bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal malignancy patients.
Authors: Kamiya Mariko , Aoyama Toru , Sugano Nobuhiro , Sato Tsutomu , Yamamoto Naoto , Taguri Masataka , Yamanaka Takeharu , Oshima Takashi , Yukawa Norio , Rino Yasushi , Masuda Munetaka 
Published: March 2017

115 Background: Delirium is one of the common postoperative complications. When postoperative delirium occurred, the patient management becomes much more difficult, leading to functional recovery delay, and is also associated with postoperative mortality and morbidity. Although many attempts to prevent and treat delirium have been developed, a higher level of evidence is needed. In the present study, we evaluated the efficacy and safety of TJ-54 (Yokukansan; one of the traditional Japanese medicines, Kampo) for the prevention and/or treatment of postoperative delirium in a randomized phase III trial for the patients receiving surgery for gastrointestinal malignancy. Methods: Patients 70 years of age or older, who were received surgery for gastrointestinal malignancy were eligible in this study. The 167 eligible patients were randomly assigned on a 1:1 ratio to receive TJ-54 or control during their perioperative care (between day 7 before surgery and day 4 after surgery). The signs and symptoms of delirium were assessed with using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV by the investigator during perioperative period. Results: We analyzed 167 eligible gastrointestinal malignancy patients (TJ-54; 83, control; 84). There were no disparities between the two PPS randomized groups. The incidence of delirium was 7.2% (6 patients) in the TJ-54 group and 10.7% (9 patients) in the control group with no significant difference (p=0.431), also no significant difference was observed in duration of delirium between the two groups (p=0.477). The ratio of patients who needed some kind of the medication which including treatment of delirium were significantly less in the TJ-54 group than in the control group (p=0.037). Conclusions: In this study, TJ-54 did not demonstrate the contribution to prevention of occurring delirium in the patients receiving surgery for gastrointestinal malignancy. However, TJ-54 might be effective in reducing the medication for treating delirium after surgery for gastrointestinal malignancy. Clinical trial information: 000005423.
Recurrence patterns of gastric cancer in the era of preoperative therapy.
Authors: Ikoma Naruhiko , Chen Hsiang-Chun , Wang Xuemei , Blum Murphy Mariela A. , Estrella Jeannelyn , Fournier Keith F. , Mansfield Paul F. , Ajani Jaffer A. , Badgwell Brian D. 
Published: March 2017

119 Background: The purpose of this study was to determine the disease sites and survival durations of patients who developed a recurrence after undergoing gastrectomy for adenocarcinoma. Methods: We collected data from a prospectively maintained database of gastric cancer patients who underwent potentially curative resection of gastric or gastroesophageal cancer at our institution from 1995-2014. Univariate and multivariate analyses were performed to determine the associations between clinicopathologic factors and treatment outcomes. Results: We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (IQR, 53-71 years), and 60% were male. The most common EUS stages were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. The majority (76%) of patients underwent extended (D1+/D2) lymphadenectomy, and the median number of examined lymph nodes was 21 (IQR, 14-29). Of the 488 patients, 125 (26%) experienced recurrence during follow up. The sites of recurrence were locoregional (n = 19 [15%]), peritoneal (n = 61 [49%]), and non-peritoneal distant at any site (n = 67 [53.6%]). The site of recurrence was not associated with neoadjuvant therapy (p = 0.35). The median time from the primary resection to recurrence was 2.7 years (95% CI, 0.8-3.2 years) for locoregional, 1.3 (0.7-1.7) for peritoneum, and 0.6 (0.5-0.9) for distant disease (p = 0.01). The median overall survival time from recurrence was 1.0 year (95% CI, 0.5-3.1 years) for locoregional, 0.6 (0.4-0.9) for peritoneum, and 0.8 (0.5-1.0) for distant recurrence (p = 0.05). A multivariate analysis revealed that age ≥ 65 years (HR, 1.52 [95% CI, 1.12-2.05 years]; p = 0.01) and advanced EUS T stage (3.06 [2.10-4.46]; p < 0.001) were associated with a shorter recurrence-free survival duration. Conclusions: Peritoneal carcinomatosis was the most common site of recurrence after curative resection of gastric cancer, with associated poor survival, and was not associated with the use of neoadjuvant therapy. Future trials should focus on treatment of the peritoneum, which may improve the survival of patients with advanced gastric cancer.
Central validation of HER2 status to determine heterogeneity of marker expression in HER2-positive gastric cancer (GC).
Authors: Haffner Ivonne , Luber Birgit , Maier Dieter , Kretzschmar Albrecht , Fischer von Weikersthal Ludwig , Ahlborn Miriam , Riera-Knorrenschild Jorge , Rau Beate , Weissinger Florian , Fuxius Stefan , Neumann Steffen , Decker Thomas , Schierle Katrin , Wittekind Christian , Lordick Florian 
Published: March 2017

