndrome patients referred to oral specialists at a rheumatology tertiary centre and factors associated with their referral
Authors: G. Levinson, U. Ahmed, C. Ciurtin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ideally all patients with Sjögren's Syndrome (SS) and symptoms of mouth dryness should be assessed by an oral specialist (OS) team at 3–6 monthly intervals for optimisation of their treatment for xerostomia and minimisation of the risk of dental loss<sup>1</sup>. However, in reality specialist input is not always offered. <h3>Objectives</h3> To determine the proportion of SS patients at a rheumatology tertiary centre who were referred to OS and evaluate if any factors were associated with referral. <h3>Methods</h3> We retrospectively collected data about 105 patients with primary or secondary SS who attended outpatient clinics in October – November 2016, including duration of symptoms and years since diagnosis, presence of SS associated symptoms, medications trialled to date, and serological, imaging and histological patient features. We have also assessed proportion of patients referred to OS, as well as the medication recommended by the OS. p&lt;0.05 was considered significant. <h3>Results</h3> In our cohort, 58.1% of SS patients were referred to an OS. We compared patient demographics and various disease features (table 1) in SS patients who were referred to OS and those who were not. The parameters that correlated with the referral to OS were oral dryness (VAS&gt;5/10) (p=0.0012<b>)</b> and the use of saliva substitutes (p=0.034). The most common OS treatment recommendations were for use of Duraphat 5000 ppm (50.8%), Salivix pastilles (44.3%), mouth wash (41%) and Glandosane (36%), apart from frequent sips of water recommended in all patients. <h3>Conclusions</h3> 58.1% of SS patients at a tertiary rheumatology centre were referred to OS. The factors that correlated with onward referral to the OS from the Rheumatologist in SS patients were oral dryness and treatment with saliva substitutes. This suggests that Rheumatologists adequately treat xerostomia and refer to OS appropriately when patients remain symptomatic. Further research is needed to assess whether there is a difference in outcome for patients referred to an OS versus those who are not. <h3>Reference</h3> [1] Price E, Rauz S, Tappuni A, Sutcliffe N, Hackett K, Barone F, et al. The British Society for Rheumatology guideline for the management of adults with primary Sjögren's Syndrome. Rheumatology2017;56(10):1828–1828. <h3>Disclosure of Interest</h3> None declared
A randomized phase III clinical trial of sequential capecitabine or 5-FU plus bevacizumab (Cape/5-FU+Bmab) followed by Cape/5-FU plus oxaliplatin plus Bmab (CapeOX/mFOLFOX6+Bmab) versus combination CapeOX/mFOLFOX6+Bmab in advanced colorectal cancer: The C-cubed (C<sup>3</sup>) study.
Authors: Hitoshi Ojima, Hideyuki Mishima, Akira Sawaki, Takeshi Nagasaka, Mototsugu Shimokawa, Michio Inukai, Katsunori Shinozaki, Hiroaki Tanioka, Junichiro Nasu, Tomohiro Nishina, Shoichi Hazama, Masazumi Okajima, Akihito Tsuji, Yasushi Tsuji, Yoshinori Munemoto, Shigeki Yamaguchi, Yoshiyuki Yamaguchi
Journal: Journal of Clinical Oncology (2018)

TPS872 Background: Less intensive regimens, focusing on survival and disease control, may be better first-line treatments in unresectable metastatic colorectal cancer (mCRC). Several randomized trials suggested that sequential cytotoxic agents in mCRC may improve overall survival compared with combination chemotherapy. This study investigated whether sequential treatment with Bmab-based first-line therapy with oxaliplatin has superior efficacy to combination treatment for unresectable mCRC. Methods: This study is a two-arm, multicenter, open-label, randomized phase III trial in Japan, comparing the efficacy and safety of sequential Cape/5-FU+Bmab with escalation to CapeOX/mFOLFOX6+Bmab versus combination CapeOX/mFOLFOX6+Bmab as the first-line treatment of mCRC. The primary endpoint is Time to failure of strategy (TFS). In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU+Bmab to CapeOX/mFOLFOX6+Bmab is recommended for progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6+Bmab to Cape/5-FU+Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6+Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin, not caused by oxaliplatin-associated toxicity, after 12 weeks of treatment. A target sample size of 304 evaluable patients is considered sufficient to detect a hazard ratio of 0.69 for the TFS of the sequential ‘wait-and-go’ approach compared with the combination ‘stop-and go’ approach with 80% power and a 2-sided significance level of 5%. From December 2014 to September 2016, 311 patients were enrolled across 81 centers in Japan. The follow-up period is until March 2018, and results are expected in 2019, and results are expected in 2019. Clinical trial information: 000015405.
Influence of mRNA expression of epiregulin (EREG) and of amphiregulin (AREG) and RAS mutationson outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).
Authors: Arndt Stahler, Volker Heinemann, Clemens Albrecht Giessen, Alexander Crispin, Alexander Schalhorn, Sebastian Stintzing, Ludwig Fischer von Weikersthal, Ursula Vehling-Kaiser, Martina Stauch, Detlef Qietzsch, Jens Neumann, Thomas Kirchner, Andreas Jung, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2014)

