bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the effects of neoadjuvant therapy on stage specific outcome estimates in patients with completely resected gastric cancer.
Authors: Lowe Michael C. , Chou Joanne F. , Capanu Marinela , Coit Daniel G.
Published: February 2017

139

Background: The current AJCC staging system for gastric cancer is based on pathologic staging and fails to take into consideration the effects of neoadjuvant therapy. We hypothesize that patients receiving neoadjuvant therapy have a worse outcome than patients with identical pathologic stage not receiving neoadjuvant therapy. Methods: We queried a prospectively maintained gastric cancer database for patients undergoing potentially curative resection for gastric adenocarcinoma between 1985 and 2012. Disease-specific survival (DSS) was estimated by Kaplan-Meier methods. The relationship between DSS and previously identified clinical risk factors was evaluated using Cox regression method. Results: A total of 2,752 patients were identified; of these 904 received neoadjuvant therapy and 1,848 received no neoadjuvant therapy. Patients receiving neoadjuvant therapy were younger (60.7 vs. 65.7 years) and more often male (72.9% vs. 62.4%). Their tumors were more often at the GE junction, but histology, differentiation, and rates of perineural and vascular invasion were similar. Of the 904 patients that received neoadjuvant treatment, 108 (11.9%) had a complete pathologic response. At a median follow up of 4.5 years, 5-year DSS is significantly worse for stage I patients (77% vs. 92%, p < 0.001) and stage III patients (18% vs. 28%, p = 0.025) receiving neoadjuvant therapy; there is a trend towards worse survival for stage II patients (60% vs. 67%, p = 0.059). Factors associated with inferior DSS include age, male sex, diffuse or mixed histology, tumor site, depth of invasion, tumor size, number of positive and negative lymph nodes, and neoadjuvant treatment. The effect of neoadjuvant treatment remains significantly associated with DSS (HR 1.30 [95%CI: 1.12-1.50], p = 0.0004) after adjusting for these other known risk factors. Conclusions: Patients receiving neoadjuvant therapy have a worse stage-specific survival compared to patients not receiving neoadjuvant treatment. The AJCC staging system should be updated to reflect this difference in survival in order to appropriately prognosticate based on pathologic staging.
Real world treatment patterns of previously treated advanced gastric and gastroesophageal junction adenocarcinoma (GC) in Mexico.
Authors: Jones Kyla , SILVA JUAN ALEJANDRO , Novick Diego , Botello Brenda S , Monroy Cruz Bárbara , Iglesias-Chiesa JM , Quintana Miguel
Published: February 2017

143

Background: Little evidence is available on the management of patients (pts) with advanced GC after 1st-line treatment (tx). Until recently, no licensed therapies for 2nd-line tx were available. This study presents real-world data on pts characteristics, tx patterns, and resource utilization for these pts in Mexico. Methods: Data from medical charts was collected from 3 centers (tertiary-level). Eligible pts were ≥ 18 years old, diagnosed Jan 2007 - Jan 2015 with advanced or metastatic GC, had received 1st-line fluoropyrimidine+platinum, had ≥ 3 months of follow-up after 1st-line discontinuation, and had not participated in a clinical trial. Data were summarized using descriptive statistics. Results: Data from 180 charts was collected; the majority from the Mexican Institute of Social Security (IMSS) (167; 92.8%). Pts' mean age was 57.2 (±12.4) years and 56.7% were male. ECOG performance status (PS) during 1st-line tx was 78.3% PS = 1, 17.2% PS = 2, 0% PS = 0. A total of 16 unique 1st-line regimes were identified, of which EOX (32.2%), XELOX (23.3%), and ECF (14.4%) were the most frequent. The most common reasons for discontinuation were completion of planned regimen (27.2%), toxicity (27.2%) and disease progression (16.7%). A total of 151 (83.9%) pts received 2nd-line chemotherapy. Of these, 54.3% were PS = 1 and 33.1% PS = 2. A total of 19 regimes were identified; with the most frequent being capecitabine (34.4%), docetaxel (16.6%), and XELOX (13.9%). Among pts who received 2nd-line chemotherapy, 50 (33.1%) received 3rd-line chemotherapy. Resource use for patients receiving 2nd-line chemotherapy was: pain interventions (7.3%), nutritional support (1.3%), radiotherapy (13.9%), transfusions (10.6%), inpatient care (15.2%), emergency room visits (2.0%) and outpatient visits (other than scheduled follow-up) (3.3%). Conclusions: This study shows considerable variation in chemotherapy regime in both 1st- and 2nd-line therapy of pts with advanced GC. Understanding GC tx patterns in Mexico will help address unmet needs. Limitations: Pts who did not receive 2nd-line tx are likely underrepresented because these pts are typically managed at local clinics and not tertiary hospitals.
S-1 in combination with docetaxel and oxaliplatin (DOS) every 2 weeks (DOS2w) or every 3 weeks (DOS3w) in patients with advanced gastro-esophageal adenocarcinoma (aGEA): Final results of 2 parallel phase I studies.
Authors: Qvortrup Camilla , Bjerregaard Jon Kroll , Pfeiffer Per
Published: February 2017

