bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS/NRAS/BRAF genotyping in patients with mestastatic colorectal cancer.
Authors: Rodriguez Salas Nuria , Miranda Jesus , Ostios Lorena , Muñoz Mario , Borobia Alberto , Gordo Gema , Tenorio Jair , Tong Hoi , García Morales Maria Teresa , Martinez Avila Jose Carlos 
Published: January 2019

718 Background: mCRC is the 2º cause of death in the world. Development of targeted therapies has increased the survival. The efficacy of these drugs (such Bevacizumab and monoclonal antibodies against EGFR) depends on the use of genetic biomarkers such as KRAS and NRAS. The BRAF status acts as prognostic factor. The objective of this study was to perform a mutational analysis of KRAS/NRAS/BRAF in a cohort of 326 Spanish patients, and correlate the findings with clinical factors. Methods: We analyzed KRAS by chip-array analysis (Infiniti System, USA), NRAS using pyrosequencing on a Pyromark Q96MD instrument (Qiagen, USA) and BRAF mutations (in 80 of these samples) by means of Infiniti System (AutoGenomics, USA). Results: KRAS mutations 129/326 patients had KRAS mutation (31.2% in codon 12 and 6.7% in codon 13). The median age was 68.9, 55% male, 66.4% had left-sided tumor, 83% histologically grade 2 tumor. The pattern of spread was liver (51.1%), lung (33.3%) and peritoneum (11.6%). There were 6 types of mutation in codon 12 (p.Gly12Asp, p.Gly12Cys, p.Gly12Val, p.Gly12Arg, p.Gly12Ser, p.Gly12Ala) and 1 type in codon 13 (p.Gly13Asp). We apply a logistic model (age&sex corrected) to location, and we found association between KRAS wild type and left location, OR 1.73 [CI:1.03-2.9] p = 0.035 NRAS mutations: 13 patients had NRAS mutation (3.98%), 8 male, 92% had left-sided, 46% liver metastasis and 53.9% lung metastasis. Type of NRAS mutation: 1.6% in exon 2 (1.2% in codon 12 and 0.4% in codon 13) and 1.8% in exon 3 (0.2% in codon 59 and 1.6% in codon 61). In exon 2 we found 2 types of changes, 1 in codon 12 (p.Gly12Asp) and 1 in codon 13 (p.Gly13Arg). In exon 3 we found 5 types of changes, 1 in codon 59 (p.Ala59Thr) and 4 in codon 61 (p.Gln61Glu; p.Gln61Leu; p.Gln61Arg; p.Gln61His). BRAF mutation: 9/80 patients harboured mutations, all of them at the residue V600E. Conclusions: In our cohort 39.5% had mutations in KRAS, 3.98% in NRAS and 11% in BRAF. KRAS mutation is associated to right-sided location.
KEYNOTE-059 cohort 1: Pembrolizumab (Pembro) monotherapy in previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer in patients (Pts) with PD-L1+ tumors—Asian subgroup analysis.
Authors: Muro Kei , Fuchs Charles S. , Jang Raymond Woo-Jun , Satoh Taroh , Machado Manuela , Sun Weijing , Jalal Shadia Ibrahim , Shah Manish A. , Metges Jean-Philippe , Garrido Marcelo , Golan Talia , Mandala Mario , Wainberg Zev A. , Catenacci Daniel V.T. , Bang Yung-Jue , Lin Jianxin , Lu Jia , Yoon Harry H. , Doi Toshihiko 
Published: January 2019

