bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective randomized crossover study of effects of traditional Japanese herbal medicine rikkunshito on food intake and plasma acylated ghrelin levels in patients with esophageal cancer administered with cisplatin-based chemotherapy.
Authors: Hamai Yoichi , Yoshiya Tomoharu , Emi Manabu , Furukawa Takaoki , Ibuki Yuta , Okada Morihito
Published: March 2017

133

Background: Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces chemotherapy-induced nausea and vomiting (CINV). Acylated ghrelin (AG) is an orexigenic gut hormone that can alleviate CINV. We evaluated whether rikkunshito (RKT), a traditional Japanese herbal medicine with an orexigenic effect, can improve CINV-induced anorexia and increase levels of plasma AG in patients with esophageal cancer administered with CDDP-based chemotherapy. Methods: This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy between July 2013 and March 2016. Tenof them were assigned to group A (1st course with 7.5 g/day RKT on days 1 - 14; 2nd course without RKT [control]) and 10 were assigned to group B (1st course without RKT [control]; 2nd course with RKT). Food intake and levels of plasma AG (fmol/mL) were compared between the control and RKT courses. Results: Data from 18 of the patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patients and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6, which is associated with delayed-onset CINV, was considerably lower in the groups given RKT than in the control (2% vs. 30%; p = 0.07). Median levels of AG significantly decreased between days 1 to 3 in the group given RKT (15.1 to 9.6 fmol/mL, p = 0.001) and the control (14.1 to 10.2, p = 0.003), and then obviously increased from days 3 to 8 in patients with both courses (RKT: 9.6 to 15.7 fmol/mL, p < 0.0001; control: 10.2 to 17.8, p = 0.0002). However, the rate at which median plasm AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control group (68% vs. 48%, p = 0.08). Conclusions: RKT might improve delayed-onset CINV as well as CINV-induced anorexia and increases in plasma AG levels among patients with esophageal cancer who undergo highly emetogenic CDDP-based chemotherapy. Clinical trial information: UMIN000010747.
Checkpoint expression pre and post chemoradiation in operable esophageal cancer.
Authors: Kelly Ronan Joseph , Zaidi Ali Hussainy , Smith Matthew , Omstead Ashten N. , Kosovec Juliann E. , Matsui Daisuke , Martin Samantha A , Finley Gene Grant , Silverman Jan F , Werts E. Day , Jobe Blair A.
Published: March 2017

139

Background: PD-L1 expression has been reported in 40% of gastroesophageal cancers, but little data exists with regards to expression of other immune checkpoints. Here, we examined baseline expression levels for multiple immune modulators in 31 resected esophageal adenocarcinomas (EAC) and investigated the change in expression levels post-chemoradiation. Methods: Slides were stained on a Ventana BenchMark ULTRA automated stainer for CTLA-4 (Santa Cruz Clone F-8, dilutions 1:100) and PD-L1 (Dako clone 22C3 prediluted). Tonsil tissue was used as a control for lymphocytes, and a provided tumor control was used for PD-L1. Positivity was classified as > 1%, and the stained cell type was recorded (lymphocytes or tumor). Additionally, laser capture microdissection was performed, and RNA was isolated and pre-amplified to determine expression levels of TIM-3, GITR, IDO-1, LAG-3, CD-137, OX-40, and KIR-3 using RT-PCR. Gene expression was calculated using the ΔΔ -Ct method, and intergroup comparisons were performed and normalized against a cohort of 15 pathologically confirmed normal esophageal epithelium cases. Results: Post-chemoradiation cases demonstrated increased expression for PD-L1, when compared to matched pre-chemoradiation controls [p-value = 0.0098]. Similarly, all immune modulators profiled by gene expression were significantly upregulated in matched post vs. pre samples, except for CD-137. There was no significant difference in percentage of 4-fold or more upregulation based on PD-L1 status for IDO-1, OX-40, CD-137 and KIR-1, indicating that these markers may function independently of PD-L1 positivity. Conclusions: PD-1 inhibiton in both the neoadjuvant and adjuvant setting is currently being investigated in EAC, but future studies may look to select patients according to personalized checkpoint expression patterns. [Table: see text]
Surgically treated esophageal cancer developed in a radiated field: Impact on peri-operative and long-term outcomes.
Authors: Mariette Christophe , Markar Sheraz , Gronnier Caroline , Pasquer Arnaud , Duhamel Alain , Behal Helene , Thereaux Jeremie , Gagniere Johan , Lebreton Gil , Brigand Cecile , Meunier Bernard , Collet Denis
Published: March 2017

150

Background: The objectives of this study were to compare peri-operative and long-term outcomes from esophageal cancer (EC) (i) that arose in a previously radiated field (ECRF) versus primary (PEC) and among ECRF patients (ii) radiotherapy-induced (RIEC) versus non radiotherapy-induced EC (NRIEC). Methods: Data was collected from 30 European centers from 2000–2010. 2489 EC patients surgically treated were included in the PEC group and 136 in the ECRF group, including 61 in the NRIEC group and 75 in the RIEC group. Propensity score matching analyses were used to compensate for differences in baseline characteristics. Results: Compared to the PEC group, the ECRF group was characterized by less use of neoadjuvant chemoradiotherapy (0% vs. 29.5%; P < 0.001), less pathological stage III/IV (31.6% vs 39.2%, P = 0.036), greater incidence of R1/2 margins (21.3% vs. 10.9%; P < 0.001), increased in-hospital mortality (14.0% vs. 7.1%; P = 0.003) and overall morbidity (68.4% vs. 56.4%, P = 0.006). After matching, 5-year overall (28.8% vs. 50.5%; HR = 1.53, 95% C.I. 1.15-2.04; P = 0.003) and event-free (32.2% vs. 42.5%; HR = 1.56, 95% C.I. 1.18-2.05; P = 0.002) survivals were significantly reduced in the ECRF group. There were no significant differences in incidence or pattern of tumor recurrence. Comparing RIEC and NRIEC groups, there were no significant differences in short- or long-term outcomes before and after matching. Conclusions: ECRF is associated with poorer long-term survival related to a reduced utilization of neoadjuvant chemoradiotherapy and an increased incidence of tumor margin involvement at surgery. Outcomes are dictated by the limitations related to previous radiotherapy administration more than the radiotherapy-induced carcinogenesis.
Geographic and site variability in the treatment of patients with metastatic gastric cancer.
Authors: Hess Lisa M. , Zhu Yajun , Liepa Astra M. , Li Xiaohong , Schelman William R. , Fuchs Charles S. , Abrams Thomas Adam
Published: March 2017

