bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcome of preoperative docetaxel with cisplatin plus S-1 therapy for advanced gastric cancer with extensive nodal metastasis (JCOG1002).
Authors: Morita Shinji , Ito Seiji , Sano Takeshi , Takahari Daisuke , Katayama Hiroshi , Mizusawa Junki , Sasako Mitsuru , Tanaka Yoichi , Kinoshita Takahiro , Terashima Masanori , Nashimoto Atsushi , Yamaue Hiroki , Fukushima Norimasa , Yamada Makoto , Fujiwara Yoshiyuki , Kimura Yutaka , Ikeda Atsuki , Yoshimura Tsunehiro 
Published: January 2019

141 Background: Neoadjuvant chemotherapy (NAC) with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis based on the results of JCOG0405. In JCOG1002, we added docetaxel to CS (DCS) to further improve the long-term outcome. However the primary endpoint, clinical response rate (RR), did not meet the expected level (Ito S, Gastric Cancer. 2017). Herein we report the long-term survival. Methods: Patients with BN and/or PAN metastasis received two or three cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1, S-1 at 40 mg/m2 twice daily for 2 weeks, were administered every four weeks) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year. Results: Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% of patients had both PAN and BN metastasis, and remaining patients had either PAN (26.4%) or BN (56.6%) metastasis. The clinical response rate (RR) was 57.7 % as assessed by RECIST v1.0, and the R0 resection rate was 84.6%, which did not exceed those in JCOG0405 (64.7% and 82.3%, respectively). The pathological RR defined as residual tumor corresponding to less than one-third the size of the original tumor was 34.6% in 52 eligible patients, which was slightly higher than in JCOG0405 (28.6%). Among all eligible patients, 5-year overall survival was 54.9% (95% confidence interval 40.3–67.3%) at the date cut-off of May 2018. Among 44 eligible patients with R0 resection, 5-year progression-free survival was 47.7% (95% confidence interval 32.5–61.5%). These were similar to the results of JCOG0405 (52.8% and 50.0%). Twenty patients developed cancer recurrence. The most frequent site of recurrence was lymph nodes (50.0% of all recurrences). Conclusions: Adding docetaxel to CS in NAC for extensive lymph node metastasis did not improve not only short-term outcomes but also long-term survival. NAC with CS followed by D2 + PAN dissection and postoperative S-1 remains standard for patients with extensive nodal metastasis. Clinical trial information: UMIN000006069.
Prognostic and predictive factors after failure of two drug lines for metastatic gastric adenocarcinomas: A French retrospective study.
Authors: Boussac Benjamin , Evesque Ludovic , Gal Jocelyn , Schiappa Renaud , Doyen Jerome , Benizri Emmanuel , Saint Angelique , Cavaglione Gerard , Francois Eric 
Published: January 2019

149 Background: There is no therapeutic consensus after failure of two drug lines for metastatic gastric adenocarcinoma. The theoretical benefit of a third-line chemotherapy has to be weighed with the potential toxicity it could generate. It is essential to have prognostic and predictive factors to better select the candidate patients for a 3rd line chemotherapy. Methods: The medical records of patients (pts) treated in our institute from 2008 to 2018 who received at least two chemotherapy lines have been retrospectively analyzed. The main objective was to look for prognostic factors after failure of two chemotherapy lines. The secondary objectives were to look for predictive factors of progression-free survival, global survival, and RECIST response in 3rd line. Results: Out of a total of 153 pts identified, 68 received at least 2 chemotherapy lines and were eligible for analysis (44%). A third line was initiated for 41 pts (27%). Overall survival from the date of failure of a 2nd line treatment was 4.4 months (95% CI: 3.2-6.2). The median of progression-free survival in 3rd line was 1.68 months (CI 95%: 1.5-3.5 months), 5% of the patients responded to the treatment. In multivariate analysis, a period of less than 12 months between the administration of the 1st line of chemotherapy and the failure of a 2nd line was associated with a Hazard Ratio (HR) for death of 2.7 (p < 0.001; 95% CI 1.44 – 5.1). Pts who did not receive a 3rd line and female patients had a HR for death of 3.7 (p < 0.001; CI 95%: 1,9–7.3), and 2.8 (p < 0.001; 95% CI: 1,3–5.8) respectively. For patients who started a 3rd line: a PS ≥ 2 increased the risk of progression by 4.05 (p < 0.001; 95% CI: 1.1–15.7). Conclusions: Nearly one-third of pts were able to receive a third line chemotherapy. However, the benefit of this chemotherapy is low given the RECIST response rate, and the short overall and progression-free survival medians. Our results suggest that the administration of a third-line chemotherapy should only be considered for pts with 12 months or older ongoing metastatic lesions and whose general health condition is unaltered.
The effect of IMRT on acute toxicity in patients with gastric cancer treated with preoperative chemoradiation.
Authors: Moningi Shalini , Ajani Jaffer A. , Badgwell Brian D. , Mansfield Paul F. , Blum Murphy Mariela A. , Ikoma Naruhiko , Ho Jennifer , Suh Yelin , Holliday Emma Brey , Herman Joseph M. , Minsky Bruce D. , Koay Eugene Jon , Koong Albert , Krishnan Sunil , Smith Grace L. , Taniguchi Cullen M. , Das Prajnan 
Published: January 2019

