bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the adoption, acceptance, and satisfaction of SurvivorLink as a communication tool for pediatric cancer survivors.
Authors: Mertens Ann , Williamson Rebecca , Gilleland-Marchak Jordan , Meacham Lillian R. , Cherven Brooke , Edwards Paula
Published: February 2017

89

Background: With the number of cancer survivors growing, focus on early recognition and treatment of late effects is even more imperative for life-long survivorship care. Electronic personal health records (PHR) potentially offer self-management and e-learning support which can empower the survivor, as well be used as a communication tool with healthcare providers (HCP). Methods: We developed a PHR, SurvivorLink (www.cancersurvivorlink.org), as a patient-centered tool to support pediatric cancer survivors, increase knowledge of late effects and survivor care, and promote communication between patients/parents and providers. Measures of success for a sustainable PHR implementation include adoption/use, acceptance, satisfaction and usability. The objectives of this feasibility study are to determine characteristics that predict the success of this PHR tool. An online pre-/post survey was administered to young adult survivors and parents of child survivors who registered on SurvivorLink. Results: Overall, 155 parents and 93 survivors completed the pre-test survey; 75% and 86% respectively have subsequently logged into SurvivorLink after initial registration. Individuals who used this PHR were more likely to be survivors (vs. parents; Odds Ratio (OR): 2.2, 95% CI: 1.1, 4.2). Other demographic variables were analyzed but no significant differences were found between users and non-users. Among users not aware of their need for specialized survivor care at the pre-survey, 52% reported awareness of the need for survivor care in the post-survey (vs 0% of non-users). Parents/survivors also reported high acceptance: 90% would use in the future, 82% stated it would help with advocating for survivor's health; and usability: 96% would recommend to other survivors/parents, 95% would recommend to their healthcare provider. Conclusions: SurvivorLink can improve knowledge around the importance of survivor care, and is both adopted and accepted by survivors/ parents independent of demographic differences. Research is underway to establish SurvivorLink's effectiveness as an advocacy/communication tool for survivor/parent with HCP in the self-management of their healthcare.
A model for coordinated delivery of individualized complementary and integrative medicine care for cancer survivors.
Authors: Niesley Michelle , Doran Kathryn , Huynh Nhu , Winters Marie
Published: February 2017

e286

Background: Cancer survivors may experience both physical and psychosocial sequelae as a result of cancer treatment. Many patients consult either their oncologist or primary care physician for lifestyle interventions to address survivorship issues. While studies demonstrate complementary and integrative medicine (CIM) therapies may reduce the risk of both all-cause mortality and cancer-specific mortality by 50% (Frenkel M et al. Curr Oncol Rep. 2015 May;17(5):445), the most effective method to ensure compliance with individualized dietary counseling, exercise, or nutritional supplement information to the patient is unknown. Here we present a multidisciplinary survivorship care model to increase compliance with CIM practices that positively impact survivorship outcomes. Methods: Each Patient Empowered Care (PEC) team at our hospital consists of a medical oncologist, naturopathic doctor, nurse care manager, and a nutritionist, who discuss the assessment and plan for each patient they will see that day. Additional integrative services include chiropractic care, acupuncture, and Oncology Rehab (physical, occupational, speech, and massage therapy). Naturopathic doctors recommend nutritional supplements specific to both the patient’s oncology regimen and other comorbidities, and also ensure these supplements do not interfere with metabolism of other active medications. Oncology Rehab encourages exercise via our Motion for Life program, where physical fitness programs are tailored to the patient’s individual needs. The Nutrition program provides individualized coaching and nutritional management. Patients continue CIM therapies long after oncology care has concluded. Results: Patients satisfaction and outcomes are improved by facilitating compliance with individualized lifestyle recommendations. Conclusions: This model increases compliance with CIM recommendations by facilitating transparent communication among PEC team members, while providing the patient with a single facility that individualizes their wellness regimen.
Patterns of failure and survival in patients with nasopharyngeal carcinoma treated with intensity modulated radiation therapy in Saudi Arabia.
Authors: Maklad Ahmed M , Bayoumi Yasser , Senosy Mohamed Abdalaziz , Elawadi AbuSaleh A. , AlHussain Hussain , Elyamany Ashraf , AlDahri Saleh , AL-Qahtani Khalid Hussain , Alqahtani Mubarak Shaie , Tunio Mutahir A.
Published: February 2017