153

Background: Previous work has demonstrated substantial heterogeneity in the treatment of metastatic gastric cancer (mGC) in the U.S. across all lines of therapy. However, the distribution of variability by region and clinical practice site is not well understood. Methods: De-identified patient-level electronic medical record (EMR) and claims data from IMS Oncology EMR and from Truven Marketscan, respectively, were used for this study. Eligible patients were age ≥ 18 years with newly diagnosed GC between 2007 and 2014. Metastases were identified by ICD-9 codes in the EMR and claims data or with evidence of stage IV or M1 disease in EMR. Patients classified with locally advanced/advanced disease were those who received chemotherapy without surgical intervention following diagnosis, regardless of absence or presence of metastases. Variability of treatment by line of therapy was measured by the Herfindahl-Herschman Index (HHI), a commonly used measure of market concentration in the business sector. The HHI was reported overall, by geographic region and practice site over time. Results: Overall, 2,368 IMS and 6,444 Truven patients treated for GC were identified; of these, 728 and 2,457 patients were classified with mGC in the IMS and Truven cohorts, respectively; 5,044 were diagnosed with advanced disease in Truven. Geographically (HHI regional scores ranged from 7-17), by line of therapy (7-17 in first line; 4-15 in second line), and over time, treatment variability was high. Practices treating a high volume of patients did not demonstrate lower variability than sites treating few patients with mGC. In the first-line setting, 83 of 87 and 223 of 228 regimens were used less than 5% of the time in patients with mGC in the IMS and Truven cohorts, respectively. Conclusions: Treatment variability was consistently high for all practice sites, geographic regions and year of diagnosis; in the business world a HHI score > 2000 is reflective of a monopoly whereas in this study, HHI scores were generally < 20, demonstrating high variability and the lack of any consistent treatment strategy. There is a need to identify best treatment practices to ensure care for patients with receive care that is in accordance with treatment guidelines.
Superior prognosis prediction performance of deep learning for gastric cancer compared to Yonsei prognosis prediction model using Cox regression.
Authors: Hyung Woo Jin , Son Taeil , Park Minseok , Lee Hansang , Kim Youn Nam , Kim Hyoung-Il , Kim Jong Won , Cheong Jae-Ho , Choi Seung Ho , Noh Sung Hoon , Kim Junmo
Published: March 2017

164

Background: Staging systems for cancer are critical to predict the prognosis of patients. Current staging systems for gastric cancer have limitations to predict individualized and precise prediction of patient’s survival after treatment. We aimed to develop prediction model based on deep learning by estimating the survival probability of patients who underwent gastrectomy. Methods: To predict the survival probability, we used a deep neural network model which consisted of 5 layers: input layer, 3 fully connected layer, and output layer with 8 characteristics (age, sex, histology, depth of tumor, number of metastatic and examined lymph node, presence of distant metastasis, and resection extent) of patients which was previously published Yonsei prediction model using Cox regression. Each layer functioned as the nonlinear weighted sum of lower layer. Five-year overall survival was predicted using the deep learning method and it was compared to Yonsei prediction model. The average area under the curve (AUC) was compared between the models. For internal validation, 5-fold cross validations were carried out. We also performed external validation with a dataset from another hospital (n = 1549). . Results: Deep learning predicted 5-year overall survival of patients with an average accuracy of 83.5% in the test set. The average AUC of deep learning by integrating 8 characteristics was significantly higher than that of Yonsei prediction model (AUC: 0.844 vs. 0.831, P < 0.001) with the same variables. In the external validation the average accuracy of survival prediction was 84.1%. The AUC was also greater in a dataset from other hospital in Korea (AUC: 0.852 vs. 0.847, P = 0.023) Conclusions: Prognosis prediction with deep learning showed superior survival predictive power compared to prediction model using Cox regression. It can provide individualized and precise stratification based on the risk using characteristics of gastric cancer patients.
Lymph node metastasis in gastric cancer: Location of positive station to predict survival after preoperative therapy.
Authors: Ikoma Naruhiko , Estrella Jeannelyn , Blum Murphy Mariela A. , Chen Hsiang-Chun , Wang Xuemei , Fournier Keith F. , Mansfield Paul F. , Ajani Jaffer A. , Badgwell Brian D.
Published: March 2017