153 Background: Two trials are currently investigating preoperative chemoradiation (CRT) for localized gastric adenocarcinoma. However, radiation therapy (RT) can be associated with relatively high rates of acute toxicity. Newer techniques, such as intensity modulated RT (IMRT), could reduce toxicity by reducing radiation dose to normal structures. Our goal was to compare rates of toxicity and toxicity-related events in patients treated with IMRT compared to 3D conformal RT (3DCRT). Methods: The records of 202 gastric cancer patients treated with preoperative intent RT at our institution from 1998-2018 were retrospectively reviewed. Demographic data, treatment details, acute and late toxicities (CTCAE 4.0 criteria), progression and survival data were recorded. Patients who had stage IV disease were excluded. Statistical analysis included descriptive statistics, Cox regression analysis, and Kaplan-Meier survival. Results: 54% were male and the median age was 63. 82 patients received 3DCRT and 120 patients received IMRT (median 45Gy, IQR, 45-45Gy in each group). 78% of patients in the 3DCRT group and 91% of patients in the IMRT group received neoadjuvant chemotherapy prior to RT. 99% of patients received concurrent chemotherapy. The rate of grade 3-4 acute toxicity was significantly lower in patients treated with IMRT compared to 3DCRT (53% vs. 73%, p = 0.004). The composite rate of toxicity-related events (hospitalization, feeding tube, IV rehydration, or RT break) was also significantly lower in patients treated with IMRT compared to 3DCRT (80% vs. 91%, p = 0.031). 72% of patients who received 3DCRT and 68% of patients who received IMRT underwent subsequent surgical resection. The 3-year OS rate was 58.1% for patients receiving IMRT and 60.2% for patients receiving 3DCRT (p = 0.649). The 3-year PFS rate was 47.5% for patients receiving IMRT and 52.7% for patients receiving 3DCRT (p = 0.486). Conclusions: Our study indicates a marked reduction in the rates of grade 3-4 acute toxicity and toxicity-associated events in patients treated with IMRT compared to 3DCRT. These findings suggest that IMRT should be considered as the radiation modality in patients treated with preoperative CRT for gastric cancer.
Characteristics of long-term survivors in stage III gastric cancer patients.
Authors: Jang Youjin , Mok Youngjae 
Published: January 2019