723 Background: The US FDA approved pembro for treating pts with 1) recurrent locally advanced or metastatic G/GEJ adenocarcinoma, whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score [CPS] ≥1), and 2) unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors that have progressed after prior therapy and who have no fitting options. We report Asian subgroup analyses from cohort 1 of KEYNOTE-059 (NCT02335411), a global, phase 2 study in advanced G/GEJ cancer. Methods: Eligible pts had measurable recurrent or metastatic G/GEJ adenocarcinoma whose disease has progressed on ≥2 prior chemotherapy regimens. Pts received pembro 200 mg Q3W up to 2 y. PD-L1+ tumors had a CPS ≥1. Primary end points were ORR (RECIST 1.1, by central review) and safety. Results: Cohort 1 enrolled 259 pts; 57% had PD-L1+ tumors. MSI status was evaluable in 174 tumor samples; of these, 7 were MSI-H. At data cutoff (4/21/2017), median (range) follow-up was 6 mo (1-25). Overall ORR was 12% (95% CI, 8-17) and median (range) DOR was 14 mo (2-19+). PFS6-mo rate was 15% and OS6-mo rate was 46%. In pts with PD-L1+ tumors, ORR was 16% (95% CI, 11-23) and median (range) DOR was 14 mo (3+-19+). In pts with PD-L1+ tumors, PFS6-mo rate was 20% and OS6-mo rate was 50%. In pts with MSI-H tumors, ORR was 57% (95% CI, 18-90) and median (range) DOR was not reached (5-14+ mo). In cohort 1, 41 pts were Asian and 218 pts were non-Asian. PD-L1+ tumors occurred in 42% of Asian pts and 60% of non-Asian pts. ORR was 12% (95% CI, 2-36) in Asian pts with PD-L1+ tumors and 17% (95% CI, 11-24) in non-Asian pts with PD-L1+ tumors. One of 7 pts with MSI-H tumors was Asian; this pt had CR. Grade 3-5 treatment-related AEs occurred in 17% and 18% of Asian and non-Asian pts, similar to the overall cohort. Conclusions: Pembro showed durable clinical benefit in previously treated pts with advanced G/GEJ cancer, especially those with PD-L1+ or MSI-H tumors. Safety and efficacy were similar in Asian and non-Asian pts. These findings highlight pembro as a standard treatment option in Asian and non-Asian pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.
Totally neoadjuvant chemoradiation therapy with mFOLFOX6 in locally advanced rectal cancer: A single-arm phase II study (FOTAC).
Authors: Deng Yanhong , Zhang Jianwei , Cai Yue , Hu Huabin , Xiao Jian 
Published: January 2019

732 Background: In our previous FOWARC study, in the group of preoperative systemic chemotherapy with mFOLFOX6 combined with radiation, the pCR rate was up to 27.5%. In another study, adding mFOLFOX6 after neoadjuvant chemo radiation in locally advanced rectal cancer improve the pCR rate to 38%. This phase II study aimed to explore whether totally neoadjuvant chemoradiation therapy with mFOLFOX6 could further improve the pCR rate in locally advanced rectal cancer. Methods: Patients with fixed cT3 or cT4 rectal cancer evaluated by pelvic MRI participated in this trial. All candidates were to receive long term radiation for 25 times and 50Gy before surgery. Four cycles of mFOLFOX6 would be performed every 2 weeks during radiotherapy, and another 4-6 cycles would be added after radiotherapy and before TME. Totally, the patients will receive 6-8 cycles of chemotherapy before surgery. The primary endpoint is the pathologic complete response rate (pCR).The secondary endpoint included 3-year disease free survival rate, 3-year local recurrence rate, and safety. Results: Between April 2016 and May 2017, 81 patients were enrolled and 79 participants had received TME. Two patients required watch and wait, because the tumor location is too low to perform sphincter-preserving operation. Of 79 patients completing chemoradiotherapy and adding chemotherapy before surgery, 32.9% (26/79) of patients achieving pCR, and 54.4% (43/79) of patients had tumor downstaging to ypstage 0-I. Among patients who received 8 cycles of chemotherapy before surgery and the interval was more than 10 weeks between radiotherapy and operation, the pCR was 45.2%. Conclusions: Totally neoadjuvant chemoradiotherapy greatly improve the pCR rate and tumor downstaging rate. Clinical trial information: NCT02887313.
A pilot feasibility study of definitive concurrent chemoradiation with pencil beam scanning proton beam in combination with 5-fluorouracil and mitomycin-c for carcinoma of the anal canal.
Authors: Wo Jennifer Yon-Li , Yeap Beow Y. , DeLaney Thomas F. , Ryan David P. , Parikh Aparna Raj , Clark Jeffrey W. , Allen Jill N. , Ben-Josef Edgar , Plastaras John Peter , Metz James M. , Drapek Lorraine C. , Hong Theodore S. 
Published: January 2019