166

Background: We sought to determine the association between the identification of positive lymph nodes on D2 lymph node dissection (LND) with stage and outcomes, in the era of preoperative treatment for gastric cancer. Methods: We reviewed data from a prospectively maintained database of gastric cancer patients who underwent resection of gastric or gastroesophageal cancer at our institution from 2005-2016. Central lymph nodes (CnLN) were defined as common hepatic, celiac, and proximal splenic artery lymph nodes (stations #8, 9, and 11p). Risk factors for CnLN metastases, and overall survival (OS) were examined. Results: We identified 356 patients, median age was 64 years (IQR 54-71) and 59% were male. Preoperative therapy was given in 66% of patients. D2 LND was performed in 80% of patients, and the median number of LN examined was 25 (IQR 18-34). Most patients (N = 244, 68%) had separately-examined CnLN in pathology and the median number of examined LNs was higher in this group (27 vs 19; p < 0.001). The CnLN positivity rate was 9.1% (22/244; #8: 4.8%, #9: 6.1%, and #11p: 4.8%), which was higher in advanced pT stage patients (pT0 - 3%, pT1 - 0%, pT2 - 6%, pT3 - 18%, pT4 - 13%; p = 0.001). If we assume that D2 LND was not performed on these patients, a total of 7 (3%, 7/244) patients would have had pN stage down-migration (6 with N1 to N0, 1 with N2 to N1). Of the 22 CnLN-positive patients, 10 (45%) had pN1, 2 (9%) had pN2, and 10 (45%) had pN3 stages. On multivariate analysis, EUS N stage (positive) was associated with positive CnLNs (OR 2.86 [95%CI 1.08-7.58]). Among 342 patients who had R0 resection, the median follow-up was 3.6 years, and the median OS was 11.6 years. Among patients who received preoperative therapy, pT3/4 stage (HR 2.44 [1.27-4.69]; p = 0.01) and positive CnLN (HR 5.44 [2.36-12.52]; p < 0.001) were negatively associated with OS by multivariate analysis. Conclusions: CnLN metastases are uncommon in gastric cancer, and are associated with an adverse impact on OS. However, long-term survival is still possible in patients with positive CnLN whom underwent a D2 lymph node dissection. Larger multi-institutional studies are needed to determine if CnLN positivity requires a separate staging category.
Retrospective analysis of neoadjuvant chemoradiotherapy with carboplatin/ paclitaxel versus FOLFOX in newly diagnosed esophageal or junctional cancers: A single instituition experience.
Authors: Nair Ranjit , Shah Usman , Kincaid Hope , Macfarlan Jennifer , Friedman Eliot Lawrence
Published: March 2017

168

Background: The retrospective study aimed to evaluate carboplatin / paclitaxel (CP) versus FOLFOX in the neoadjuvant combined modality setting for newly diagnosed esophageal or junctional cancers. Methods: Patients with esophageal or junctional cancers treated in combined modality setting were included. During the study period, there were seventy three patients who had T2-4N0-1M0 esophageal and junctional carcinomas. Results: 49 (67%) patients received CP and 24 (33%) patients received FOLFOX. Concurrent radiation was delivered 5400-cGy in CP arm and 5040-cGy in FOLFOX arm. 38 (78%) patients in CP arm and 19 ( 79 %) in FOLFOX arm underwent curative resection. In CP arm, 11(12%) did not undergo curative resection due to disease progression (5/11), death secondary to infection (2/11) and poor functional status post chemotherapy (4/11). In FOLFOX arm, 5(21%) patients did not have surgery due to progressive disease (3/ 5), sepsis ( 1/ 5) and Tracheo–esophageal fistula ( 1 / 5). In patients who underwent curative resection, overall response rate (RR) was 92% in the CP arm with *CR–10(26%), PR–25 (66%), NR–3 (8%); in FOLFOX arm, RR was 100 % with *CR–6(32 %), PR–13(68 %), NR- 0 (p = 0.06). Median follow-up in all patients was 22 months, with median overall survival (OS) for the CP group 20-months and the FOLFOX group 30.5-months.With curative resection the median OS was 23-months in CP arm and 41-months in FOLFOX arm. Median relapse free survival (RFS) was 9.5-months in CP arm and 11 months in FOLFOX arm. 45% relapsed in the CP arm and 42% relapsed in the FOLFOX arm after curative resection. Conclusions: With CROSS trial in esophageal and juntional cancers, there has been a paradigm shift away from infusional 5-FU based regimens (5FU/cisplatin and FOLFOX). With this study, we demonstrated the activity of FOLFOX in comparison to CP in the neoadjuvant setting with concurrent radiotherapy in the treatment of localized esophageal cancers. There was a trend in clinical efficacy and response rate towards FOLFOX when combined with curative resection. To definitively assess this and compare the efficacy, long term prospective studies are needed.
Young age, disparities, and survival in gastric adenocarcinoma: Implications for screening strategies.
Authors: Gaitonde Shrawan G , Fischer Trevan D , Jones Maris S , Bandera Bradley , Stern Stacey , Goldfarb Melanie
Published: March 2017

17

Background: Recent foreign publications have demonstrated increasing frequencies of gastric cancer in younger patients with differing biology and outcomes. This study will be the largest of gastric adenocarcinoma (GA) in young adults and aims to examine disparities and the impact of age on overall survival (OS). Methods: All patients diagnosed with primary GA from 2004-2013 in the National Cancer Data Base (NCDB) were reviewed for patient demographics, tumor characteristics, and treatment. Patients were grouped by age (AYA < 40, adult ≥ 40) and appropriate statistical analyses performed. Results: Of 49,278 patients, 1517 (3%) were < 40 years old. Compared to older adults, AYAs were more commonly female, represented an ethnic minority, and had more markers of socioeconomic disadvantage (SES) (all p < 0.001). They presented with higher grade tumors, higher tumor and nodal staging, and more metastatic disease at diagnosis (all p < 0.001). AYAs also more commonly received adjuvant radiation and/or chemotherapy (all p < 0.001). Five-year OS in AYAs was 32.9% vs 29.4% for older adults (p < 0.001). After controlling for competing factors, higher tumor grade (HR 1.61, CI 1.32-1.97), distant metastases (HR 2.22, CI 1.84-2.68), and increasing tumor (HR 2.69-5.44) and nodal stage (HR 1.84-2.35) independently decreased OS in AYAs whereas Hispanic (HR 0.78, CI 0.65-0.93) or Asian ethnicity (HR 0.72, CI 0.56-0.93) and receipt of adjuvant chemotherapy improved OS (HR 0.62, CI 0.52-0.75). Similar results were seen in older adults except that all markers of low SES decreased OS also. Age < 40 had an independent effect on OS only for early stage (stage I/II) disease, resulting in a 19% survival advantage compared to older adults (HR 0.81, CI 0.71-0.93). Conclusions: Young patients with GA are more ethnically diverse and SES disadvantaged compared to older adults, with disparities effecting OS more in older patients. When diagnosed at an early stage, young age independently improves OS, emphasizing the importance of early diagnosis especially in this age group. Further research is needed to address whether national screening strategies could improve survival for selected young patients.
Risk factors of lymph node metastasis in undifferentiated early gastric cancers.
Authors: Kim Il , Cheung DaeYoung , Kim Jin Il , Kim Jae J.
Published: March 2017