12 Background: 10-20% of GC overexpress HER2, a membrane-bound receptor tyrosine kinase (RTK) which belongs to the epidermal growth factor receptor (EGFR) family. Drugs directed against HER2 have shown mixed success in the treatment of advanced GC. While trastuzumab, a monoclonal antibody addressing HER2 has been approved for 1st-line treatment of stage IV HER2+ GC, trastuzumab-emtansine failed to improve outcomes in 2nd-line and lapatinib, a small molecular RTK inhibitor of HER2 and EGFR was not effective in 1st- and 2nd-line. Until now, primary and secondary resistance against HER2-directed treatment of GC is not well understood. The VARIANZ study aims to assess mechanisms influencing efficacy of trastuzumab in HER2+ GC. Methods: In this multicenter study, patients who receive medical treatment for advanced GC are recruited in 31 sites. The HER2 status is verified centrally by two dedicated GI pathologists using immunohistochemistry (IHC, DCS, HI608C0I) and chromogenic-in-situ hybridization (CISH, Zytomed Systems, C-3022-40). Results: From May 2014 to August 2016, we have enrolled 316 patients in this ongoing project (72% male, median age 64 years). At present, 281 samples were fully characterized for the HER2 status. According to criteria from the Trastuzumab for Gastric Cancer (ToGA) study, 53 of 281 samples were characterized HER2+ by central testing. In 38 samples that were diagnosed as HER2+ by local pathologists the HER2 status could not be verified centrally. 7 HER2- probes in local testing were characterized as HER2+ by central testing. The overall deviation rate between local and central testing is 27%. HER2 gene amplification in HER2+ tumors with deviating local report (mean HER2/CEP17: 2.8 ± 0.9, range between 1.9 and 4.5) is lower compared to HER2+ tumors and confirmed local report (mean HER2/CEP17: 5.5 ± 2.6; range between 2.2 and 11.0; p = 0.014). Conclusions: HER2-expression in GC is heterogeneous and still not easy to assess. Variability between local and central HER2 assessment is significant. Robust biomarkers predicting response or resistance to HER2 and other target therapies are needed. Clinical trial information: NCT02305043.
Standard personalized medicine platform integrating clinical genomics and patient-derived xenograft models for gastric cancer.
Authors: Yang Han-Kwang , Lee Hyuk-Joon , Suh Yun-Suhk , Kim Min Jung , Kim Woo Ho , Na Deukchae , Park Hansoo , Kim Jong-Il , Lee Charles 
Published: March 2017

120 Background: Research and development of patient-derived tumor xenograft (PDX) model has gradually increased for preclinical study as well as tailored treatment of patient individual. We report our experience of development and application of gastric cancer PDX model using NSG mouse. Methods: From May 2014, primary tumor tissue and corresponding normal mucosa were sampled immediately after gastrectomy to reduce ischemic time. Corresponding normal mucosa was obtained as far as possible from tumor. Size of samples for implantation is 2x2x1mm/unit. After harvest, these tissue were injected at both flank of NSG mouse (2 times of injection per each mouse). If engrafted primary tissue (P0) would not grow after 90 days of engraftment or grow up to 2,000mm3/unit, model was considered as graduated. Genomic profiles from exome and RNA sequencing was analyzed between human primary tumor and P0. Results: We implanted gastric cancer tissue from 341 patients, and identified 135 P0 cases as tumor growth models (124 cases of primary tumor, 5 cases of metastatic nodes, and 6 cases of paired primary tumor and metastatic nodules). The mean time between fresh tissue sample and reposition at refrigerator was 18 min. The success rate of implantation was 39.6% (135/341). Out of P0 tumor growth models, 51 cases were diagnosed as adenocarcinoma, and 49 cases as lymphoid proliferation pathologically. Compaing pathologic and genomic data between primary tumors and P0 tumors identified as adenocarcinomas, we observed a similar frequency of genome-wide copy number (gain/loss) across overall cases. Moreover, genomic variations between each primary and P0 sample was also similar as shown in a Circos plot indicating somatic mutations, loss of heterozygosity and copy number variations. Relative high expression levels of cancer-related genes including MET and ERBB2 of primary tumors maintained in corresponding P0, when compared to expression levels in normal tissues. Conclusions: We successfully established gastric cancer PDX model which will be a useful tool for tumor biology study and the preclinical study in gastric cancer.
ARDS in the setting of FOLFOX/cetuximab based chemoradiotherapy for locally advanced esophageal adenocarcinoma (E2205).
Authors: Kasozi Ramla NAMISANGO , Choudhary Anita , Gibson Michael K. , Catalano Paul J. , Kleinberg Lawrence , Staley Charles A. , Sokoll Lori J. , Song Wei , Mulcahy Mary Frances , Leichman Lawrence P. , Benson Al Bowen 
Published: March 2017