733 Background: Definitive chemoradiation (CRT) with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) for anal cancer yields high rates of long term survival. However, CRT has significant acute and long term toxicity. Pencil beam scanning proton beam (PBS-PT) may potentially reduce this toxicity. This is a pilot study evaluating the feasibility of definitive concurrent CRT with PBS-PT with 5-FU/MMC for anal cancer. Methods: Pts were enrolled on an NCI sponsored, prospective, multi-institutional, pilot study (NCT 01858025). Key eligibility were ECOG 0-2, age 18+, invasive SCC of the anal canal, clinically staged T1-4, N0-3. Pts were treated per RTOG 0529 RT schema; for T1-2, N0: 50.4 Gy to primary CTV, 42 Gy to elective LNs; for T3+ or N+: 54 Gy to primary CTV, 50.4-54 Gy to involved LN, and 45 Gy to elective LNs. Pts received 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with 5-FU/MMC, determined if grade 3+ dermatologic toxicity is < 48% (grade 3+ dermatologic toxicity from RTOG 98-11). The secondary endpoint was rates of overall grade 3+ toxicities, clinical complete response (cCR) rate and patterns of local regional tumor recurrence. Results: Between February 2014 to April 2017, we enrolled 25 patients into our study, all of whom were analyzed. 23 pts (92%) completed treatment per protocol, 2 pts died on treatment due to underlying comorbidities. Median time to completion of treatment was 42 days (range 38-49). The Grade 3+ radiation dermatitis was 24% (Table 1). With a median follow-up of 17.6 months (range 7.7-42.0) among the 21 patients still alive, the 1 year local control, progression-free survival, and overall survival are 100%, 83% and 87%, respectively. Conclusions: In our prospective, pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. While felt to be unrelated to the study, the two Grade 5 adverse events on this small study highlights potentially treatment related risks of this effective yet toxic regimen. Clinical trial information: NCT01858025. [Table: see text]
The impact of research presented at annual gastrointestinal cancers symposium.
Authors: Sehdev Amikar , Dadi Neelakanta , Haggstrom David Andrew , Koniaris Leonidas George , O'Neil Bert H. 
Published: January 2019

757 Background: The Gastrointestinal (GI) Cancers Symposium provides a multidisciplinary forum to both present research and gain expertise in the management of GI cancers. We conducted a study to understand the research trends, publication rate and the overall impact of research presented. Methods: A bibliometric review of the conference proceedings of the Symposium from 2013-2015 was undertaken. Data collected on each abstract included author number, demographic information of the presenting author, presentation type, cancer type, research focus (multidisciplinary treatment; prevention, diagnosis and screening; translational research) and research design. A PubMed search was used to determine overall and specific publication data. Descriptive statistics were compiled. Chi-square was used to compare groups. Results: The number of abstracts presented has increased (584 in 2013, 652 in 2014 and 794 in 2015). Fraction of oral presentations by year were similar (2.0%, 2.1% and 1.8%). Median number of authors per abstract was 9 (range 1-20). The subject area in all three years was dominated by multidisciplinary treatment (mean 58.6%), followed by translational research (mean 25.5%) and lastly Prevention, Diagnosis and Screening (mean 15.8%). The most common study design was observational (mean 43.5%), followed by case series (mean 27%), clinical trial (mean 19.8%) and other (mean 9.2%). Overall, 51.5%, 46.9% and 40.4% of the abstracts presented in 2013, 2014 and 2015 were published. The median time to publication was 14.5 months (range 0-49 months). The majority of published abstracts were published in journals with impact factor (IF) < 5 (mean 66.5%) and a small percentage (mean 8.4%) of abstracts were published in high impact journals (IF > 10). Abstracts selected for oral presentation were associated with publication in a journal with high IF (p < 0.001). The presenting author was more commonly male (70%) and a medical oncologist (61.5%). Conclusions: Overall participation is increasing in the Symposium. Selection for oral presentation appeared to be a good marker for both publication and higher impact. Prevention, diagnosis, and screening studies were under-represented and clinical trials were also relatively uncommon.
The fine line between regional and metastatic pelvic lymph nodes in rectal cancer: Patterns of care among U.S. radiation oncologists.
Authors: Yahya Jehan , Herzig Daniel , Farrell Matthew , Degnin Catherine , Chen Yiyi , Holland John M. , Brown Simon , Jaboin Jerry Jeff , Tsikitis Vassiliki Liana , Lu Kim , Thomas Charles R. , Mitin Timur 
Published: January 2019

758 Background: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis – the stage we refer institutionally to as Stage 3.5 – is controversial. Asian investigators consider internal, external and common iliac lymph nodes (LNs) as regional disease and treat these patients (pts) with curative intent, which often includes LPLN dissection. Conversely, AJCC 7thedition classifies internal iliac LNs as regional, whereas both external and common iliac LNs as metastatic. NCCN guidelines recommend definitive trimodality therapy for Stage III rectal cancer, and palliative chemotherapy for Stage IV disease. Radiation oncologists (ROs) in the U.S. irradiate iliac LNs in the setting of other pelvic malignancies, but it is unknown how they approach newly diagnosed rectal cancer pts with LPLN involvement. Methods: We conducted an anonymous IRB-approved online survey of practicing U.S. ROs, probing their approach to management of rectal cancer pts with clinically involved LPLNs. Results: We received 220 responses. Among the responders, 85 are academically affiliated and the majority self-declared a specialization in treating GI malignancies, with 98 seeing more than 10 rectal cancer pts annually. Among respondents, 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders – 98.6% and 94.5% – treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). Conclusions: Our analysis reveals that the vast majority of surveyed U.S. ROs approach pts with involved LPLNs, both regional (internal iliac) and metastatic (i.e. common iliac) with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of pts with Stage 3.5 rectal cancer.
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with advanced solid tumors.
Authors: Fujiwara Yutaka , Koyama Takafumi , Helwig Christoph , Watanabe Morihiro , Doi Toshihiko 
Published: January 2019