153

Background: S-1 in combination with cisplatin is one of several accepted doublets, but triplet combinations with docetaxel (D) increase efficacy and substitution with oxaliplatin (O) and oral fluoropyrimidines (S-1) ease the administration. Based on our recent phase I study, we wanted to establish a recommended dose (RD) for an every 3 week regimen (DOS3w) but inspired by promising data from the GATE study, we also sought for an every second week regimen (DOS2w). Therefore we designed this dose-finding study which present the first experience with the combination of D+O+S-1 (DOS) in Caucasian patients (Clinical trial ID: 2011-003471-11). Methods: All pts had chemo-naïve aGEA. We used a standard 3+3 phase I design. DOS2w (dose levels 1A-4A) was given with escalating doses of D (30 to 50 mg/m2 day 1) and S-1 (2x30 to 2x35 mg/m2/day - days 1-7) with a fixed dose of O (70 mg/m2day 1) every 2 weeks for a maximum of 9 cycles. DOS3w (dose levels 1B-3B) was given with escalating doses of D (40 to 60 mg/m2 day 1) and fixed doses of O (100 mg/m2 day 1) and S-1 (2x25 mg/m2/day - days 1-14 every 3 weeks) for a maximum of 6 cycles. After the planned number of DOS, S-1 maintenance therapy (2x30 mg/m2days 1-14 every 3 weeks) was administered until PD or toxicity. Toxicity was evaluated according to NCIC-CTC 4.0. Dose-limiting toxicity (DLT) was evaluated after the first course of DOS and defined as non-hematological toxicity grade ≥ 3 or febrile neutropenia. RD was defined as the highest level at which less than 2/6 of pts experienced a DLT. Once RD was established, this level was expanded to at least 6 pts. Results: From Oct. 2013 to Mar. 2015, 18 and 16 patients received DOS2w and DOS3w, respectively. Median age was 63 years (49-78). DLTs in both cohorts were febrile neutropenia. Response rates were 56% and 57% and OS were 13.8 and 11.6 months, respectively. Conclusions: We recommend DOS2w at dose level 3A (D 40 mg/m2 day 1; O 70 mg/m2 day 1 and S-1 2x35 mg/m2/day orally days 1-7 every 2 weeks) and DOS3w at dose level 2B (D 50 mg/m2 day 1; O 100 mg/m2 day 1 and S-1 2x25 mg/m2/day orally days 1-14 every 3 weeks). Both regimens are well-tolerated in an out-patient setting. Clinical trial information: 2011-003471-11.
Impact of anatomical location of positive lymph node on TNM classification in patients with node positive gastric cancer.
Authors: Tokunaga Masanori , Hikage Makoto , Makuuchi Rie , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Terashima Masanori
Published: February 2017

155

Background: In the 7th edition of TNM classification, node positive gastric cancer is subclassified into three categories (N1, 1-2 positive nodes; N2, 3-6 positive nodes; N3, 7 or more positive nodes) according to the number of positive lymph node (LN). However, anatomical location of positive LN is not taken into account in the TNM classification, although Japanese classification for gastric cancer had adopted anatomical location oriented nodal staging system and had shown relevance between location of positive LN and survival outcome. The aim of the present study is, therefore, to clarify the impact of anatomical location of positive LN on numerical number oriented, latest TNM nodal staging system. Methods: The present study included 1047 node positive gastric cancer patients who underwent curative gastrectomy at the Shizuoka Cancer Center between September 2002 and December 2014. Survival outcomes were compared between patients with positive extra-perigastric lymph node (PEPLN) and those with positive perigastric lymph node (PPLN) in each nodal stage according to the 7th edition of TNM classification. Results: The present study included 471 N1 patients, 309 N2 patients, and 267 N3 according to the 7th edition of TNM classification, and 5-year survival rates (5ysr) were 81.8%, 70.5%, and 51.9%, respectively. In the N1 group, 5ysr was 75.4% in patients with PEPLN, while it was 83.2% in those with PPLN, and the difference was not statistically significant (P = 0.105). It was also similar between patients with PEPLN (64.2%) and those with PPLN (73.8%, P = 0.343) in the N2 group. However, in the N3 group, survival outcome was significantly worse in patients with PEPLN (47.9%) than in those with PPLN (63.9%, P = 0.036). Conclusions: In the N1 and N2 group, involvement of extraperigastric LN did not have impact on survival outcome. On the contrary, in the N3 group, patients with PEPLN showed worse survival outcome than those with PPLN, and they could be potential candidates for intense postoperative adjuvant treatment.
Accuracy of clinical staging with EUS for early stage esophageal cancer: Are we denying patients beneficial neoadjuvant chemo-radiation?
Authors: Luu Carrie , Garcia-Henriquez Norbert , Klapman Jason , Harris Cynthia L. , Almhanna Khaldoun , Hoffe Sarah E. , Pimiento Jose Mario , Fontaine Jacques
Published: February 2017

163

Background: Esophagectomy alone has been considered the standard of care for early stage esophageal cancer (EC) while neoadjuvant therapy is now standard for locally advanced disease. The choice of treatment therefore hinges on accurate locoregional staging by endoscopic ultrasound (EUS). Our objective is to evaluate the accuracy of EUS performed in a high-volume tertiary cancer center in clinical stage T1N0 (cT1N0) and T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy without neoadjuvant therapy. Methods: A retrospective review of the esophageal cancer database at a single institution was performed. Patients with cT1N0 and cT2N0 esophageal cancer based on EUS undergoing esophagectomy without neoadjuvant treatment were evaluated. Patient demographics, tumor characteristics, and treatment were reviewed. Surgical pathology was compared to EUS staging. Results: Between 2000 and 2015, 139 patients were identified. There were 25 (18%) female and 114 (82%) male patients. The tumor location included the middle 1/3 of the esophagus in 11 (8%) and lower 1/3 and gastroesophageal junction in 128 (92%) patients. Eighty-one percent of patients had adenocarcinoma, 9% had squamous cell carcinoma, 9% had Barrett’s dysplasia, and 1% had mixed histology. Clinical staging were as follows: 110 (79%) patients had cT1N0 and 29 (21%) patients had cT2N0 tumors. For the entire cohort, preoperative EUS matched the final surgical pathology in 76/139 patients for an accuracy rate of 53%. Twenty-nine patients (21%) were under-staged by EUS; of those, 19 (14%) had unrecognized nodal disease. This included 12/109 (11%) of cT1N0 and 7/29 (24%) of cT2N0 patients. Conclusions: The accuracy of preoperative EUS staging in early esophageal cancer remains sub-optimal. Interestingly, a significant proportion (24%) of cT2N0 EC patients were found to have positive lymph nodes on surgical pathology, and perhaps these patients could have benefitted from neoadjuvant therapy. In light of these findings, the current management of cT2N0 esophageal cancer should be reconsidered.
Outcomes of minimally invasive versus open esophagectomy for esophageal cancer: A single-center case-control study.
Authors: Santos Sousa Hugo Miguel Teixeira Ferraz Dos , Mesquita Márcio , Aral Marisa , Costa-Maia José
Published: February 2017