e295

Background: We aimed to investigate the patterns of failure (locoregional and distant metastasis), associated factors, treatment outcomes in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT) combined with chemotherapy, results of reirradiation in recurrent cases and its toxicity. Methods: From April 2006 to December 2011, 68 NPC patients were treated with IMRT and chemotherapy at our hospital. Median radiation doses delivered to gross tumor volume (GTV) and positive neck nodes were 66–70 Gy/33-35fractions. For recurrent cases reirradiation was given by SRS 25 -30 Gy/5 fractions or IMRT 50-60 Gy/25-30 fractions according to volume of recurrence and surrounding critical structures. The clinical toxicities, patterns of failures, locoregional control (LRC), distant metastasis control (DMC), disease free survival (DFS) and overall survival (OS) were observed. Results: The median follow up time was 52.2 months (range: 11-87). EBV infection positive was 63.2%.There were 7 locoregional recurrences, 3 regional recurrences with distant metastases and 11 distant metastases. The median interval from the date of diagnosis to failure was 26.5 months (range, 16-50 months). 6/10 (60%) locoregional recurrences were treated with re-irradiation +/- concurrent chemotherapy. Acute grade 3 and 4 mucositis were observed in 2 patients (28.6%); however no significant late toxicities were seen after reirradiation. Nodal recurrences were salvaged by neck dissection. The 5-year LRC, DMC, DFS and OS rates of whole cohort were 81.1%, 74.3%, 60.1% and 73.4% respectively. Cox regression analyses revealed that neoadjuvant chemotherapy, age and Epstein-Barr virus (EBV) were independent predictors for DFS. Conclusions: Distant metastasis is the most common pattern of failure after IMRT with SIB technique with or without neoadjuvant and concurrent chemotherapy in Saudi patients with NPC. Early detection of local and locoregional recurrences is important as reirradiation with IMRT or SRT with or without chemotherapy is still feasible option with acceptable toxicity. However, efforts should be made for proper patient selection.
Retrospective comparison of long-term outcomes in patients with stage II/III (UICC-TNM6th) esophageal squamous cell carcinoma treated with 60 Gy or 50.4 Gy of definitive chemoradiotherapy with fluorouracil and platinum.
Authors: Hirano Hidekazu , Kato Ken , Nakamura Shoko , Sasaki Yusuke , Takahashi Naoki , Iwasa Satoru , Honma Yoshitaka , Okita Natsuko , Takashima Atsuo , Hamaguchi Tetsuya , Ito Yoshinori , Itami Jun , Boku Narikazu
Published: February 2017

109

Background: Deﬁnitive chemoradiotherapy (dCRT) is one of the treatment options for stage II/III esophageal squamous cell carcinoma (ESCC). RTOG9405 demonstrated that a higher dose of radiation (64.8 Gy) offered no additional survival benefit over the standard dose (50.4 Gy). We compared the long-term outcomes of dCRT with radiation doses of 60 Gy and 50.4 Gy for ESCC. Methods: Selection criteria included thoracic ESCC, stage II/III (non T4), performance status (PS) 0-2, age 20-75 years, adequate organ function and no other active malignancy. We retrospectively analyzed patients who received dCRT as a first-line therapy between Jan. 2000 and Nov. 2011 in our hospital. Group A (n = 180) received 2 cycles of cisplatin (C) (40 mg/m2 on day 1 and 8) with fluorouracil (F) infusion (400 mg/m2/day on day 1-5 and 8-12), or 2 cycles of C (70 mg/m2 on day 1) with F infusion (700 mg/m2/day on day 1-4) repeated every 4 weeks and concurrent radiotherapy at a dose of 60 Gy. Group B (n = 62) received 2 cycles of C (75 mg/m2 on day 1) with F infusion (1000 mg/m2/day on days 1–4) repeated every 4 weeks and concurrent radiotherapy at a dose of 50.4 Gy. Overall survival (OS) and progression free survival (PFS) were estimated with the Kaplan-Meier method and compared with log-rank test. The Cox regression model was used for multivariate analysis to assess the prognostic factors for OS. Results: Characteristics of both groups were as follows (Group A: Group B): median age, 64:62; male/female, 154/26:55/7; PS 0/1/2, 81/98/1:46/16/0; T1/2/3, 39/27/114:19/9/34; N0/1, 41/139:6/56. Median follow-up period was longer than 40 months for both groups. 5-year survival rates were 44.5% for Group A and 60.0% for Group B. Median PFS and median OS were 16.5 months and 36.2 months for Group A, 41.1 months and 98.3 months for Group B. By multivariate analysis, Group B (hazard ratio [HR] 0.617: 95% confidence interval [CI]:0.400-0.951, p = 0.029), T1/2([HR] 0.383: 95% [CI]: 0.260-0.566, p < 0.001) were significant prognostic factors for OS. Conclusions: CRT with 50.4 Gy showed better long-term survival than with 60 Gy.
Phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (pac) in patients (pts) with DKK1+ relapsed or refractory esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ).
Authors: Bendell Johanna C. , Murphy Janet E. , Mahalingam Devalingam , Halmos Balazs , Sirard Cynthia A. , Landau Steven B. , Ryan David P.
Published: February 2017