171

Background: The aims of this retrospective study were to analyze risk factors of lymph node metastasis undifferentiated-type early gastric cancer (UD-type EGC) and to select the suitable patient for endoscopic resection. Methods: We analyzed 368 patients who had undergone gastrectomy with lymphadenectomy for UD-type EGC between November 2001 and July 2016 at the Yeouido St. Mary’s Hospital. Using clinicopathological factors of patient age, size, an endoscopic macroscopic tumor form, ulceration, depth, histology, lymphatic involvement (LI) and venous involvement (VI), LNM risk was examined and stratified by univariate analysis and multivariate analysis. Results: Of the 368 patients, the lymph node metastases rate in patients with EGC was 48 patients (13%). 204 (55 %) had mucosal cancers and 164 (45 %) had submucosal cancers. Univariate analysis revealed > 60 age, > 2 cm, submucosal(sm), poorly cohesive carcinoma as significant prognostic factors. On multivariate analysis, > 60 age (odd ratio , 2.20; 95% confidence interval, 1.19~4.06), submucosal(odd ratio , 9.38; 95% confidence interval, 4.08~21.56), poorly cohesive carcinoma (odd ratio, 0.33; 95% confidence interval, 0.12~0.86) were independent risk factors for lymph node involvement. Conclusions: LNM-related factors in undiff-EGC were age, depth and pathology. We proposed that risk factors for metastases should be considered when choosing surgery for EGC.
Dosimetric effects of deep inspiration breath hold for radiation treatment of esophageal cancer based on tumor location.
Authors: Doke Kaleigh , Badkul Rajeev , Aguilera Nathan , Mitchell Melissa Pulfer , Shen Xinglei , Lominska Chris
Published: March 2017

173

Background: Deep inspiration breath hold (DIBH) has been shown to reduce heart and lung doses in radiation treatment of breast cancer and lymphoma. We investigated its application for treatment of esophageal cancer. Methods: Five patients who had DIBH simulation for diagnoses with chest scans were studied. Patients were simulated supine with 2 CT scans each: free breathing (FB) and DIBH using surface infrared markers. The patients were contoured using standard volumes as per RTOG 1010, including a 45 Gy planning target volume (PTV). Both a mid-esophagus and distal PTV were created for each of the model patients, by contouring 5 cm tumor volumes at the level of the carina and gastroesophageal junction. Normal structures were contoured as well. For distal tumors, the celiac nodes were covered electively as per RTOG 1010. Uniform three dimensional conformal radiotherapy plans were generated and normalized to provide 100% dose coverage to 95% of the PTV. Dose volume histograms were generated and evaluated. A 2-tailed paired student’s T-test was used to evaluate statistical significance. Results: When comparing the changes in dose to the normal structures with breath hold, a contrasting trend was seen between proximal and distal tumors. The mean heart dose and V40 decreased with breath hold for proximal tumor plans, however the heart dose metrics increased with breath hold for distal tumors. For the proximal tumor plans, the lung mean, V20, V10 and V5 decreased with breath hold in all patients. For distal tumors, mean lung doses trended towards an increase. Conclusions: Dosimetric parameters uniformly improved for proximal tumors with DIBH. By contrast, distal tumors often showed worsening of heart and lung dosimetry with DIBH. This appeared to be related to entry of the lung volume into the celiac nodal field, among other factors. [Table: see text]
Interim FDG-PET imaging during neoadjuvant chemoradiotherapy for esophageal cancer: Correlation with pathologic response.
Authors: Tandberg Daniel , Hong Julian C. , Cui Yunfeng , Ackerson Brad , Czito Brian G. , Willett Christopher , Palta Manisha
Published: March 2017

175

Background: In this prospective study we evaluated whether changes in metabolic tumor parameters on interim flurodeoxyglucose positron emission tomography (FDG-PET) performed during neoadjuvant chemoradiotherapy (CRT) for esophageal cancer correlates with histopathologic tumor response. Methods: From February 2012 to February 2016, 60 patients with esophageal cancer underwent PET scans before therapy and after 30-36 Gy. Patients who underwent surgery after carboplatin/paclitaxel CRT were eligible for the current analysis. PET metrics of the primary site including maximum standardized uptake value (SUVmax), SUV mean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were extracted from the pre-treatment and interim PET based on a manual contour and SUV 2.5 threshold. Patients were called histopathologic responders if they had a complete or near complete tumor response based on the modified Ryan scheme. Relative changes in PET metrics between pre-treatment and interim PET were compared between histopathologic responders and non-responders using the Mann-Whitney test and binary logistic regression. Results: Twenty-six patients were included in the analysis. Adenocarcinoma was the most common histology (n = 23). Eleven patients (42%) had a complete or near complete pathologic response to CRT (histopathologic responders). Changes in PET metrics from pre-treatment to interim PET based on the manual contour were not significantly different between responding and nonresponding tumors. The relative reduction of SUVmax (Mean ± SD) was 38.2% ± 28.4% for histopathologic responders and 27.9% ± 31.4% for non-responders. The relative reduction in MTV, SUV mean and TLG was 36.1% ± 26.2%, 23.5% ± 21.3%, and 49.3% ± 28.3% for histopathologic responders and 28.6% ± 32.0%, 11.8% ± 19.1%, and 33.1% ± 38.5% for histopathologic non-responders, respectively. When analyzed based on the SUV 2.5 threshold there continued to be no significant difference in PET metrics. Conclusions: In this pilot study we observed changes in metabolic tumor parameters on PET performed during CRT for esophageal cancer. However, these changes did not predict for histopathologic responders.
Analysis of tumor immune protein expression and clinical outcomes in gastric adenocarcinoma.
Authors: Blakely Andrew M. , Matoso Andres , Miner Thomas J.
Published: March 2017