171

Background: Esophagectomy is a major surgery associated with significant morbidity and mortality. There is growing evidence in literature that the minimally invasive approach in esophagectomy (MIE) may decrease morbidity. The aim of this study was the comparative analysis of the outcomes between MIE and open esophagectomy (OE) for esophageal cancer. Methods: Analysis (case-control study) of a prospective database with esophageal cancer cases submitted to curative intent surgery, between May 2006 and October 2014, in an Upper GI Surgery Unit. For this analysis, cases of non-resectional surgery were excluded. Results: From the initial population (n = 79), 65 cases (Group A: 24 MIE - 13 totally MIE and 11 hybrid MIE; Group B: 41 OE, including 5 cases of conversion from MIE) were included. Both groups were matched for gender, age, comorbidities, BMI, tumor location and histology, staging (cT and cN), neoadjuvant therapy and type of surgery. The presence of postoperative morbidity was 37,5% in MIE vs 61% in OE (p = 0,058), with a rate of respiratory complications of 16,7% and 22%, respectively (p = ns). Statistically significant differences were seen in Clavien classification of postoperative morbidity (p = 0,018) and in postoperative mortality (MIE 0% vs OE 22%, p = 0,021). Conclusions: The results of this case-control study provide further evidence for the feasibility and possible improvements in the postoperative morbidity and mortality of MIE, when performed in differentiated centers.
Accuracy of AASLD guidelines for pre-operative diagnosis of hepatocellular carcinoma in a surgical population.
Authors: Yang Edwin , Tiffany Hennedige Priyanti , Lim Miaoshan , Thng Choon Hua , Chow Pierce K. H.
Published: February 2017

198

Background: The diagnosis of Hepatocellular Carcinoma (HCC) is mainly by dynamic imaging techniques based on guidelines such as that of the American Association for Study of Liver Disease (AASLD). No biopsy is required if criteria in the guidelines are met due to high pre-test probability of disease, risk of tumor seeding and patient morbidity that occurs with invasive liver biopsy. The 2005 AASLD guidelines mandates that there be liver cirrhosis before an imaging diagnosis of HCC can be made. However, updates to the guidelines in 2010 have been expanded to patients with either cirrhosis and/or chronic Hepatitis B carriers. AIM: To compare the sensitivity and positive predictive values of the 2005 and 2010 guidelines in a Hepatitis-B endemic region. Secondary aim: To evaluate proportion of patients who avoided unnecessary biopsies. Methods: A retrospective study of 176 patients from 2006-2010 from a joint cancer service in our centre who had undergone surgical resection for presumptive diagnoses of HCC, were analysed. Their hepatitis status and imaging findings were also examined. Multiphasic CT Liver images were re-examined by 2 oncologic radiologists and the diagnosis of HCC and cirrhosis was only made when there was concordance in opinion. Results: Of all cases, 89.6% of patients were histologically proven HCCs. Sensitivity of detecting cirrhosis on CT was 83.2% with an accuracy of 81.5%. Sensitivity of diagnosis based on the 2010 and 2005 guidelines were 58.1% and 57.4% respectively. When the sensitivities of the previous vs revised guidelines were compared using Mcnemar’s Test, the 2010 guidelines showed a 24.6% increase in sensitivity (p < 0.05). 4.65% more cases avoided unneeded biopsies when applying the 2010 criteria. Conclusions: Diagnosis of HCC under the 2005 AASLD guidelines were based on the pre-operative diagnosis of cirrhosis which in this centre, was of high sensitivity and accuracy. The increase in the sensitivity of diagnosing HCC in the 2010 criteria may reduce the need for invasive biopsy and likelihood for tumor seeding.
Resectability assessment of enhanced CT and contrast-enhanced endoscopic ultrasonography for the periampullary neoplasm.
Authors: Yu Pengfei
Published: February 2017

199

Background: To evaluate the efficacy of enhanced CT and contrast-enhanced endoscopic ultrasonography (CE-EUS) for assessment of the resectability of periampullary neoplasm. Methods: a prospective analysis of 93 patients with periampullary neoplasm underwent CT and CE-EUS was conducted to compare the imaging data with the surgical and pathological findings, in order to evaluate their efficacies for the resectability assessment. Results: There was no significant difference in sensitivity and specificity between CT and CE-EUS in adjacent organ invasion, lymph node metastasis and liver metastasis (p > 0.05). For the diagnosis of periampullary neoplasm and assessment of vascular invasion, CE-EUS was better than CT (94.6% vs 84.1%,P = 0.023; 96.2% vs 85.9%, P = 0.041). Logistic regression showed that the accuracy of CE-EUS in determining adjacent organ invasion was correlated with the tumor size, and vascular invasion was correlated with the tumor location and size. Conclusions: CE-EUS has advantages in the assessment of the resectability of periampullary neoplasm, especially for the assessment of vascular invasion, and can be used as a supplementary Imaging technology to the enhanced CT.
The optimal time-interval to re-resection for incidentally discovered gallbladder cancer: A multi-institution analysis from the US Extrahepatic Biliary Malignancy Consortium.
Authors: Ethun Cecilia Grace , Postlewait Lauren McLendon , Pawlik Timothy M. , Buettner Stefan , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Jin Linda , Weber Sharon M. , Salem Ahmed I. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Maithel Shishir Kumar
Published: February 2017