111

Background: DKK1, a secreted protein, is an indirect inhibitor of canonical Wnt signaling and was recently shown to directly activate non-canonical Wnt pathways including Rho, ROCK and JNK. High DKK1 concentrations in EC tumor tissue correlate with shorter overall survival (OS); published data suggests increased activity of non-canonical signaling by DKK1 may be a reason for shortened OS. DKN-01 is a humanized monoclonal antibody to DKK1 with demonstrated activity in non-small cell lung cancer. This study evaluated the MTD, safety and early activity of DKN-01 in combination with pac in EC and GEJ cancer pts. Methods: In Part A, pts with DKK1+ EC or GEJ cancer by IHC staining received DKN-01 in two dose escalation cohorts (150 or 300 mg) with pac 80 mg/m2 on days 1, 8, 15 and 22 of each 28 day cycle. Part B (dose expansion) is ongoing. Responses were assessed using RECIST version 1.1. Results: > 90% of screened EC (70 pts) had DKK1+ tumor tissue. In Part A, 9 pts with advanced EC or GEJ cancer were enrolled: 3 in Cohort 1 (150 mg) and 6 in Cohort 2 (300 mg); 5 pts had a diagnosis of EC [3 with adenocarcinoma (AC); 2 with squamous cell] and 4 pts with GEJ AC. Median number of prior therapies was 2 (range 1, 8). One DLT, G3 peripheral neuropathy, was seen at 300 mg. Frequent adverse events (AEs) were cough (5 pts), alopecia, leukopenia, neutropenia and peripheral/sensory neuropathy (each 4 pts) and fatigue, anemia, and nausea (each 3 pts); AEs were mostly Grade 1/2. The MTD of DKN-01 + pac was determined to be 300 mg. Among the 7 AC pts, 3 pts had a partial response (one having had prior pac); 3 pts had stable disease. Responders were on therapy between 3 and 10 mos. Conclusions: Part A is complete. Most EC and GEJ pts express tumor DKK1 and have obviated the need for evaluation of tumor DKK1+ expression as a study entry prerequisite. Combination of DKN-01+ pac is well-tolerated; the addition of DKN-01 to pac does not appear to alter the known pac safety profile. There are initial signs of enhanced clinical activity with DKN-01; further investigation is ongoing. Clinical trial information: NCT02013154. Clinical trial information: NCT02013154.
Outcomes of surgical intervention in gastric carcinoid disease.
Authors: Callahan Ann Falor , White Michael , Ituarte Philip HG , Woo Yanghee , Singh Gagandeep , Fong Yuman , Melstrom Laleh
Published: February 2017