163 Background: Stage III gastric cancer patients had poor prognosis. This study aims to evaluate prognostic factor of stage III gastric cancer. Methods: We retrospectively studied 126 patients who were treated for stage III gastric cancer from Jan. 2007 to Dec. 2010 at Korea University Hospital and performed complete follow up for five years. Long-term survivor was defined more than five years survivor after gastrectomy. Results: Long-term survivor was 70 patients (55.6%). Tumor size, lymph node involvement, lymphatic invasion, venous invasion and neural invasion had prognostic significance on univariate analysis. But location of tumor, gross type, depth of invasion, TNM stage, combine resection, complication, histologic differentiation, type of operation and adjuvant treatment had no prognostic significance. The most common recurrence pattern was peritoneal recurrence (57.4%) according to analysis of recurrence pattern. The disease free survival according recurrence pattern was peritoneal recurrence (21.3 months), hematogenous recurrence (32.1 months), distant lymph node recurrence (12.0 months) and locoregional (12 months). The disease specific survival according recurrence pattern was peritoneal recurrence (9.2 months), hematogenous recurrence (11.3 months), distant lymph node recurrence (16.2 months) and locoregional (26.9 months). Conclusions: Lymph node involvement were the most significant prognostic factors on stage III gastric cancer after curative resection. Therefore, postoperative surveillance and adjuvant therapy were very carefully selected in stage III gastric cancer patient with extensive lymph node metastasis.
Tumor regression grade in gastric cancer after preoperative therapy.
Authors: Ikoma Naruhiko , Estrella Jeannelyn , Das Prajnan , Minsky Bruce D. , Fournier Keith F. , Mansfield Paul F. , Blum Mariela A. , Ajani Jaffer A. , Badgwell Brian D. 
Published: January 2019

168 Background: The AJCC 8th edition updated ypStage TNM grouping for patients with gastric cancer due to the increasing use of preoperative therapy. We previously reported that nodal status after preoperative therapy (ypN) was most predictive for overall survival (OS). We intended to investigate if tumor regression grade (TRG) of the primary tumor scored by pathologists is helpful to predict survival of gastric cancer patients treated with preoperative therapy. Methods: We reviewed an institutional database to identify patients with clinically non-metastatic gastric adenocarcinoma who underwent gastrectomy after preoperative chemo- or chemoradiation therapy. Pathology reports were reviewed, and TRG was classified into following categories: 0 (complete response), 1 (few clusters of viable tumor cells, £1-2%), 2 (significant response, viable cells £ 50%), 3 (minor or no treatment response, viable cells > 50%). Associations between TRG and clinicopathological factors were examined. Univariable and multivariable Cox regressions were performed to determine associations with OS. Results: We identified 356 patients who met study criteria, including 80 (23%) patients with GEJ tumors; 56% were white and 60% were male. Preoperative chemoradiation therapy was given to 268 (75%). Fifty-six (16%) had TRG 0, 57 (16%) had TRG 1, 128 (36%) had TRG 2, and 115 (32%) had TRG 3. There were no associations between TRG and pretreatment factors. TRG 2 or 3 was associated with advanced ypT and ypN categories (both p < 0.001), ypM1 (p = 0.004), and R1 resection (0.052). Of all patients, median OS was 6.6 y, and 5-year OS was 54.1%. TRG 3 was associated with worse OS than other groups ( p = 0.015), while there was no significant OS difference among TRG 0-2 groups ( p = 0.803) in univariate analyses. On multivariable analysis, TRG was not associated with OS after adjustment for ypN status. Conclusions: In patients with gastric cancer who underwent preoperative therapy, TRG 3 was associated with advanced ypStage and R1 resection. Patients with TRG 3 had worse OS, due to associated advanced ypStage, particularly ypN+ status. Further studies are warranted to identify better definitions of treatment response and to identify the optimal modality for obtaining ypN0 status.
Integrative molecular profiling and response to chemotherapy on the COMPASS trial.
Authors: O'Kane Grainne M. , Fischer Sandra , Denroche Rob , Jang Gun Ho , Zhang Amy , Dodd Anna , Grant Robert C , Grunwald Barbara , Masoomian Mehdi M , Moura Shari , Elimova Elena , Prince Rebecca M. , Zogopoulos George , Notta Faiyaz , Wilson Julie , Gallinger Steven , Knox Jennifer J. 
Published: January 2019