121 Background: E2205 was a single-arm, phase II trial that added an epidermal growth factor receptor (EGF-R) inhibitor, cetuximab (C), to CRT. The trial was closed early due to pulmonary toxicity. We investigated the potential role of cetuximab and type of radiation (IMRT vs conventional). Methods: Patients were treated with CRT: Oxaliplatin (OX) 85mg/m2 days 1,15,29; infusional 5-fluorouracil (5-FU) 180mg/m2/24hours x 35 days; C 400mg/m2 day 1 then 250mg/m2days 8,15,22,29 and radiation (IMRT allowed) 180cGy/day x 25 fractions (Monday-Friday), followed by esophagectomy. Results: Of 21 eligible patients enrolled, 17 had surgery (died pulmonary embolism 4 days after CRT, died G3 diarrhea/PD during CRT, died sepsis/hypoxia during CRT). pCR = 7/17. Four post-op deaths from acute respiratory distress syndrome (ARDS) resulted in 7 total study-related deaths. None of the patients who received IMRT died (0/3). 1/6 had ARDS if more than 4 fields with conventional or 3D planning was used. 3 of 15 treated with RT that met the criteria of E1201 guidelines (no more than 3-4 RT fields, normal lung more than 2 cm outside the target volume < 40 Gy, no IMRT). Overall, there was no demonstrable association of ARDS to radiation technique: 4/22 overall, 0/3 if IMRT was used. Conclusions: This regimen is not recommended. There is no clear association between use of IMRT and ARDS. The cause of ARDS remains undetermined. Cetuximab may have played a role. Clinical trial information: NCT00551759.
Short and long term outcomes with robotic assisted esophagectomy.
Authors: Meredith Kenneth L , Huston Jamie , Briceno Pedro , Shridhar Ravi 
Published: March 2017

125 Background: Surgical resection remains piviotal in the management of patients with esophageal cancer. Minimally invasive esophagectomy(MIE) has demonstrated superior operative outcomes compared to the open approaches. Robotic assistance has potential to further improve outcomes, however the long-term follow with this technique is lacking. Methods: Utilizing the National Cancer Database we identified patients who underwent esophagectomy and stratified by approach: open (OE), laparoscopic (LE) or robotic (RE). Baseline comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis as appropriate. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was performed using the Kaplan-Meier method comparing survival curves with the log-rank test. All statistical tests were two-sided and α (type I) error < 0.05 was considered significant. Results: We identified 18,869 patients who underwent esophagectomy with a mean age of 65 ± 10 years. There were 10,882 (57.7%) OE, 7,102 (37.6%) LE, and 885 (4.6%) RE. There was no difference in T stage or N stage among groups. Thirty and 90-day mortality was 3.2% and 6.9% and was lower in the MIE groups compared to open 6.2% vs 7.9% p < 0.001. Median length of hospitalization in RE, LE and OE was comparable at 9, 10, and 10 days respectively, p = 0.06. Neoadjuvant therapy was administered in 9,118 (48.3%) patients and was more frequent in the RE 66.0% vs 57.5% OE vs LE 32% p < 0.001. Oncologic quality as indicated by R0 resections and median lymph node harvested were improved in patients undergoing RE: 836 (94.9%) and 16, LE: 5,322 (86.7%) and 4, and OE: 9,631 (91.1%) and 12, p < 0.001. The median and 5-year survival by approach: RE, LE and OE was 54.4 months and 47.7%, 55.6 months and 50.3%, and 47.4 months and 43.7%, p < 0.001. MVA demonstrated that age, location, neoadjuvant therapy, T-stage, N-stage, hospital volume, MIE, and R0 resections were predictive of survival. Conclusions: Short and long-term outcomes with robotic assisted esophagectomy demonstrates low mortality with superior R0 resections and lymph node harvest. Overall survival is benefited in patients undergoing MIE.
A Phase I/II trial of fruquintinib in combination with paclitaxel for second-line treatment in patients with advanced gastric cancer.
Authors: Xu Rui-hua , Zhang Dongsheng , Shen Lin , LI Jin , Huang Jing , Gong Jifang , Guo Weijian , Zhang Yang , Fan Songhua , Li Ke , Hua Ye , Su Weiguo 
Published: March 2017