177

Background: Up- and down-regulation of various immunomodulating proteins may reflect gastric tumor aggressiveness, possibly correlating with disease progression. Although a growing focus of investigation, literature is still lacking on which proteins may be predictors of patient outcomes. Methods: Retrospective review of a prospective database was performed of patients who underwent gastrectomy for adenocarcinoma with curative intent, 2003 to 2013. Patient demographics, operative details, pathology data, and outcomes were captured. Results: 86 of 105 gastrectomy patients had sufficient tissue for microarray analysis. Patients were mostly males (65.1%); median age was 74 years. 31 patients (36.0%) underwent total gastrectomy; the remainder underwent subtotal resection. 59 specimens (68.6%) had ≥ 15 lymph nodes harvested. Median tumor size was 4.9 cm; 55 (64.0%) were at least stage T3 and 63 (73.3%) had nodal involvement. 13 margins (15.1%) were positive, 50 had lymphovascular invasion (LVI, 58.1%), and 43 had perineural invasion (PNI, 50.0%). Median follow-up was 43 months; 28 patients (32.6%) died in follow-up. 9 patients (10.5%) developed local recurrence while 27 (31.4%) had regional/distant recurrence; median time to recurrence was 12 months. Recurrence was associated with LVI (50.0% vs. 25.0%, p = 0.028) and PNI (53.5% vs. 30.2%, p = 0.029). LVI was associated with microsatellite instability (MSI) (70.0% vs. 20.0%, p = 0.021). PNI was associated with suppressed programmed death-ligand 1 (PD-L1) expression in epithelium (73.1% vs. 41.4%, p = 0.0072) and lymphocytes (60.0% vs. 37.1%, p = 0.038). PD-L1 positive lymphocytes were associated with positive margins (21% vs 2%, p = 0.004). Epithelial indoleamine dioxygenase (IDO) expression was associated with lower recurrence (30.0% vs. 57.1%, p = 0.012). Conclusions: Histopathologic analysis of gastric cancer specimens may help identify which patients are more likely to develop recurrent disease. Downregulation of immunosuppressive proteins such as PD-L1 and IDO and MSI suggest more aggressive tumor biology. Knowledge of tumor protein expression profiles could be used to tailor adjuvant therapy to improve long-term oncologic outcomes.
Gastrointestinal stromal tumors (GISTs) of the esophagus and gastroesophageal junction (GEJ).
Authors: Briggler Andrew M. , Graham Rondell P , Westin Gustavo Figueiredo Marcondes , Folpe Andrew , Jaroszewski Dawn E. , Okuno Scott H. , Halfdanarson Thorvardur Ragnar
Published: March 2017

179

Background: GISTs arise from interstitial cells of Cajal anywhere within the gastrointestinal tract, but those of the esophagus and GEJ are exceedingly rare ( < 1% of cases). Our aim was to characterize clinicopathological features and outcomes of esophageal and GEJ GISTs and compare survival with a population-based registry (SEER). Methods: 28 cases were identified using the Mayo Clinic Cancer Registry from 1997 to 2016, and 378 cases from the SEER 18 registry from 2000 to 2013. Mayo cases were re-reviewed by Mayo pathologists. We analyzed patient characteristics, tumor location, TNM staging, mitotic index, molecular diagnostics, IHC staining, and histomorphology. JMP software was used to calculate time to recurrence (TTR) and overall survival (OS) utilizing Kaplan-Meier and log-rank. Results: At Mayo, 60% of tumors arose in the distal esophagus. Mean tumor size was 5.73 cm. 42% of cases were low grade. None had nodal involvement. Five cases were metastatic at diagnosis, all to the liver. 86.7% had spindle cell morphology. IHC staining was positive for KIT in 92%, followed by CD34 (52%), DOG-1 (24%), and actin (16%). Mutational analysis was done on 10 cases and KIT mutation was found in 8 cases; 2 were wild-type. Two-thirds of patients underwent surgery, mostly esophagectomy. 14 patients received adjuvant imatinib. Median time to diagnosis from symptom onset was 2 months; median time to surgery from diagnosis was 1 month. Of 10 patients with complete follow-up, 2 had recurrences: 1at the anastomotic site and 1 in the liver. Median TTR from surgery was 36.5 months. Median follow-up time was 31.5 months. Median OS from diagnosis for the Mayo cohort was 129.5 months (95% CI 55.7-x). SEER cohort median OS was 81 months (95% CI 63-101), and females had superior OS compared to males (HR 0.67; 95% CI 0.48-0.93, p = 0.016). Conclusions: Patients undergoing surgical resection for esophageal and GEJ GISTs had a favorable prognosis, but recurrences occurred. The superior OS seen in the Mayo cohort suggests early resection and adjuvant imatinib may improve outcomes.
The impact of new-onset atrial fibrillation on short- and long-term outcomes after esophagectomy for esophageal cancer.
Authors: Booka Eisuke , Takeuchi Hiroya , Fukuda Kazumasa , Suda Koichi , Nakamura Rieko , Wada Norihito , Kawakubo Hirofumi , Kitagawa Yuko
Published: March 2017