201

Background: Current recommendation is to perform re-resection for select patients with incidentally discovered gallbladder cancer. The interval time to re-resection that optimizes both patient selection and long-term survival is not known. Methods: All patients with incidentally discovered gallbladder cancer who underwent re-resection at 10 institutions from 01/2000-05/2015 were included. The interval time to re-resection was analyzed. Primary outcome was overall survival (OS). Results: Of 449pts with gallbladder cancer, 233 (52%) were discovered incidentally and underwent attempted re-resection at 3 different time-intervals from the date of original cholecystectomy: Group A: 0-4wks (49pts, 21%); B: 4-8wks (91pts, 39%); C: > 8wks (93pts, 40%). All 3 groups were similar with regards to T-stage, LN involvement, grade, and post-operative complications. Group A tended to have distant disease found less frequently at the time of re-resection (11% vs 20% vs 19%; p = 0.38) and was least likely to have residual disease on pathologic analysis (29% vs 47% vs 49%; p = 0.048). Despite these findings, patients who underwent attempted re-resection between 4-8 weeks had the longest median OS (Group B: 40.4mo) compared to those who underwent early (Group A: 18.1mo) or late (Group C: 23.6mo) re-exploration (p = 0.015). A 4-8 week time interval to re-resection, presence of residual disease, advanced T-stage, LN involvement, high grade, and positive margin were associated with decreased OS on UV Cox regression (all p < 0.05). Only a 4-8 week time interval to re-resection (HR 0.43, 95%CI 0.21-0.90; p = 0.02), advanced T-stage (HR 2.65, 95%CI 1.16-6.09; p = 0.02), and margin positivity (HR 2.46, 95%CI 1.16-5.22; p = 0.02) persisted on MV analysis. Conclusions: The optimal time-interval for attempted re-resection for incidentally discovered gallbladder cancer appears to be between 4-8 weeks after the date of the original cholecystectomy.
Adjunctive role of preoperative liver magnetic resonance imaging added to computed tomography among resected pancreatic cancer patients.
Authors: Kim Hyoung Woo , Hwang Jin-Hyeok , Lee Jong-chan , Paik Kyu-hyun , Kang Jingu , Kim Jaihwan , Park Young Soo
Published: February 2017

207

Background: Multi-detector computed tomography using pancreatic protocol (pCT) has been a preferred diagnostic imaging modality before resection of the pancreatic ductal adenocarcinoma (PDAC), because an adjunctive role of liver magnetic resonance imaging (MRI) is still unclear. The current study evaluated whether liver MRI added to pCT can help to select proper surgical candidates, and reduce the risk of early recurrence, eventually result in longer survival in resected PDAC patients. Methods: Among 197 PDAC patients who underwent curative-intended surgery, 167 patients who achieved complete resection with no grossly visible tumor were enrolled retrospectively. All patients had no metastatic lesions on pCT and/or MRI, preoperatively. Among them, 102 patients underwent pCT alone (CT group), and 65 patients liver MRI as well as pCT (MRI group). Results: By adding the liver MRI, hepatic metastases were newly discovered in 3 of 58 patients (5.2%) with no hepatic lesions on pCT and in 17 of 53 patients (32.1%) with indeterminate hepatic lesions on pCT. Among 167 patients who achieved R0/R1 resection, the median overall and disease-free survival were 20.1 vs 29.3 months and 8.5 vs 10.0 months in the CT and the MRI group, respectively (p = 0.011 and = 0.012), during median follow-up of 16.4 months. 80 (78.4%) patients in the CT group and 39 (60.0%) in the MRI group experienced recurrence during follow-up. Cumulative initial hepatic recurrence rate was higher in the CT group than in the MRI group (43.7% vs 18.5% at 1yr and 57.4% vs 26.9% at 2yr, p < 0.001), although the other sites recurrence did not differ in both groups. Conclusions: Liver MRI added to pCT has an incremental value in detecting PDAC hepatic metastases. Furthermore, because PDAC patients who underwent resection after liver MRI as well as pCT expect lower rate of hepatic recurrence and better survival than pCT alone, therefore, liver MRI added to pCT is needed to patients who planned curative resection of PDAC.
Significance of lymph node metastasis in pancreatic neuroendocrine tumors.
Authors: Taki Katsunobu , Hashimoto Daisuke , Ozaki Nobuyuki , Tomiyasu Shinjiro , Inoue Risa , Yamamura Kensuke , Kitano Yuuki , Arima Kota , Kaida Takayoshi , Higashi Takaaki , Imai Katsunori , Chikamoto Akira , Beppu Toru , Takamori Hiroshi , Hirota Masahiko , Baba Hideo
Published: February 2017