112

Background: Gastric carcinoids are rare entities, representing 8.7% of all gastrointestinal carcinoids. Although this disease is often stratified into subtypes with differing clinical courses, the prognosis is generally improved by surgical resection. We evaluated the outcomes of patients with gastric carcinoids in a large cancer registry. Methods: We queried the California Cancer Registry (CCR), merged with the California Office of Statewide Health Planning and Development (OSHPD) database, for patients with a diagnosis of gastric carcinoid disease. Demographic, clinicopathologic characteristics, surgical treatment, and outcomes were analyzed. Results: Among the 1,012 patients who met our criteria, 64% had localized disease (644), 9.4% (95) had regional disease and 13.4% (133) had distant metastases. Most of these patients underwent gastric surgery (56.7%, n = 574 vs 43.2%, n = 438). Surgery at the primary site conferred a survival advantage in patients with local and regional disease (regional disease: 27 months with surgery vs 5 months without, p = 0.007; local disease: median survival was not reached, p < 0.0001). Patients who underwent resection of the primary tumor and any hepatic metastases showed a similar median survival to patients without hepatic metastases (26 vs 27 months, p = 0.8). Conclusions: Although the biology of the disease is the most significant predictor of overall outcome, aggressive surgical intervention, including resection of the primary tumor and any metastatic disease in the liver, should be offered when it is technically feasible. Surgical intervention in patients with hepatic metastases results in a survival similar to surgically managed patients without distant disease.
Multidisciplinary approach for cT1bN0 esophageal cancer.
Authors: Iizuka Toshiro , Kikuchi Daisuke , Hoteya Shu , Kaise Mitsuru , Udagawa Harushi
Published: February 2017

133

Background: The standard treatment for cT1bN0 esophageal squamous cell carcinoma (ESCC) was once surgery, but endoscopic submucosal dissection (ESD) following by additional treatment (ESD+α) are now being applied. Accordingly, we examined treatment outcomes for cT1bN0 ESCC to assess the validity of these treatments in terms of diagnostic accuracy and post-treatment prognosis. Methods: A total of 174 patients with ESCC were diagnosed as cT1b by endoscopic ultrasound (EUS) and white-light imaging between January 2008 and December 2014. Twenty-six patients diagnosed as cN+ by EUS or CT/PET were excluded. The diagnostic accuracy of invasion depth and lymph node metastasis was analyzed along with the post-treatment prognosis. Results: Initial treatment was ESD for 102 patients (ESD group) and surgery for 46 patients (surgery group). The histological diagnosis was T1a in 63 patients and T1b in 85 patients, meaning that 57.4% of the patients were accurately diagnosed. In the surgery group, 30 patients (65.2%) were accurately diagnosed as cN0. In the ESD group, 80 patients had an invasion depth of T1a-MM or deeper, which has a potential risk of metastasis. Additional surgery was performed for 15 patients, additional chemotherapy or chemoradiotherapy was performed for 43 patients, and follow-up without additional treatment was for 22 patients. Recurrence during follow-up was observed in 8 patients (lymph nodes in5 patients; other organs in 3 patients). Of the 16 patients with histological lymph node metastasis in the surgery group, 10 underwent adjuvant chemotherapy. Recurrence was noted in 3 patients (lymph nodes in 1 patient; other organs in2 patients). The mean follow-up period was 39 months for the ESD group and 45.8 months for the surgery group. Three- and five-year survival rates were respectively 93.1% and 79.3% in the ESD group and 89.8% and 85.1% in the surgery group, with no significant differences between the groups. Conclusions: Accuracy of preoperative diagnosis of invasion depth is still not high, which makes the ESD+α strategy an acceptable. As mid- to long-term outcomes were favorable in both groups, it appears that favorable outcomes can be obtained by performing multidisciplinary therapy based on the histological diagnosis.
PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
Authors: Le Dung T. , Uram Jennifer N. , Wang Hao , Kemberling Holly , Eyring Aleksandra , Bartlett Bjarne , Goldberg Richard M. , Crocenzi Todd S. , Fisher George A. , Lee James J. , Greten Tim F. , Laheru Dan , Azad Nilofer Saba , Donehower Ross C. , Luber Brandon , Koshiji Minori , Eshleman James R. , Anders Robert A , Vogelstein Bert , Diaz Luis A.
Published: February 2017