183

Background: AF is common after thoracic and esophageal surgical procedures. The full spectrum of risk factors, associations, and implications are unclear. Objective:The aim of this study was to assess the impact of new-onset atrial fibrillation (AF) after esophagectomy on short- and long-term outcome. Methods: A retrospective analysis was performed on patients with esophageal cancer who underwent esophagectomy with thoracotomy and laparotomy, with R0 or R1 resection between January 1997 and December 2012. For the 402 patients included in this study, we analyzed the stage of disease, neoadjuvant therapies, surgical approaches, surgical complications, postoperative medical complications, and overall and relapse-free survivals using medical records. Results: The median age was 62 (range 34-82). Most patients were male (90.0%) and had squamous cell carcinoma (90.3%). Pathological staging of the esophageal cancers according to UICC 7th TNM classification system was categorized as follows: 17 (4.2%), 96 (23.9%), 16 (4.0%), 43 (10.7%), 57 (14.2%), 78 (19.4%), 39 (9.7%), 37 (9.2%), and 19 (4.7%) patients were designated as stage 0, ⅠA, ⅠB, ⅡA, ⅡB, ⅢA, ⅢB, ⅢC and Ⅳ respectively. Of the 402 patients studied, 42 (10.6%) had AF, 87 (21.6%) had pneumonia, 80 (20.0%) had anastomotic leakage, and 69 (17.2%) had recurrent laryngeal nerve paralysis. At a median follow-up of 133 months, the median survival was 49 months, and 5-year survival was 48% in the AF group, compared with 138 months and 60% in the non-AF group (p = 0.212). AF was significantly associated with recurrent laryngeal nerve paralysis (p = 0.001), but not with pneumonia or anastomotic leakage. Conclusions: New-onset AF is common, mostly associated with recurrent laryngeal nerve paralysis, but not with pneumonia or anastomotic leakage. AF has no impact on oncologic outcomes.
Analysis of predictive factors of ramucirumab plus paclitaxel for advanced gastric cancer.
Authors: Fukuda Naoki , Takahari Daisuke , Osumi Hiroki , Matsushima Tomohiro , Nakayama Izuma , Wakatsuki Takeru , Ogura Mariko , Ichimura Takashi , Ozaka Masato , Suenaga Mitsukuni , Shinozaki Eiji , Chin Keisho , Yamaguchi Kensei
Published: March 2017

185

Background: Ramucirumab (RAM) is a novel anti-VEGF antibody approved in 2015 in Japan. Predictive factors for RAM in combination with paclitaxel (PTX) remain largely unknown. Methods: We reviewed 77 consecutive advanced gastric cancer patients who were treated with RAM plus PTX between June 2015 and June 2016 in our institution. We evaluated treatment outcome and analyzed potential predictive factors by univariate and multivariate analyses. Results: Median age was 67 years (range 35-83) and 51 % of the patients were male. The ECOG performance status (PS) was ≥ 2 in 8 patients. 89% (69/77) patients were treated as second line chemotherapy. Objective response rate (ORR) in patients who have measurable disease was 52 % (17/33). Median progression free survival (PFS) and overall survival (OS) and was 6.0 months (95% confidence interval [CI] = 4.3-7.1) and 10.4 months (95% CI 6.8-13.6), respectively. The most frequent adverse events were peripheral neuropathy (44%), G3 ≥ neutropenia (34%), hypertension (32%) and bleeding (27%). At multivariate analysis, hypertension was independent factor for OS (Hazard ratio [HR] = 0.35, 95% CI = 0.14-0.90, P = 0.03). Also, bleeding (HR = 0.23, 95% CI = 0.09-0.55, P = 0.001) was independent factor for PFS and hypertension (HR = 0.47, 95% CI = 0.22-1.02, P = 0.06) had trend toward to show better PFS. Conclusions: RAM plus PTX showed promising efficacy for advanced gastric cancer. RAM related toxicities such as hypertension and bleeding/hemorrhage were independent factors for better outcome. Further investigation is warranted to verify our analysis.
Association between markers of malnutrition (MN) and toxicity (T) during neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer (EC).
Authors: Jain Rishi , Shaikh Talha , Yee Jia-Llon , Au Cherry , Handorf Elizabeth , Dotan Efrat , Meyer Joshua E.
Published: March 2017