3522 Background: Our aim was to investigate the impact of EREG/AREG expression and RAS (KRAS/NRAS) mutations in patients with metastatic colorectal cancer (mCRC) receiving systemic treatment without monoclonal antibodies. Methods: In total, 208 (of 479) patients with mCRC of a randomized trial receiving 5-FU/LV plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) as first-line treatment were included in this analysis. Median progression-free-survival (PFS) and overall survival (OS) of the subset were well comparable to the whole study population. RAS mutation detection was performed by pyrosequencing of exons 2-4 of the KRAS- and NRAS- gene (codons 12, 13, 61 and 146). mRNA expression was quantified by RT-qPCR. To discriminate high and low expression, a ROC analysis resulted in a cut-off value using the maxima of sensitivity and specificity for overall response rate. RAS mutation and mRNA expression of AREG and EREG were correlated with response, PFS and OS. Results: In 107 of 208 patients (51.4%) a RAS mutation could be detected. mRNA expression was analysed in 192 patients, concerning AREG (low: 161 vs high: 31) and EREG (low: 103 vs high: 89). RAS wild-type tumors were not associated with better PFS (8.7 vs 8.2 months, HR: 0.93, p=0.62) and OS (21.9 vs 18.6 months, HR: 0.88, p=0.41). High compared to low AREG expression did not influence outcome concerning PFS (10.0 vs 8.2 months, HR: 0.68, p=0.07) and OS (24.6 vs 18.7 months, HR: 0.72, p=0.11). High compared to low EREG expression correlated with prolonged PFS (9.7 vs 7.0 months, HR: 0.58, p<0.01) and OS (25.8 vs 15.5 months, HR: 0.48, p<0.01). The favourable prognostic effect of high EREG expression was evident independently of RAS mutation (OS: HR wild-type: 0.50, HR mutated: 0.44; p<0.01), and treatment (OS: HR FUFIRI-arm: 0.42, HR mIROX-arm: 0.53; p<0.01). Conclusions: EREG expression appears as powerful prognostic marker in patients with mCRC receiving systemic therapy without monoclonal antibodies. Neither RAS mutations nor AREG expression showed a significant correlation with outcome in the FIRE1-trial.
A Bayesian multiple-treatments meta-analysis of neoadjuvant treatments for locally advanced, resectable esophageal cancer.
Authors: Kelvin K. Chan, Keemo Delos Santos, Keya Shah, Gemma Cramarossa, Rebecca Wong
Journal: Journal of Clinical Oncology (2014)

4074 Background: While many studies have compared the different neoadjuvant treatments in patients with locally advanced, resectable esophageal cancer, the relative benefit and risk across these treatments remain unclear. Methods: A systematic review was conducted using MEDLINE, EMBASE and Cochrane Central of Registered Trials to identify randomized controlled trials (RCTs) up to June 2013 investigating the following regimens in esophageal cancer patients: resection alone, neoadjuvant chemotherapy (N-CT), neoadjuvant radiotherapy (N-RT) and neoadjuvant chemoradiotherapy (N-CRT). Two reviewers independently reviewed the studies and discrepancies were resolved either by discussion or by a third reviewer. Data including characteristics of studies and outcomes such as overall survival (OS), postoperative mortality, site of recurrence and quality of the studies were extracted. Parmar method was used to extract survival outcomes. A Bayesian multiple treatments meta-analysis (MTM) with random effect was constructed using WinBUGS to compare the relative efficacy and postoperative mortality of all neoadjuvant treatments simultaneously. Results: Thirty-three RCTs involving 6710 patients were identified. For the comparison between N-CRT vs. N-CT, 2 RCTs involving 194 patients were identified. Direct pairwise meta-analysis showed that there is a trend that N-CRT might result in better OS when compared to N-CT but not reaching statistical significance (HR: 0.83 95% CI (0.59-1.18)). When combining both direct and indirect evidence in MTM to improve precision, N-CRT was found to be statistically superior to N-CT for OS (HR: 0.84 95% credible regions (CR) (0.71-0.97)). In addition, there was no direct RCT comparing N-CRT to N-RT identified. The results of MTM showed that N-CRT was better than N-RT for OS (HR: 0.80 95% CR (0.67 – 0.97)). Probabilistically, N-CRT has a 98% chance of being the best treatment. There were no significant differences in the risk for postoperative mortality. Conclusions: This study provides additional evidence that N-CRT is the optimal neoadjuvant therapy with respect to OS without increasing postoperative mortality when compared with N-CT or N-RT.