210

Background: Pancreatic neuroendocrine tumor (PNET) is uncommon, and its prognosis is generally better than that of pancreatic cancer. Although some PNET patients have lymph node metastasis, its effect on their prognosis is unclear, lymph node dissection for PNET is controversial. Our study aimed to clarify the significance of lymph node metastasis in PNET. Methods: We retrospectively examined 83 PNET patients who underwent pancreatic resections at Kumamoto University Hospital, Saiseikai Kumamoto Hospital and Kumamoto Regional Medical Center from April 2001 to December 2014. We excluded NET G3 from them. Their clinicopathological parameters were analyzed by the absence or presence of lymph node metastasis, and with regard to disease-free survival (DFS) and overall survival (OS). Results: Although 5-year DFS was lymph node metastasis group: 73.3%, and no lymph node metastasis group: 85.0% (P = 0.474); and 5-year OS was lymph node metastasis: 91.7% and no lymph node metastasis: 96.2% (P = 0.055), lymph node metastasis was not an independent risk factor for DFS or OS in multivariate analysis. However, tumors larger than 1.8 cm were found to be an independent prognostic factor. Conclusions: Although lymph node metastasis was not an independent prognostic factor, tumors larger than 1.8 cm were an independent prognostic factor, and warrant lymph node dissection for PNET patients with tumors of this size.
The prognostic value of stroma desmoplasia in pancreatic ductal adenocarcinoma.
Authors: Fokas Emmanouil , Silva Michael A , D'Costa Zenobia , Bockelmann Robin , Soonawalla Zahir , Liu Stanley K. , O'Neill Eric , Mukherjee Somnath , McKenna William Gillies , Muschel Ruth J , Wang Lai Mun
Published: February 2017

211

Background: Pancreatic ductal adenocarcinoma (PDAC) often presents an abundant desmoplastic stroma. We assessed the prognostic value of stroma density and activity in patients with resectable PDAC treated with surgery and adjuvant gemcitabine-based chemotherapy. Methods: FFPE-tissue originating from the pancreatectomy of 145 patients was immunohistochemicallystained for haematoxylin-eosin and Masson’s trichrome to assess stroma density, and alpha-smooth muscle actin (αSMA) expression for activated pancreatic stellate cells. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS). Results: After a mean follow-up of 20 months (range, 2-69 months), the median OS was 21 months and the 3-year OS was 35.7 %. In multivariate analysis, highly-dense stroma was an independent prognostic parameter for OS (p = 0.001), PFS (p = 0.007), LPFS (p = 0.001) and DMFS (p = 0.002), while αSMA expression lacked significance. Interestingly, highly-dense stroma retained significance for the four clinical endpoints only in early (pT1-2) but not late (pT3-4) stage tumors. Additionally, late pT-stage (pT3-4), the presence of lymph node metastases (pN+ vs pN0), perineural/neural invasion PNI and adjuvant chemotherapy also correlated with prognosis in multivariate analysis. Conclusions: In summary, stroma density represents an independent prognostic marker in PDAC patients treated with adjuvant chemotherapy. Our findings highlight the complexity of desmoplasia and indicate that highly-dense stroma is associated with better outcome. Further validation of the prognostic value of stroma as a biomarker and its role in PDAC biology is warranted and will be performed in a prospective study.
Conditional survival probability of long-term survival after resection of peri-hilar cholangiocarcinoma.
Authors: Buettner Stefan , Ethun Cecilia Grace , Maithel Shishir Kumar , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Fields Ryan C. , Krasnick Bradley , Weber Sharon M. , Salem Ahmed I. , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Beal Eliza W , Hatzaras Ioannis , Shenoy Rivfka , Pawlik Timothy M.
Published: February 2017

212

Background: Traditional survival analyses focus on factors determined at the time of surgery and may not be accurate over time. Conditional survival (CS) estimates future prognosis based on survival time accrued following treatment. We sought to define differences between actuarial and CS among patients after resection of peri-hilar cholangiocarcinoma (PHCC). Methods: 242 patients who underwent resection for PHCC between 2000-2014 were identified from 10 major HPB centers. Cox regression models were used to evaluate factors associated with overall survival. CS was calculated as the probability of surviving an additional 3 years at “x” years after surgery using the formula CS3=S(x+3)/Sx. Results: Median patient age was 67 yrs (IQR:57-73) and the majority (73.6%) of patients had a major hepatic resection. Surgical margin status was R0 (n=160; 66.1%) or R1 (n=82; 33.9%). Tumor grade was well- (n=43; 19.1%), moderate- (n=131; 58.2%) or poorly- (n=51; 22.6%) differentiated. Most patients had T1 (13.8%) or T2 (66.4%) disease, while a smaller subset had T3 (17.3%) or T4 (2.6%) disease. Lymph node metastases were present in 79 (32.6%) patients. While actuarial survival decreased over time from 46.3% at 2 years to 18.2% at 5 years following surgery, 3-year CS increased over time among those patients who survived. The CS3 at 2 years (i.e. the probability of surviving to postoperative year 5 after having already survived to year 2) was 39.3% and increased to 54.4% at year 5 (Table). Factors associated with worse OS included lymph node metastases (HR 1.71; 95%CI, 1.24-2.36) and perineural invasion (HR 1.54; 95%CI, 1.02-2.33) (both P<0.05). CS3 for high-risk patients exceeded the actuarial survival, e.g. patients with perineural invasion had an actuarial survival of 15.4% at 5 years vs. a CS3 at 2 years of 37.6% (Δ=22.2%). Conclusions: CS provides a more dynamic means to estimate future survival among patients who have accrued survival time, especially in high-risk patients who were predicted to have short survival times. [Table: see text]
Interim results of a screening protocol for early detection of pancreatic cancer in asymptomatic high-risk patients.
Authors: Gangi Alexandra , Malafa Mokenge Peter , Klapman Jason
Published: February 2017