195

Background: Mismatch repair (MMR) deficient tumors harbor hundreds to thousands of mutations that may produce neoantigens that can be recognized and targeted by T cells. We have shown that MMR deficiency can serve as a predictive biomarker for selection of tumors across tumor histologies that may respond to programmed death-1 (PD-1) blockade. MMR deficiency is present in 15% of colorectal (CRC) however is also detected in 2-20% of gastric, small bowel, and hepatobiliary cancers. Methods: We conducted a phase II study to evaluate anti-PD-1, pembrolizumab, in patients with previously-treated, progressive, advanced cancer. Twenty-one patients with MMR deficient tumors were enrolled onto the non-CRC cohort with an additional 50 patient expansion underway. The pembrolizumab dose is 10mg/kg intravenously every 2 weeks. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) will be reported in at least the first 17 patients with non-CRC gastrointestinal (GI) cancers. Results: As of September 18, 2015, 17 patients with non-CRC GI cancers have been enrolled on the protocol with additional patients identified. The diseases represented are ampullary (N=4), pancreas (N=4), biliary (N=3), small bowel (N=3), and gastric (N=3) cancers. For the 10 evaluable patients at the time of abstract admission, ORR is 50 % (N=5/10), disease control rate is 70% (N=7/10), OS is 21 months and the median duration of response (range 5.5-17+ months) and PFS have not been reached. The median follow up duration is 7.6 months. Conclusions: PD-1 blockade shows promising activity in mismatch repair deficient GI cancers. Clinical trial information: NCT01876511.
A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.
Authors: Bekaii-Saab Tanios S. , Mikhail Sameh , Langleben Adrian , Becerra Carlos , Jonker Derek J. , Asmis Timothy R. , Cote Gregory Michael , Wu Christina Sing-Ying , Kwak Eunice Lee , Spira Alexander I. , Braiteh Fadi S. , Richey Stephen Lane , Hume Stephanie , Hitron Matthew , Li Chiang
Published: February 2017

196

Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.
Small bowel neuroendocrine tumors: A critical analysis of diagnostic work-up and operative approach.
Authors: Ethun Cecilia Grace , Postlewait Lauren McLendon , Baptiste Gillian G. , Le Nina , McInnis Mia R. , Cardona Kenneth , Russell Maria C. , Kooby David A. , Staley Charles A. , Maithel Shishir Kumar
Published: February 2017

203

Background: Small bowel neuroendocrine tumors (SB-NET) are rare, and often small and multifocal. They are difficult to localize preoperatively and can be overlooked during operative exploration. The optimal work-up and operative approach is not known. Methods: Patients who underwent resection of SB-NET at a single institution from 2000-2014 were included. Primary aim was to describe the diagnostic work-up, pathologic characteristics, and compare minimally-invasive (MIS) to open resection. Results: 93pts underwent resection for SB-NET. Median age was 61yrs; 52% were male. On presentation, 71% of pts were symptomatic and underwent an average of 3 diagnostic tests prior to resection: 45% had octreoscans, which identified the region of primary disease in 85%; 11% had small bowel enteroscopy, with a 10% diagnostic yield; 19% had capsule endoscopy, which saw a lesion in 83%, but in only 21% was the correct number of tumors seen. The diagnostic yield of capsule was 28% overall, but 82% in pts presenting with GI bleeding. 79pts (85%) underwent curative-intent resections. Median tumor size was 1.8cm and multiple primary tumors were seen in 34pts(42%), of whom 50% had > 3 tumors. 37% had metastatic and 70% had LN positive disease. 27pts underwent MIS resections vs 66 open. MIS pts were younger (56vs61yrs;p0.035) and less likely to have obstructive symptoms (4vs24%;p = 0.19) and metastatic disease at resection (19vs44%;p = 0.038). Compared to open, the MIS group had smaller (1.7vs2.4cm;p = 0.03) and fewer tumors resected (2vs5;p = 0.049), but similar LN yield (13vs12;p = 0.7). In pts without metastases undergoing curative-intent resection, MIS approach was still associated with fewer tumors removed compared to open (1.5vs4;p = 0.034). Conclusions: Capsule endoscopy appears to be better than small bowel enteroscopy at identifying occult small bowel neuroendocrine tumors, particularly when pts present with bleeding, but still may underestimate tumor burden. While MIS may be appropriate in select patients, recognizing the limitations of preoperative evaluation is critical when selecting the operative approach for these tumors, as heightened operative vigilance is often required.
Noninvasive markers to predict malignant intraductal papillary mucinous neoplasms of the pancreas.
Authors: Orcutt Sonia Tewani , Permuth-Wey Jennifer , Choi Jung W. , Chen Dung-Tsa , Chen Lu , Malafa Mokenge Peter
Published: February 2017