128 Background: Advanced gastric cancer (AGC) is a major problem particularly in Asian countries. The treatment options are limited after standard first line chemotherapy. This phase I/II study aimed to evaluate the tolerability, pharmacokinetics and preliminary efficacy of fruquintinib, a selective oral VEGFR inhibitor, combined with paclitaxel as second-line therapy in Chinese patients with AGC. Methods: This open arm phase I/II trial (NCT02415023) consisted of dose finding and dose expansion stages. In the dose finding stage, 3 dose levels of fruquintinib (2, 3, 4 mg; once daily for 3 weeks) were evaluated in combination with standard 80 mg/m2 paclitaxel (once weekly on Days 1, 8 and 15) in a 28-day cycle until the maximum tolerated dose or recommended phase II dose (RP2D) was reached. Additional patients were enrolled at the RP2D to further assess the efficacy, safety and pharmacokinetic profile. Results: As of Sept. 10, 2016, a total of 32 patients were enrolled including 15 during dose escalation. The RP2D regimen was determined to be fruquintinib 4mg daily combined with paclitaxel 80mg/m2 weekly for 3 weeks followed by 1 week off in a 4 week cycle. Two patients at 4mg experienced dose-limiting toxicity, both with febrile neutropenia. The grade 3 or 4 treatment emergent adverse events were neutropenia (40.6%), leukopenia (28.1%), decreased hemoglobin (6.25%), hand-foot skin reaction (6.25%), neurophlegmon (6.25%), and hypertension (6.25%), more frequent in the 4mg cohort. At steady state, Fruquintinib AUC (AUCss) increased dose-proportionally and within the historic range as a single agent, while paclitaxel exposure, at the RP2D regimen, increased by approximately 30% compared to the AUC prior to fruqintinib dosing. Twenty-eight of 32 patients were evaluable for response, and of these, 10 patients had partial response (Objective Response Rate = 35.7%), 9 patients experienced stable disease for at least 8 weeks (Disease Control Rate = 67.9%). At RP2D, ≥ 16w-PFS = 50% and ≥ 7m-OS = 50%. Conclusions: Combination of fruquintinb and paclitaxel appeared to be generally well-tolerated with promising tumor response. Further evaluation in a controlled phase II study is warranted. Clinical trial information: NCT02415023.
Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in oesphageal squamous cell carcinoma.
Authors: Jiang Yu-Bo , Xu Jian-Ming , Lo Anthony W.I. , Wong Angela , Chen Wen-Feng , Wang Yan , Lin Li 
Published: March 2017

13 Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression and tumor-infiltrating immune cells (TILs) in tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 428 archival formalin-fixed, paraffin-embedded (FFPE) ESCC samples were collected between 2004 and 2014 from treatment naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy. Expression of PD-L1 was assessed by IHC. The degree of TILs infiltration was evaluated by examining the H&E-stained specimens. Associations of PD-L1 expression and TILs with clinicopathological features were evaluated by non-zero correlation test. Survival distribution was compared by Kaplan-Meier and a log-rank test. The median follow-up time was 34.4 months(0.3-147.1 m). Changes of PD-L1 expression between paired tumor samples, which were collected before and after chemotherapy (2 cycles and 4 cycles or more), were also evaluated. Results: In the entire cohort, 79.7% (341/428) of specimens were PD-L1+ (defined as having ≥ 1% of tumor cell membranes showing ≥ 1+ intensity). In the intent-to-treat group (patients received curative esophagectomy or definitive chemoradiation therapy), PD-L1 positivity was associated with a significantly poorer DFS and OS. Neither PFS nor OS in palliative chemotherapy group presented a significant difference corresponding to PD-L1 expression. Furthermore, PD-L1 expression was positively associated with TIL density. Changes in PD-L1 expression was examined in 17 paired tumor tissues collected before and after treatments. Results showed that an increase in PD-L1 expression was associated with disease progression, a decrease in PD-L1 expression was associated with satisfactory chemotherapy treatment response. Conclusions: PositivePD-L1 expression was associated with a significantly worse prognosis in ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.
Is three years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up.
Authors: Lin JianXian 
Published: March 2017