223

Background: Pancreatic cancer (PC) is the 4th leading cause of cancer deaths in the US but is rarely diagnosed at an early curable stage. Early detection of PC will have measurable improved outcomes in affected patients. This study sets out to evaluate if EUS can detect early stage pre-cancerous or cancerous changes in the pancreas of high risk (HR) patients. Methods: After IRB review, a clinical trial (NCT01662609) to evaluate HR patients was opened to accrual. Study subjects met specified inclusion and exclusion criteria as defined by the protocol. Enrolled subjects underwent EUS followed by screening as defined by study protocol: subjects with normal EUS underwent repeat EUS at 1 year; subjects with abnormal EUS underwent fine needle aspiration (FNA) if a mass or cyst was found and measured ≥ 5mm and did not undergo FNA if the lesion measured < 5mm. Those with indeterminate or benign FNA underwent pancreatic CT scan with repeat EUS/FNA at 3 or 6 months respectively. Those with positive FNA were treated appropriately based on findings. Patients with mass/cyst < 5mm underwent repeat EUS/FNA at 3 months. Targeted follow-up is 5 years. Results: Of the 52 subjects accrued thus far, 41 were available for interim analysis. Twenty-seven (67%) subjects had a normal EUS while 14 (34%) subjects had abnormal findings. Two patients had large cysts with FNA consistent with an intraductal papillary mucinous neoplasms (IPMN). These 2 subjects ultimately underwent surgical resection. The 12 remaining subjects had at least 1 subcentimeter lesion and are being routinely screened per the outlined protocol. Conclusions: EUS screening of asymptomatic individuals who are at high risk for pancreatic cancer as defined by our inclusion criteria frequently detects abnormal lesions in the pancreas. These lesions include high risk IPMNs that warrant surgical resection. Our results validate the results of other high risk screening protocols and support the screening of individuals who are at high risk for development of pancreatic cancer. Clinical trial information: NCT01662609.
A reappraisal of staging laparoscopy in three subtypes of cholangiocarcinoma: A multi-institution analysis from the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Davidson Jesse , Jin Linda , Krasnick Bradley , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Weber Sharon M. , Salem Ahmed I. , Hawkins William G. , Strasberg Steven M. , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Maithel Shishir Kumar , Fields Ryan C.
Published: February 2017

226

Background: Staging laparoscopy (SL) has been shown to be useful in extrahepatic biliary tumors (EHBTs) to avoid unnecessary laparotomies in unresectable disease. However, the added value of SL for EHBTs has not been well characterized in the era of modern imaging. Methods: We reviewed patients from ten institutions who underwent attempted resection of EHBTs between 1998 and 2015, including gallbladder, distal, and hilar subtypes. Yield of laparoscopy = (Number of positive SL / Total number of SL). Accuracy of laparoscopy = (Number of positive SL / Patients with unresectable disease). These data were compared by use of the chi-squared test and significance was p <.05. Results: A total of 1,075 patients were taken to the OR for attempted curative resection, of which 250 patients (23%) underwent staging laparoscopy. SL identified unresectable disease in 42 patients (yield 17%). Of 208 patients who underwent exploratory laparotomy (EL) after negative SL, 19 were found to be unresectable (false negative rate 9%). Amongst gallbladder, hilar, and distal pathology types, the yield of SL were 18%, 13%, 17%, respectively (p=0.78). Accuracy of SL was 61%, 71%, and 91% respectively (p=0.17), with an accuracy of 68%. A total of 825 patients went directly to EL, of which 103 (13%) failed. The rate of failure for patients going straight to EL was significantly higher for patients with gallbladder (n=66/287, 23%) when compared with hilar (n=15/274, 6%) and distal EHBT (n=22/264, 8%) (p<0.001). Conclusions: Our analysis demonstrates that staging laparoscopy still has added utility in preventing unnecessary laparotomies in unresectable disease for selected patients with EHBTs, although the overall yield is low. Patients with gallbladder cancer had high rates of failed laparotomies, representing a subset who may benefit from more frequent use of staging laparoscopy at the time of resection. [caption]Yield and accuracy of detecting unresectable disease with staging laparoscopy. [/caption] [Table: see text]
Does receptor status impact survival of patients with mid-gut neuroendocrine tumors?
Authors: Wang Yi-Zarn , Beyer David T
Published: February 2017

227

Background: Neuroendocrine tumors (NETs) are rare neoplasms increasing in incidence due to greater awareness among patients and physicians. The most reliable diagnostic imaging study has been the 111In-pentetreotide scan which binds to somatostatin receptors of the tumor. It is known that breast cancer treatment outcome is tightly correlated with degree of tumor cell differentiation and receptor status. We hypothesize that receptor status determined by 111In-pentetreotide (Octreoscan) and 123I-Metaiodobenzylguanidine (MIBG) imaging results can predict prognosis for small bowel NETs. Methods: A database with all patients seen at the LSU/Ochsner NET Program was queried for nuclear medicine scan results. Included patients had a histologically confirmed ileal, jejunal, or small intestinal NET and Octreoscan and MIBG imaging results. Kaplan-Meier survival analysis was performed and statistical significance was determined by Log-rank test (p<0.05). Results: 110 patients diagnosed between July 1994 and September 2013 were included. There were 64 females (64/110, 58%) and 46 males (46/110, 42%). Seventy-three (73/110, 66%) and sixty-three (63/100, 57%) patients had positive Octreoscan and MIBG imaging results, respectively. 5- and 10-year survival was calculated and sorted into four groups based on imaging positivity. Conclusions: Most midgut NETs present with positive Octreoscans which reflect positive receptor status; a favorable feature in prognosis based on the well-established breast cancer treatment experience. Unexpectedly, our data have shown receptor scintigraphy studies result has no baring in short term survival. More surprisingly, patients with double positive scan demonstrate a substantial survival disadvantage over a longer interval. Further longitudinal studies are required to determine if NET receptor status can reliably predict patient prognosis and the mystery of the reversal relation of the receptor status of NET patients and their prognosis. [Table: see text]
Symptomatic presentation as a predictor of recurrence in gastroenteropancreatic neuroendocrine tumors: A single institution experience over 15 years.
Authors: Baptiste Gillian G. , Postlewait Lauren McLendon , Ethun Cecilia G. , Le Nina , McInnis Mia R. , Russell Maria C. , Winer Joshua H. , Kooby David A. , Staley Charles A. , Maithel Shishir Kumar , Cardona Kenneth
Published: February 2017