762 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in Asian patients (pts) with advanced solid tumors. Methods: NCT02699515 is a phase 1, open-label, 3 + 3 dose-escalation study. Pts receive M7824 at 3, 10 or 20 mg/kg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics (PK), immunogenicity and best overall response per RECIST v1.1. Results: As of 28 February 2017, 14 heavily pretreated pts (85.7% received ≥3 prior therapies) received M7824 for a median duration of 5.9 weeks (range: 2-40 weeks). Grade (gr) ≥3 treatment-related adverse events occurred in 3 pts (21.4%): 1 pt (3 mg/kg) had gr 4 hyponatremia and gr 3 hypopituitarism; 1 pt (20 mg/kg) had gr 3 intracranial tumor hemorrhage (dose-limiting toxicity; treatment discontinued [TD]); 1 pt (20 mg/kg) had gr 3 increased blood creatine phosphokinase, hyponatremia and hypoacusis (TD). PK data showed a dose-linear increase in exposure. Signs of efficacy were seen across all dose levels: 2 pts (colorectal cancer [CRC] associated with Lynch syndrome [3 mg/kg] and ovarian cancer [20 mg/kg]) achieved a confirmed partial response (PR) and 3 pts (gastric/gastroesophageal junction cancer [3 mg/kg], gastric cancer [3 mg/kg] and adenoid cystic carcinoma of the tongue [10 mg/kg]) achieved stable disease. Durations of response were 1.1+ months (ovarian; PR occurred after TD, with no further anticancer therapy) and 7.0+ months (CRC; treatment ongoing); both PRs were ongoing beyond the data cutoff. Conclusions: M7824 had a manageable safety profile in Asian pts with heavily pretreated advanced solid tumors; the MTD was not reached. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.
Interplay of grade and stage on survival outcomes in appendiceal adenocarcinoma: Corroboration of the AJCC (8th edition) Cancer Staging Classification.
Authors: Raghav Kanwal Pratap Singh , Fournier Keith F. , Johnson Benny , Taggart Melissa W. , Foo Wai Chin , Matamoros Aurelio , Mehdizadeh Amir , Ahmed Shahab U. , Guerra Jennifer L. , Mansfield Paul F. , Royal Richard Eldon , Eng Cathy , Overman Michael J. 
Published: January 2019

773 Background: Histological grade is a key prognostic factor in appendiceal adenocarcinomas (AAs) and has been incorporated in classification of stage IV AAs (IVA – Grade 1: Well; IVB – Grade 2/3: Moderately/Poorly differentiated) in AJCC Cancer Staging (8th edition). The purpose of the study was to corroborate the prognostic impact of this staging classifier. Methods: We performed a retrospective review of 98 AA patients (pts) at UTMDACC (2013 - 2017). Kaplan-Meier method was used to estimate median overall survival (mOS), compared with log-rank tests with emphasis on stage and grade. Results: The cohort included 18, 8, 14, 47 and 11 cases of stage II, III, IVA, IVB and IVC AAs. Histologically, 75 were mucinous (21 non mucinous) and 19, 35 and 42 were grade 1, 2 and 3 respectively. Median age of cohort was 54 years. Median follow-up was 46 months (m). The mOS of stage II, III, IVA, IVB and IVC was 136, 106, 140, 48, 23 m, respectively (P < 0.0001). The mOS of grade 1, 2 and 3 was 160, 75 and 33 m, respectively (P < 0.0001). In univariate analysis (restricted to stage IV pts), grade, AJCC stage, and cytoreductive surgery (CRS) were found to be associated with OS. In multivariate analyses (restricted to stage IV pts), only AJCC stage (HR 3.9, 95% CI: 1.5 - 10.6, P = 0.005) and CRS (HR 3.4, 95% CI: 1.4 – 8.3, P = 0.009) were found to be independently associated with poor OS. In subgroup of mucinous AAs, mOS of grade 3 (32 m) was significantly shorter than grade 2 (54 m) (P = 0.02). In non-mucinous AAs, mOS of grade 3 and grade 2 pts was 38 and 29 m, respectively (P = 0.97). Conclusions: AJCC staging classification has a strong prognostic value in AAs. Beyond the well differentiated AAs which are regarded as a distinct entity in stage IV disease, moderate and poor differentiation also has strong and dissimilar prognostic impact which appears to be dependent on mucinous or non-mucinous subtype in stage IV AAs. Further efforts are needed to incorporate the complex interplay of all grades and mucinous characteristics within the staging system for better prognostication and management.
Association of adjuvant hepatic artery infusion chemotherapy after resection of colorectal liver metastases with improved survival in patients with both right- and left-sided primary tumors.
Authors: Gholami Sepideh , Kemeny Nancy E. , Gonen Mithat , Cercek Andrea , Kingham Peter , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian 
Published: January 2019