130 Background: The therapy for gastrointestinal stromal tumors (GIST) has changed significantly since the use of Imatinib Mesylate (IM). However, the appropriate duration of receiving adjuvant IM for patients with high-risk GIST who underwent R0 resection is still controversial. Methods: From Jan. 2005 to Dec. 2014, 234 patients who underwent R0 resection and were treated with adjuvant IM were identified from a database. The effect of the medication duration on the long-term outcomes was analyzed. Results: In this study, the 5 year recurrence-free survival (RFS) rate and overall survival (OS) rate in the whole groups were 76.2% and 83.4%, respectively. The patient's prognosis was improved due to the prolongation of the time of receiving the Imatinib treatment (P < 0.05). According to the risk stratification analysis, the survival of the moderate-risk patients who received IM adjuvant therapy for 1 year, 1-3 years and more than 3 years showed improved, but the difference was not statistically significant (P > 0.05). However, in the high-risk patients, the RFS rates of the 1 year group, 1-3 years group, 3-5 years group and more than 5 years group were 36.5%, 68.7%, 71.2% and 90.8%, respectively, and the OS rates were 36.7%,76.6%, 84.0% and 97.4%, respectively (P < 0.001). Additionally, linear regression analysis showed that the long-term outcomes of patients with high-risk GIST significantly improved due to prolonged adjuvant IM treatment durations (P < 0.05). The RFS rate of patients receiving IM more than 5 years was significantly better than those receiving it for less than 5 years. Multivariate analysis in the patients with high-risk GIST showed that tumor located in small intestine was an independent risk factor, while receiving IM treatment was an independent protective factor for prognosis. Conclusions: The long-term outcomes of patients with high risk GIST improved due to the prolongation of the IM treatment. To reduce the recurrence and improve the long-term survival, we suggest that patients with high-risk GIST receive Imatinib treatment for at least 5 years.
Impact of squamous histology on the response to treatment and long-term outcomes of patients with distal esophageal cancer.
Authors: Shah Parth Kishore , Cameron Miles , Frakes Jessica M. , Fontaine Jacques , Coppola Domenico , Hoffe Sarah E. , Almhanna Khaldoun , Pimiento Jose Mario 
Published: March 2017

135 Background: Squamous cell carcinoma (SCC) has been traditionally linked to a better response to treatment and overall survival when compared to adenocarcinoma (AC) of the esophagus. Recent advances in staging, neoadjuvant therapy (NAT) and increasing surgical management of patients with EC have led to improved overall survival of these patients. The aim of this study is to analyze the impact of squamous histology on treatment response and long term outcomes in patients with distal EC. Methods: A retrospective review of patients who underwent esophagectomy for EC at a single institution over a 16 year period (1999-2015) was performed. Pre-operative clinical parameters, stage as well as oncologic management were compared between SCC and AC of the distal esophagus and the difference in response to treatment and overall survival were analyzed using descriptive statistics. Results: Esophagectomy was performed on 945 patients with EC of which 839 patients (89%) had distal EC. The mean age of this group was 63 years and majority were male (87%). Histology was SCC for 78 patients (9.4%) and AC for 747 patients (90.6%). Pretreatment clinical stage was similar between groups (p = 0.16). NAT administration was similar between groups (p = 0.13). Although SCC patients had higher rate of complete response (54% v/s 36%, p = 0.01) we found no difference in the overall survival after surgery (33 months for SCC v/s 40 months for AC, p = 0.72) irrespective of whether they received NAT (p = 0.95) or not (p = 0.55). Conclusions: Squamous cell histology had a favorable impact on the rate of pathologic response for patients with distal EC; however, this improvement did not alter their overall survival. This could provide an insight into the decreasing significance of the histology in the management and expectations from treatment of EC while emphasizing the continuing need for multimodality therapy to assure good outcomes on these patients.