204

Background: Despite guidelines to preoperatively distinguish malignant from benign intraductal papillary mucinous neoplasms (IPMN), many patients undergo invasive testing and morbid pancreatic resection but ultimately have benign disease on pathology. A blood-based microRNA signature (SIG, including miR-200a-3p, miR-1185-5p, miR-33a-5p, miR-574-4p, and miR-664b) has been shown to preoperatively discriminate malignant from benign IPMN, with expression lower in malignant IPMN. This study was designed to develop a model to improve preoperative prediction of IPMN pathologic status combining radiographic markers and SIG values. Methods: An institutional database was used to identify patients undergoing resection for IPMN (2006-2011) with preoperative computed tomography (CT) scans and SIG values. CTs were read by a single radiologist blinded to pathology to assess predetermined radiographic features. The outcome was malignant pathology (MP, invasive carcinoma and high-grade dysplasia) vs. benign pathology (BP, low- and moderate-grade). Results: Of 38 eligible patients, 20 (53%) had MP and 18 (47%) had BP. 72% with MP had main pancreatic duct (PD) involvement vs. 20% with BP, p = 0.003. Median cyst size was higher in the MP group (3.9 vs. 2.8cm), p = 0.018. 83% of those with MP had ≥ 1 “high-risk stigmata” (PD size ≥ 10mm, enhancing solid component, or obstructive jaundice), vs. 15% of those with BP (p < 0.001), yet ≥ 1 “worrisome” feature (acute pancreatitis, PD size 5-9mm, cyst size > 3cm, thickened enhanced cyst walls, or non-enhanced mural nodules) was not associated with malignancy (p = 0.734). SIG was significantly lower in the MP group, p < 0.001. Multivariate logistic regression analyses revealed that high risk stigmata and SIG retained significance (43.0 [4.64-398.8], p = 0.001 and 0.30 [0.10-0.86], p = 0.026, respectively). The area under the receiver operating characteristic curve resulted in 0.950 for the model with both variables, compared to 0.841 and 0.836 for each variable independently. Conclusions: Combining high-risk stigmata from preoperative CT scans with a blood-based miRNA genomic classifier may improve the ability to noninvasively predict IPMN status preoperatively.
Presentation, clinical behavior, outcomes and therapies for patients with advanced pancreas adenocarcinoma (PAC) who present with or develop ascites.
Authors: Mier Hicks Angel , O'Reilly Eileen Mary , Capanu Marinela , Lowery Maeve Aine , Yu Kenneth H.
Published: February 2017

209

Background: Ascites develops in a subset of patients with PAC at presentation or as the disease advances. Limited data exist on the prognostic importance of malignant ascites in PAC. Our hypothesis is that this information will provide an understanding of the natural history and facilitate management decisions. Methods: We conducted a retrospective analysis of N = 180 patients treated at Memorial Sloan Kettering Cancer Center diagnosed between January 1, 2009 and December 31, 2014, with PAC and ascites either at presentation or which developed during the disease course. Results: For the 180 patients, overall survival was 15 months. Time from diagnosis to ascites presentation was 11 months and survival time after ascites development was 4 months. Of 62 patients (34%) who had ascitic fluid analyzed, N = 36 (58%) had positive cytology, N = 51 (82%) patients had a serum ascites albumin gradient (SAAG) ≥ 1 and N = 11 (18%) had SAAG < 1.1. Sixty-four (36%) of patients had their ascites managed solely by serial paracenteses. A total of 116 patients required a catheter, from these, N = 108 (93%) had a Tenckhoff catheter, N = 4 (3%) Pleurx catheter, N = 3 (2%) Pigtail catheter and one (1%) a Denver catheter. Eight (4%) patients required two catheters to be placed and N = 6 (3%) Tenckhoff catheters had to be removed. Main observed complications: spontaneous bacterial peritonitis in N = 7 (11%) of patients managed with paracenteses vs. N = 34 (19%) who had a catheter placed, catheter malfunction in N = 8 (4%), acute renal failure in N = 6 (3%). After ascites development N = 79 (44%) of patients received active therapy and N = 101 (56%) patients were managed with supportive care alone. Conclusions: In patients with PAC the presence of ascites is a poor prognostic factor. Serial paracenteses and indwelling catheters are common methods used for alleviating patients’ discomfort. The complication rate was higher with indwelling catheters, primarily associated with infections (e.g. bacterial peritonitis) with low rates of complications occurring related to catheter malfunction, acute renal failure or bowel perforation.
Recurrent feature after radiofrequency ablation therapy for hepatocelluar carcinoma: Risk of increasing malignant behavior.
Authors: Yamada Shinichiro , Shimada Mitsuo
Published: February 2017