776 Background: Patients with a right-sided (R) and/or KRAS-mutated (KRAS-MUT) primary tumors have inferior outcomes compared to patients with left sided (L) and/or KRAS-wildtype (KRAS-WT) cancers. Adjuvant hepatic artery pump infusion (HAI) chemotherapy improves overall survival (OS) in patients with colorectal liver metastases (CRLM). We investigated the impact of HAI in relation to the laterality and KRAS status of the primary tumors. Methods: Patients with resected CRLM and available KRAS-status, treated with and without adjuvant HAI were reviewed from a prospective institutional database. Rectal tumors were excluded. Correlations between adjuvant HAI, clinicopathological factors including laterality, KRAS status and OS were analyzed. Cox proportional hazard regression was used to assess survival outcomes comparing R (cecum to transverse colon, excluding appendix) versus L (splenic flexure to sigmoid) colon cancers. Results: 490 patients (R, n = 183; L, n = 307) were evaluated between 1993-2012 (median follow up of 6.5 years). Fifty-six percent (n = 277) received adjuvant HAI. Adjuvant HAI was associated with improved median OS in both R (7.0 vs. 4.4 years, p = 0.006) and L tumors (10.5 vs. 5.4 years, p < 0.01). On multivariate analysis, HAI remained associated with improved OS (HR 4.49, p = 0.001) independent of primary tumor site and other clinical predictors (Table). Conclusions: Adjuvant HAI after resection of CRLM is independently associated with improved OS regardless of laterality of primary tumor. Treatment with adjuvant HAI correlates with improved prognosis in patients with resectable L/KRAS-MUT and R/KRAS-WT tumors. The biological difference for these outcomes requires further investigation. [Table: see text]
Up-front short-course radiotherapy and systemic chemotherapy for locally advanced rectal cancers with distant metastasis: Does it provide meaningful benefit?
Authors: Kapoor Akhil , Ostwal Vikas S. , Pande Nikhil , Ramaswamy Anant , Kothari Rushab , Engineer Reena , Desouja Ashwin , Arya Suprita , Ramadwar Mukta , Saklani Avanish 
Published: January 2019

778 Background: The optimal sequencing of treatment for locally advanced rectal cancer with distant metastasis (mLARC) is not well established. Methods: We retrospectively reviewed the records of mLARC patients receiving SCRT (25Gy/5#) and chemotherapy between July 2013 and December 2016. Patients were evaluated for surgery after SCRT and chemotherapy with the decision for further treatment being taken in a multidisciplinary team. Those patients who underwent surgery also received adjuvant chemotherapy as per the standard practice. Results: One hundred five consecutive mLARC patients were included in this study. Median age was 48 years (range 16-78) and 60 patients (57%) were male. Thirty-six patients (34%) had a single site of metastases. Sixty-one patients (58%) had obstruction at baseline and required stoma placement and another 19 patients (18%) had near obstructive lesions; these patients did not require stoma post SCRT and chemotherapy. With first line chemotherapy, objective response rate was 39% while 29% patients had stable disease. Twenty-four patients (23%) underwent definitive surgery. Median PFS and OS for entire cohort was 10.5 months (95% CI: 9.1-11.8) and 15.7 months (95% CI: 10.2-21.2), respectively. Median PFS was 23 months (95% CI: 18.7-27.7) for patients who could undergo surgery while it was 7.7 months (95% CI: 5.9-9.5, HR 5.0) (log rank <0.001) for patients in whom surgery was not possible. Median OS was not reached for patients who underwent surgery while it was 10.9 months (95% CI: 9.6-12.3, HR 9.8) (log rank p<0.001) for patients in whom surgery was not possible. OS at 3 years was 60% for patients who underwent surgery while it was only 7% in whom surgery was not possible. Conclusions: Upfront SCRT followed by systemic chemotherapy with delayed surgery in locally advanced rectal cancer with distant metastasis is an effective, feasible and attractive option. [Table: see text]