191

Background: EC is associated with significant MN. Resultant weight loss (WL) can be further exacerbated by toxicity of nCRT. We evaluated the association of surrogates of MN and T during nCRT for EC. Methods: A retrospective analysis of EC patients (pts) treated with nCRT as part of tri-modality therapy between 2002-2014 was performed. The following pre and post-CRT factors were assessed: presence of jejunostomy tube (J-tube), weight change (gain, loss of < 5%, 5-10%, ≥ 10%) and albumin change (decrease by < 0.5 or ≥ 0.5). We recorded rates of chemotherapy (ctx) dose reduction/interruption (DRI), hospitalizations (H), grade 3/4 T (G3+T), any grade non-hematologic (NHT) or hematologic T (HT). Multivariate regression analyses (MVA) were used to determine associations between MN and T, adjusting for age, gender, smoking status, stage, CRT regimen, performance status, and co-morbidities. Results: 125 patients were identified. Median age was 63 (range 35-80). Pre-CRT body mass index ranged from 17-45 kg/m2, with 74% overweight or obese. Mean WL during nCRT was 10 lbs (5%). Increased WL was noted in pts who received cisplatin/5-FU as compared to other ctx (p < 0.001) or ≥ 50 Gy (p = 0.025). In MVA, increased NHT was noted in pts with ≥ 5% WL (p < 0.05) and more G3+T was noted in pts with ≥ 10% WL (p = 0.002). A decrease in albumin by ≥ 0.5 was associated with increased DRI (p = 0.043), NHT (p = 0.004), HT (p = 0.002), and G3+T (p = 0.004). Sixty-three pts (50%) had a J-tube prior to nCRT. Pts with a J-tube had reduced mean WL (8 lbs vs 13 lbs) during nCRT. No differences in T were noted based on J-tube status. No associations between MN and H rates were observed. Conclusions: Hypoalbuminemia and WL during nCRT were associated with multiple T endpoints. The presence of a prophylactic J-tube did not reduce T rates. Other methods to prevent MN and reduce T during nCRT should be studied.
The impact of dose modification or termination of S-1 as adjuvant therapy on survival of locally advanced gastric cancer underwent curative gastrectomy.
Authors: Kawakami Takeshi , Machida Nozomu , Bando Etsuro , Hayashi Kaori , Shirasu Hiromichi , Kawahira Masahiro , Kawai Sadayuki , Kito Yosuke , Yoshida Yukio , Hamauchi Satoshi , Todaka Akiko , Tsushima Takahiro , Yokota Tomoya , Yamazaki Kentaro , Fukutomi Akira , Terashima Masanori , Yasui Hirofumi
Published: March 2017

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Background: Adjuvant S-1 therapy for pStage II/III gastric cancer (GC) patients (pts) after curative resection is standard treatment in Japan, however, prognosis of pStage III is still poor. There are few reports investigating the association of treatment exposure with survival. Therefore, we investigated the impact of dose modification or termination of S-1 as adjuvant therapy on overall survival (OS). Methods: The data of locally advanced GC pts who underwent gastrectomy with D2 lymph-node dissection in Shizuoka Cancer Center between Jan 2007 and Aug 2013 were retrospectively collected. Inclusion criteria were as follows: age 20 to 80 years; ECOG PS 0 or 1; histologically proven adenocarcinoma; pStage III under TNM 7th edition; R0 resection; initiation of S-1 within 56 days after surgery. S-1 was administered for 4 weeks followed by a 2 weeks rest. We defined completion of planned S-1 therapy as continuation of S-1 one year after surgery. Results: One hundred and six pts satisfied inclusion criteria. Pts’ characteristics were as follows: median age, 67 years (range, 38-78); male/female, 77/29 pts; ECOG PS 0/1, 72/34 pts; primary tumor location EGJ/U/M/L, 1/27/45/33 pts; and pStage IIIA/IIIB/IIIC, 25/41/40 pts. Fifty-five pts (51%) needed dose modification (dose reduction and/or schedule alteration). Eighty-two pts (77%) achieved completion of planned S-1 therapy. Five year OS rate was 59.9%. Among potential prognostic factors for OS in univariate analysis (age, PS, pStage, completion of planned S-1 therapy, dose modification), completion of planned S-1 therapy (HR 0.26; 95% CI 0.13-0.51; p < 0.001) and PS 0 (HR 0.52; 95% CI 0.27-0.99; p = 0.048) were good prognostic factors and dose modification was not prognostic factor (HR 1.06; 95% CI 0.53-2.12; p = 0.876) for OS. Conclusions: This study suggested that completion of planned adjuvant S-1 therapy and PS 0 were good prognostic factors for OS and appropriate dose modification might not worsen their prognosis.
Application of very low dose-rate brachytherapy in gastrointestinal cancer.
Authors: Herskovic Arnold M. , Rivard Mark , Rothstein Richard I , Moodie Karen L , Corcoran Kathleen , Swanson Lynne , Clerc Claude
Published: March 2017

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Background: Despite treatment intensity escalation, the high local recurrence rate for esophageal cancer has frustrated clinicians for decades. Conventional High Dose Rate brachytherapy, particle therapies, and other sophisticated treatment methods are encouraging but often fiscally and/or biologically infeasible. Additionally, these technologies often burden patients with numerous hospital visits, decreasing patient quality of life. Very low dose-rate brachytherapy (vLDR), with sources emitting relatively low energy, can be more cost effective than conventional radiation treatments, particularly in underserved communities, and can replace many hospital visits with one procedure. The dose distribution advantages of vLDR are irrefutable, especially in regard to doses to other tissues. vLDR seeds are currently used regularly in the prostate and have been tested in several other anatomical sites with good safety results. In the present study, a radioactive(RA) stent platform was developed and tested to apply vLDR therapy to cancers of the gastrointestinal (GI) system. Methods: Monte Carlo simulations were used to guide design of a RA esophageal stent. A design was chosen that minimized surface dose variation while using commercially available RA seeds. RA stents loaded with 60 -125 Seed-in Carrier, GE Healthcare were endoscopically placed in the naïve esophagus of 3 Yucatan swine. Previously, mock treatments using dummy seeds were performed in three similar pigs. Stents were left in place for between 4 and 7 weeks and reaction of the mucosa was assessed macroscopically and histologically. Results: Porcine esophageal tissue received doses in the range of 132-160 Gy at the mucosal surface and 39-48 Gy at a distance of 5mm from the stent surface. Tissues were collected at 0, 1 and 10 weeks after stent removal. No macroscopic radiation damage was seen at autopsy and pathological analysis yielded no radiation-related damage in evaluable tissues. Conclusions: In this preliminary study, no local or systemic damage due to radiation was observed after treatment of normal esophageal tissue with a vLDR stent device. Ongoing research aims to determine dose tolerance in esophageal tissue and target application of vLDR in other locations in the GI tract.
CUSUM analysis of mortality following esophagectomy to allow for identification and intervention of quality problems.
Authors: McLaren Patrick James , Hart Kyle D , Dolan James P. , Hunter John G.
Published: March 2017