188 Background: Predictive mutational and transcriptional features in advanced PDAC are needed for improved patient stratification and treatment selection. Methods: Patients (pts) on the COMPASS trial with advanced PDAC are prospectively recruited prior to first-line chemotherapy for WGS and RNAseq. Tumor tissue undergoes enrichment by laser capture microdissection with genomic analyses available within eight wks. Tumor responses and clinical outcomes in this maturing cohort were correlated with molecular characteristics. Results: 157 pts underwent a tumor biopsy between Dec 2015 and Jul 2018 with over 95% success in achieving results. 141 genomes have been reported in pts planned to receive chemotherapy; the median time from biopsy to report was 35.5 days. In the ITT population,118 pts are summarised for first-line response. The median age was 63 yrs (29-81), 55% were male, and 16% had locally advanced disease. 66 (56%) received modified FFX as first-line treatment. 25 (21%) tumors displayed the Moffitt basal-like RNA signature which associated with chemotherapy resistance, with tumor shrinkage mainly observed in the classical RNA subtype (p = 0.002). GATA6 expression (log10 scale) clearly separated Moffitt subgroups with classical tumors exhibiting high expression (p < 0.0001). GATA6 in situ hybridization strongly correlated with RNAseq, (r = 0.89, p < 0.001) with strong correlation also seen with GATA6 IHC. The median overall survival (OS) in the classical group was 8.5 mths vs. 6.6 mths in the basal-like group (HR 0.53, 95% CI 0.32-0.89 p = 0.015). In those treated with mFFX, median OS was 10.1mths in classical versus 6.6mths in the basal-like subtypes, (HR 0.32, 95% CI 0.16-0.63, p=0.001). 30% of pts had potentially actionable genetic alterations including BRAF variants (n = 4) and an NTRK3-EML4 fusion in KRAS WT tumors (8%). Signatures of homologous recombination deficiency (HRD) were found in seven pts; two additional pts with BRCA germline variants did not exhibit somatic HRD hallmarks. Conclusions: Subsets of pts with advanced PDAC have actionable variants including those with HRD signatures and patients with KRAS WT tumors. GATA6 is a putative predictive biomarker of transcriptomic subgroups which should be incorporated in clinical trials. Clinical trial information: NCT02750657.
Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05).
Authors: Unno Michiaki , Motoi Fuyuhiko , Matsuyama Yutaka , Satoi Sohei , Matsumoto Ippei , Aosasa Suefumi , Shirakawa Hirofumi , Wada Keita , Fujii Tsutomu , Yoshitomi Hideyuki , Takahashi Shinichiro , Sho Masayuki , Ueno Hideki , Kosuge Tomoo 
Published: January 2019

189 Background: Despite improvements of postoperative adjuvant therapy for resected pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor. A randomized controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S1 (NAC-GS) with upfront surgery (Up-S) for patients with PDAC planned resection. Methods: Patients were enrolled after the diagnosis of resectable PDAC with histological confirmation. They were randomly assigned as either NAC-GS or Up-S. In NAC-GS, gemcitabine was provided at a dose of 1 g/m2 on day 1 and 8 and oral S-1 was administered at a dose of 40 mg/m2 twice daily on 1-14 days. Patients received 2 cycles of this regimen. S-1 adjuvant for 6 months was administered for the patients with curative resection and fully recovered within 10 weeks after surgery in both arms. The primary endpoint for the phase III part was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. The target sample size required 163 patients (α-error 0.05; power 0.8) in each arm. The trial was conducted by the Health Labor Sciences Research Grant (H22-009) of Japan and registered with the UMIN Clinical Trials Registry as UMIN000009634. Results: From January 2013 to January 2016, 364 patients were enrolled in 57 centers (182 to NAC-GS and 182 to Up-S). Of these, two were excluded because of ineligibility, therefore 182 patients in NAC-GS and 180 in Up-S constituted the ITT analysis-set. The median OS was 36.7 months in NAC-GS and 26.6 months in Up-S; HR 0.72 (95% confidential interval 0.55-0.94; p=0.015 [stratified log-rank test]). Grade 3 or 4 adverse events frequently (72.8%) observed in NAC-GS were leukopenia or neutropenia. However, the resection rate, R0 resection rate, and morbidity of the operation were equivalent in the two groups. There was no perioperative mortality in either group. Conclusions: This phase III study demonstrated the significant survival benefits of NAC-GS treatment. Therefore, the results indicated that neoadjuvant chemotherapy could be a new standard for patients with resectable PDAC. Clinical trial information: UMIN000009634.
Pembrolizumab treatment of advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study.
Authors: Strosberg Jonathan R. , Mizuno Nobumasa , Doi Toshihiko , Grande Enrique , Delord Jean-Pierre , Shapira-Frommer Ronnie , Bergsland Emily K. , Shah Manisha H. , Fakih Marwan , Takahashi Shunji , Piha-Paul Sarina Anne , O'Neil Bert , Thomas Sajeve , Lolkema Martijn P. , Wang Jiang Dian , Ibrahim Nageatte , Pruitt Scott K. , Hadoux Julien 
Published: January 2019