213

Background: Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, several reports demonstrated the aggressive local recurrence after RFA, suggesting the induction of further malignant transformation of HCC. Methods: Eighty-eight patients with HCC who underwent hepatic resection were included in this study. Hepatectomy was indicated for local recurrence of HCC after RFA (n = 10, RFA group) and for the HCC without prior RFA (n = 78, non-RFA group). Clinicopathological data and patient’s prognosis after hepatectomy were compared between the two groups. Expression levels of HIF-1, EpCAM, CD44, VEGF and EMT markers mRNA in the tumor tissues were examined. We also investigated miR-34a and miR-200c expressions in the two groups. Results: RFA group showed higher frequency of portal vein invasion and less tumor differentiation compared with the non-RFA group (p < 0.05). Overall and disease-free survival rates in the RFA group were significantly worse than those in the non-RFA group (p < 0.05). HIF-1 and EpCAM mRNA expression levels in the RFA group were significantly higher than those in the non-RFA group (p < 0.05). The expressions of TGF-β, Twist and Snail-1 in RFA group were significantly higher than those in non-RFA group (P < 0.05), and Vimentin expression in RFA group tended to be higher than that in non-RFA group (P = 0.07). Regarding to miRNA, miR-200c and miR-34a expressions in RFA group were significantly lower than those in non-RFA group (miR-200c: P = 0.04, miR-34a: P < 0.01). Conclusions: Recurrent HCC after RFA showed the highly malignant potential through the expressions of HIF-1, cancer stem cell and EMT markers.
Could the PD-1 pathway be a potential target for treating small intestinal adenocarcinoma?
Authors: Shi Chanjuan , Thota Ramya , Berlin Jordan
Published: February 2017

233

Background: The programmed death 1 (PD-1) pathway is up-regulated in the immune microenvironment of many cancers. PD-1 blockage has been shown to be effective in treating some malignancies. In colorectal cancers, inhibition of PD-1 pathway appears to be selectively efficacious in microsatellite instable (MSI) tumors. In this study, we examined the immune microenvironment of small intestinal adenocarcinoma by immunohistochemistry. Methods: Twenty two small intestinal adenocarcinomas were identified from our Pathology Archives from 01/01/2002 to 05/01/2014. Immunohistochemical studies were employed to evaluate expression of CD3, CD4, CD8, CD20, CD56, PD-1 and programmed death ligand 1 (PD-L1). CD3+, CD4+, and CD8+ T cells were estimated under high power fields (HPF) and compared between PD-L1+ and PD-L1- tumors. Results: The 22 cases included 9 females and 13 males, with age ranging from 38 to 92 years. PD-1 was expressed in 18 of 22 (82%) cases, by tumor surrounding lymphocytes and lymphoid aggregates as well as tumor infiltrating lymphocytes if present. PD-L1 expression was observed in 10 of 22 (45%) cases, including 2 MSI, 2 microsatellite stable (MSS) and 6 tumors with unknown MSI status. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the infiltrating front. Expression of PD-L1 was also seen in tumor cells surrounding by the histiocytic caps. All the 10 cancers also expressed PD-1. The tumors expressing PD-L1 contained more CD3+ (440±22/HPF versus 238±31/HPF, p < 0.01), CD4+ (172±26/HPF versus 287±25/HPF, p < 0.01) and CD8+ T cells (58±17/HPF versus 153±33/HPF, p = 0.013) than those without expression of PD-L1. CD20+ cells were mainly seen in lymphoid aggregates. There were rare or none C56+ inflammatory cells. Conclusions: PD-1 and PD-L1 are expressed by inflammatory cells (mainly histiocytes) and tumors cells in most small intestinal adenocarcinoma. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.
Non-invasive monitoring of patient-derived orthotopic xenograft: An optimal system for rapid in vivotesting.
Authors: Rios Perez Mayrim V. , Pratt Michael , Kang Ya'an , Fleming Jason B.
Published: February 2017