228

Background: The prognostic implications on outcomes of symptomatic presentation of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) remains unclear. Methods: Patients who underwent curative-intent resection of nonfunctional, well-differentiated GEP NETs from 2000-2014 at a single institution were analyzed. Patients were classified as symptomatic if clinical symptoms were present at diagnosis. Primary end points were distant recurrence-free survival (DRFS) and overall survival (OS). Results: A total of 339pts were identified, of which 208pts (61%) were symptomatic at presentation. Symptomatic presentation was associated with younger age at presentation (55vs59yrs, p = 0.001), higher tumor grade (38vs21%, p = 0.027), LVI (58vs33%, p < 0.001), PNI (53vs30%, p = 0.002), and advanced disease (T3/T4/N1/M1 63vs44%, p = 0.002), but not tumor size (2.6vs2.5cm, p = 0.74). Symptomatic presentation was associated with decreased DRFS but not OS. When accounting for race, tumor size, positive resection margins, presence of metastatic disease, and positive lymph nodes on multivariate analysis (MVA), symptomatic presentation remained independently associated with reduced DRFS (HR 3.51, p = 0.007). On subgroup analysis of patients only with advanced disease (T3/T4/N1/M1), symptomatic presentation was still associated with decreased 3-yr DRFS (67vs79%, p = 0.012), but not OS. On MVA, symptomatic presentation persisted as an independent factor associated with decreased DRFS in patients with advanced disease (HR 2.89, p = 0.014). Conclusions: Symptomatic presentation of GEP NETs is associated with more aggressive pathologic features and worse DRFS than incidentally diagnosed NETs irrespective of tumor size. As our armamentarium of therapeutic agents for NETs expands and improves, trials assessing the value of adjuvant therapy for advanced GEP NETs are needed, and symptomatic presentation may be considered as one inclusion criterion. Following resection, symptomatic presentation should be taken into account when planning follow-up strategies, as these patients may require closer surveillance than their incidentally diagnosed counterparts.
Early tumor shrinkage as a predictor of favorable outcomes in patients (pts) with advanced pancreatic cancer treated with FOLFIRINOX.
Authors: Kaga Yasuhiro , Sunakawa Yu , Kubota Yutaro , Tagawa Teppei , Yamamoto Taikan , Ikusue Toshikazu , Uto Yu , Kitahara Yu , Toshima Hirokazu , Kobayashi Kouji , Hisamatsu Atsushi , Ichikawa Wataru , Sekikawa Takashi , Shimada Ken , Sasaki Yasutsuna
Published: February 2017

237

Background: Results from the phase III PRODIGE 4/ACCORD 11 trial provided one of current standard regimens for advanced pancreatic cancer (PC), consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX), which has superior response rate (RR) and survival benefit even with severe toxicity (Thierry C, et al. N Engl J Med 2011;364:1817-1825). There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in PC. We therefore analyzed retrospectively whether the ETS will predict outcomes in pts with PC treated with FOLFIRINOX therapy. Methods: Advanced PC pts with ECOG PS of 0 or 1, who received FOLFIRINOX as 1st- or 2nd-line treatment between November 2012 and July 2015 in 3 institutes of Showa University were included in this analysis. ETS was defined as a reduction ≥ 20% of target lesions’ diameters measured at 8 weeks from treatment start. We evaluated the association of ETS with progression-free survival (PFS) and overall survival (OS) but also addressed the correlation between outcomes and DpR, which was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Results: Fifty-nine PC pts with median age of 63 (range 34-76) years and males of 68% were enrolled: 80% of pts had metastatic disease. In the population, RR, median PFS, and OS were 28%, 5.4 months, and 10.7 months, respectively. Among 46 (78%) evaluable pts for the ETS, 12 (26%) pts experienced ETS. The PFS was significantly longer in pts with ETS compared to pts with no ETS (9.0 vs. 4.2 months, HR 0.43, 95%CI 0.17-0.96, log-rank P= 0.045). Moreover, pts with ETS had a better OS although no statistical significance (HR 0.53, log-rank P= 0.25). Median DpR was 11.1% (from -75.7 to 100), and the correlation of DpR with clinical outcome was observed (P= 0.024 for PFS, P= 0.22 for OS). Conclusions: This retrospective analysis suggests that the early response to FOLFIRINOX treatment may predict better outcomes in pts with advanced PC. The ETS may serve as a novel predictor of prolonged survival time in PC pts treated with FOLFIRINOX.
Systemic treatment patterns in small bowel and appendiceal adenocarcinomas (SBA and AA): A population-based study.
Authors: Beca Jaclyn Marie , Fallahpour Saber , Chan Kelvin K. , Redmond-Misner Ruby , Kennedy Erin Diane , Earle Craig , Berry Scott R. , Meyers Brandon Matthew , Welch Stephen , Hoch Jeffrey S. , Liovas Anna , Maloul Asmaa , Gavura Scott , Biagi James Joseph
Published: February 2017