190 Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in a subset of patients (pts) with heavily pretreated neuroendocrine tumors (NET). The KEYNOTE-158 study (NCT02628067) is a phase II basket study investigating the antitumor activity of pembro in 10 specific cancer types. An analysis of the 107 pts included in the NET cohort is presented. Methods: Key eligibility criteria for this cohort included well- and moderately-differentiated NET of the lung, appendix, small intestine, colon, rectum, or pancreas; progression on or intolerance to ≥ 1 line of standard therapy; ECOG PS 0 or 1; and provision of a tumor sample for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 wks for the first 12 mo, and every 12 wks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥ 1, was evaluated retrospectively by IHC. Primary endpoint was ORR assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included DOR, PFS, OS, and safety. Results: 107 pts were treated. Median age was 59 (range, 29-80) y, 44.9% had ECOG PS 1, and 67.3% received ≥ 2 prior therapies for advanced disease. 15.9% of enrolled pts had PD-L1+ tumors. As of the January 15, 2018 data cutoff, the median follow-up duration was 18.6 (range, 0.2-22.7) mo. ORR was 3.7% (95% CI, 1.0-9.3), with 0 CR and 4 PR (3 pancreatic and 1 gastrointestinal [unknown primary]). 61 pts had SD as best response. The 4 responses were observed in pts with PD-L1 negative tumors. Median DOR had not been reached (range, 4.1-15.9+), with 3 of 4 responses ongoing after ≥ 9 mo follow-up. Median (95% CI) PFS was 4.1 (3.5-5.4) mo, and the 6-mo PFS rate was 38.2%. Median OS (95% CI) had not been reached (18.8-not reached), and the 6-mo OS rate was 84.6%. Treatment-related AEs occurred in 75.7% of pts, and the most common was fatigue (21.5%). 20.6% of pts had treatment-related grade 3-4 AEs. Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in pts with previously treated advanced NET. Clinical trial information: NCT02628067.
The clinical implication of CD45RA+ naive T cells and CD45RO+ memory T cells in advanced pancreatic cancer: A proxy for tumor biology and outcome prediction.
Authors: Hang Junjie , Wu Lixia , Xu Kequn 
Published: January 2019

196 Background: Naive and memory T cells play a pivotal role in solid tumor pathogenesis but their role in pancreatic cancer progression remains elusive. Thus, we aimed to investigate their clinical potential in advanced pancreatic cancer (APC). Methods: Flow cytometry was performed to evaluate the level of peripheral naive and memory T cells from APC patients. Interrelationships between naive, memory T cells and clinicopathological variables were evaluated using pearson’s correlation. The prognostic impact of naive and memory T cells were assessed by Kaplan-Meier analysis and Cox regression. The correlation between naive/memory T cells and tumor progression was investigated by Student’s t test. Results: CD4+ naive/memory ratio showed close correlations with hemoglobin, red blood cell (RBC), absolute neutrophil count (ANC) and platelet while CD8+ naive/memory ratio was correlated with hemoglobin, RBC and CEA. Higher baseline lever of CD4+CD45RO+/CD4+ was correlated with better overall survival (OS) (P = 0.036). Patients with CD4+ naive/memory ratio ≥ 0.36 had a poorer OS than those with CD4+ naive/memory ratio < 0.36 (P = 0.021). In addition, CD4+ naive/memory ratio showed independent prognostic impact (HR 1.427, 95%CI 1.033-1.973, P = 0.031). Furthermore, poorer clinical response was correlated with higher level of CD8+ naive/memory ratio after the third cycle of chemotherapy (P = 0.01). Besides, patients with an low level of CD8+ naive/memory ratio had longer progression-free survival (PFS) (P = 0.028). Conclusions: We propose CD4+ naive/memory ratio as a novel prognostic biomarker for APC. In addition, CD8+ naive/memory ratio can be a candidate marker for predicting PFS and the change of its level may reflect the progression of APC.