203

Background: CUSUM analysis is an analytic tool for monitoring institutional quality and clinical outcomes. CUSUM is a summative plot of an event that occurs over time. The slope that is generated can be used to determine rates of occurrence and deviations from an accepted rate. CUSUM can be used to monitor mortality rates following esophagectomy. Methods: A single institution prospectively maintained esophageal disease registry was used to construct CUSUM plots for in-hospital and 30-day mortality. All patients undergoing esophagectomy with reconstruction from 1995-2015 were included for analysis. Time points that deviated from an accepted mortality rate of 5% were evaluated for cause analysis. Results: From 1995-2015, 485 esophagectomies were performed with a cumulative in-hospital mortality rate of 4.7%. In 2008 our institution shifted to a primarily minimally invasive approach. Prior to March 2008 in-hospital mortality was 7.4%. After this time, in-hospital mortality was 2.1%, corresponding with a decreased slope of the CUSUM plot. A second period was investigated from September 2012-October 2012. Eight esophagostomies were performed with 3 deaths for a 37.5% mortality rate. All 3 patients were deaths related to ARDS and multisystem organ failure; this prompted an institutional epidemiologic investigation, as well as review of our enhanced esophageal recovery pathway. Since this time frame in-hospital mortality has been 1%. Conclusions: CUSUM analysis offers a useful observational tool to monitor institutional quality following esophagectomy. Investigations into mortality can identify quality problems and can lead to implementation of improved process measures that may lead to improved future outcomes.
Toxicity and survival in older versus younger esophageal cancer (EC) patients (pts) treated with neoadjuvant chemoradiotherapy (nCRT).
Authors: Jain Rishi , Yee Jia-Llon , Shaikh Talha , Au Cherry , Handorf Elizabeth , Meyer Joshua E. , Dotan Efrat
Published: March 2017

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Background: Trimodality therapy (TMT) for EC is associated with significant toxicity. Limited data are available on the safety of nCRT in vulnerable populations such as older pts. We evaluated the associations between age and toxicity as well as survival in pts treated with nCRT as part of TMT. Methods: A retrospective review of pts with EC treated with nCRT as part of TMT at an academic cancer center between 2002-2014 was conducted. We assessed the impact of age (<65 versus ≥65) on chemotherapy dose reduction/interruption (DRI), hospitalizations (H), and toxicity including grade 3/4 (G3+T), and composite number of any grade non-hematologic (NHT) or hematologic (HT) toxicity. Relapse free (RFS) and overall survival (OS) were assessed with the Kaplan-Meier (KM) method. Univariate (UVA) and multivariate regression analyses (MVA) were performed. Results: 125 pts were identified. The median age was 63 (range 35-80) with 46% of patients ≥65.There were increased co-morbidities in older pts and more active smokers in younger group. Otherwise,baseline characteristics were well balanced. In UVA, advanced age was associated with increased HT, and a trend towards increased G3+T (table 1). After adjusting for covariates in MVA, no differences in toxicity were noted between older and younger pts. There were no differences in RFS or OS between groups (table).Conclusions: Our study demonstrates similar rates of toxicity and outcomes among older and younger EC patients treated with nCRT as part of TMT. Advanced age alone should not be a barrier to nCRT. [Table: see text]
Predictive factors for long-term survival after conversion surgery for unresectable gastric cancer: A retrospective analysis.
Authors: Sagawa Tamotsu , Hamaguchi Kyoko , Sakurada Akira , Tamura Fumito , Hayashi Tsuyoshi , Fujikawa Koshi , Takahashi Yasuo , Sato Yasushi
Published: March 2017

205

Background: Chemotherapy occasionally converts an initially unresectable gastric cancer to a resectable cancer. However, the association between clinical factors and long-term prognosis after conversion surgery for unresectable gastric cancer has not been investigated. Methods: We retrospective reviewed 36 gastric cancer patients who underwent conversion surgery at our institute between 2005 and 2015. Clinicopathologic characteristics and patient outcomes were analyzed, with particular focus on the potential to predict long-term survival. Results: The number of incurable factors was one in 31 patients and two in 5, including metastases to non-regional lymph node in 22, peritoneum in 10, liver in 6, and lung in 3. The regimen of chemotherapy was Docetaxel/CDDP/S-1 in 23 patients, Docetaxel/CDDP/S-1+Trastuzmab in 7, S-1/CDDP in 2, Docetaxel/S-1 in 1, CPT/CDDP in 1, and S-1 monotherapy in 1. Complete resection with no residual tumor (R0) was achieved in 25 of 36 patients, microscopic residual tumor status (R1) in 10, and macroscopic residual tumor (R2) in 1. The 3-year overall survival (OS) rate among the 36 patients who underwent conversion surgery was 60.3 % (median survival time, 1200 days). The 3-year OS rate among patients who underwent R0 resection was 70.8 % (median survival time, 1503 days). Patients who underwent R0 resection had significantly longer OS times than those who underwent R1 and R2 resection ( p=0.0124). We selected 16 variables in addition to residual tumor for Kaplan–Meier analysis. According to the log rank test, the following four variables were significantly associated with a better OS: clinical response to 1st line therapy (CR or PR vs. SD or PD)( p=0.0283), pathological response grade (1b-3 vs. 0-1a) ( p=0.0304), pathological tumor depth (CR or T1~T3 vs. T4) ( p=0.0261), and pathological nodal stage (N0〜2 vs. N3) ( p=0.0086). Conclusions: Our data indicates that clinical response to 1st line therapy in preoperative characteristics, R0 resection, pathological response grade, pathological tumor depth, pathological nodal stage in postoperative characteristics are predictive factors that can be expected to long-term survival.