242

Background: There is uncertainty regarding the optimal systemic treatment for patients with SBA and AA due to the limited available evidence for these uncommon malignancies and conflicting recommendations in existing guidelines. However, on the basis of biologic similarities between SBA, AA and colorectal cancer (CRC), common practice is to use the same systemic therapies as for CRC. We compared the utilization of chemotherapeutic agents for SBA and AA to that of CRC patients in Ontario, Canada. Methods: The provincial tumour registry in Ontario, Canada was used to identify patients diagnosed with SBA, AA or CRC from 2010-2014. Subsequent chemotherapy utilization and costs were captured from single-payer government administrative databases. We studied the use of oxaliplatin, irinotecan, capecitabine, bevacizumab, cetuximab, panitumumab, and raltitrexed, which are funded for CRC treatment. Patients were excluded if they had multiple primary cancer sites, morphology codes inconsistent with adenocarcinomas, or missing identification data. Statistical analyses were used to report and test patterns of utilization and average costs per patient. Results: Our cohort consisted of 30,946 patients over a 5-year period. On average, 160 and 80 patients were diagnosed annually in Ontario with SBA and AA, respectively, together representing less than 4% of the total diagnoses each year. Among SBA and AA patients, 30-40% initiated therapy with the selected systemic therapies, similar to the proportion in CRC. SBA and AA patients were less likely to receive adjuvant oxaliplatin (SBA 9%, AA 13%) compared to CRC (18%) patients, but more likely to use first and second-line oxaliplatin or irinotecan for metastatic disease. Bevacizumab was added to first-line therapy for SBA and AA patients in fewer cases than CRC (SBA 29%, 45% AA, 72% CRC). Third-line EGFR inhibitors panitumumab and cetuximab were used infrequently in all groups ( < 2% of those diagnosed). Average per patient costs were similar across disease sites (p > 0.05). Conclusions: On a population level, SBA and AA patients appear to be managed similarly to CRC patients and at similar cost. Future research will evaluate survival outcomes.
The use of plasma microRNAs to predict toxicty following liver stereotactic body radiation therapy.
Authors: Cuneo Kyle Clifford , Sun Yilun , Schipper Matthew J , Tewari Muneesh , Lawrence Theodore Steven , Feng Mary Uan-Sian
Published: February 2017

245

Background: Stereotactic body radiation therapy (SBRT) is an effective treatment for patients with hepatocellular carcinoma or liver metastases. Predictive biomarkers for liver toxicity would allow for careful patient selection and the adaptation of therapy. Prior studies have shown specific miRNAs are elevated prior to clinical signs of toxin induced liver injury. We hypothesized that miRNAs can be used to predict radiation induced liver toxicity prior to clinical manifestations. Methods: As part of an IRB approved clinical trial (NCT01522937) patients with liver tumors underwent a split course of SBRT. All patients underwent liver function testing using indocyanine green clearance (ICG) followed by three SBRT fractions. One month later ICG was reassessed and two more fractions were given if the patient did not have a decline in liver function. Plasma samples were obtained at baseline and 1 month after finishing three of five SBRT fractions for 89 patients. For this exploratory analysis, we selected the 10 patients that had a 2+ point increase in Child-Turcotte-Pugh score within 6 months of completing therapy and 19 additional patients without toxicity. The levels of 752 miRNAs were quantified for each sample using qPCR. We then used a univariate tree based classifier and the elastic net with 10-fold cross validation to calculate the AUC for predicting liver toxicity in individual and small groups of miRNAs, respectively. Results: Several miRNAs were found to be potentially predictive of toxicity on univariate tree based classifier analysis including the liver specific microRNA miR.122.3p, the epithelial specific miR.141.3p and miR.200b.3p, the neuroendocrine related miR.375 and miR.217, and miR.125a.5p which plays a role in hepatitis and regulates ERBB2 and ERBB3 signaling. The elastic net model achieved a conservative AUC estimate of 0.74 +/- 0.04 using 69 baseline miRNAs and 0.76 +/- 0.06 using 11 mid-treatment miRNAs to predict toxicity. Conclusions: Our preliminary analysis of the miRNAome from 29 patients receiving liver SBRT shows promising results for the ability of these markers to select patients at risk for radiation induced liver toxicity. Further validation in a larger patient cohort is needed. Clinical trial information: NCT01522937.
Assessment of hyaluronic acid in tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (CCA).
Authors: Padrnos Leslie Jane , Marella Mathieu , Kosiorek Heidi , Thind Komal , Barrett Brandon , Garrovillo Sheryl , Jiang Ping , Mounajjed Taofic , Ramanathan Ramesh K. , Borad Mitesh J.
Published: February 2017

248

Background: Improved understanding of TME in CCA may allow for development of novel therapeutics targeting stromal components. Hyaluronic acid (HA) is a polysaccharide that has been found in the TME of a number of solid tumors characterized by desmoplastic stroma, such as pancreatic cancer. Elevated HA levels were prognostic in these malignancies. HA prevalence and association with clinic-pathological features in CCA is unknown. Methods: A retrospective study was conducted using clinically annotated formalin-fixed paraffin embedded tissue from resected intrahepatic CCA samples. Specimens were analyzed for HA, scored using a positive pixel count algorithm (Aperio Imagescope) and positivity was calculated as % of total pixel count. Clinical variables were examined by chi-square or ANOVA F-test. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method and compared via log-rank test. Multivariate analysis was conducted using Cox proportional hazards regression models. Results: 142 patient samples were stained for HA. HA was identified in all samples (100%), with a range of HA positivity of 32.8 – 91.8%. Median HA value was 67.1% and 95% of patients had HA positivity ≥ 45%. Factors associated with higher than median HA ( > 67%) included perineural invasion (PNI) (40% vs. 21%, p = 0.011), necrosis (67% vs. 41%, p = 0.003), lymph node positivity (32% vs. 14%, p = 0.027), and small tumor size ( < 6.8 cm vs. > 8.4cm, p = 0.014). Stratification of HA staining by median positivity value was not an independent predictor of survival based on multivariate analysis. OS for patients with HA > 67% was 40.1 months (mo) vs 48.5 mo with HA ≤ 67%, p = 0.537. PFS for patients with HA > 67% was 14.4 mo vs. 25.7 mo with HA ≤ 67%, p = 0.177. Conclusions: Prevalence of HA staining in resected CCA is higher than seen in many solid tumors and is ubiquitous in our study. Absence of statistically significant association with OS and PFS might be attributable to ubiquitous prevalence, narrow signal range, and association with known negative prognostic factors. Further pre-clinical and clinical evaluation would be warranted.