235

Background: Heterotopic patient-derived xenografts (PDX) have been used to assess response to therapy however they underrepresent the role of tumor microenvironment and rarely develop metastasis, both of which are overcome by orthotopic models. Fluorescent orthotopic mouse models require invasive measures to determine tumor bioluminescence. Ultrasonography (US) is a cost-effective, non-invasive imaging technique that has been used in genetically engineered mouse models of pancreatic cancer for a three-dimensional (3D) acquisition of tumor volume, which allows rapid and safe in vivo drug testing. We intend to demonstrate that this technique allows real time monitoring of in vivo response to therapy using patient-derived orthotopic xenograft (PDOX) of pancreatic ductal adenocarcinoma (PDAC). Methods: A non-survival study using PDOX was designed with control (n = 5) and treatment (n = 5) groups. Weekly 3D US images were obtained pre and post-treatment over 4 weeks. Tumor growth curves were generated to monitor progression of disease. Metastatic burden was determined during necropsy. Results: One mouse was excluded from control and treatment groups due to baseline tumor size exceeding 300mm3 and drug toxicity, respectively. Pre-treatment average tumor volumes for control and treatment groups were (36±12)mm3 and (34±12)mm3, respectively. No difference was found in average tumor growth over time between groups (p = 0.9120). A 20% tumor regression was observed per group. Both groups exhibited gross metastasis to spleen, peritoneum, and omentum. Liver, periportal metastasis and local extension to the gastrointestinal and genitourinary system were present on the treatment group. Conclusions: This study describes a rapid technique for in vivo drug response by using 3D US to monitor PDOX; failure of response to therapy correlated with metastatic burden observed. PDOX regression could be explained by tumor heterogeneity. PDOX models, as challenging as they could be, remain to be necessary in vivo models to show therapeutic response to human PDAC, which could be easily monitored using 3D US imaging.
The value of endoscopic ultrasonography in a PET/CT upfront model in staging esophageal cancer with respect to treatment decision.
Authors: Hulshoff Jan-Binne , de Boer Hiske E.M. , Noordzij Walter , Nagengast Wouter B. , van Dullemen Hendrik M. , Mul Veronique E.M. , Plukker John Theodorus
Published: February 2017

25

Background: The optimal sequence of endoscopic ultrasonography (EUS) and positron emission tomography with computed tomography (PET/CT) in esophageal cancer (EC) is a matter of debate. The use of EUS with fine needle aspiration (FNA) after PET/CT seems to increase the efficacy of curative intended neoadjuvant or definitive chemoradiotherapy. Retrospectively, we assessed the impact of EUS in the PET/CT upfront model on the treatment decision making in EC patients. Methods: In the period 2009 to 2015, 298 EC patients were staged with hybrid PET/CT or PET with CT, and EUS if applicable, in a non-specific order to assess curability (T1-4a,N0-3M0). We determined the feasibility of EUS and whether the initial or additional EUS changed the primary decision suspicious incurable (T4b and M+) into curable disease or added extra nodal information leading to up/downstaging or exhibit suspected nodes at different lymph node stations. In addition, we assessed if EUS changed the radiation area (i.e. lymph nodes > 3.5 cm from the defined radiation target volumes) in the PET/CT “upfront model”. Results: EUS was complete in 185 (62.1%) and incomplete due to stricture from a relative obstructing tumor in 59 (19.8%) patients. Fifty-four patients (18.1%) did not receive EUS because of stenosis (n = 46; 15.4%), patient dependent reasons (n = 4; 1.3%) or other reasons (n = 4; 1.3%). EUS after hybrid PET/CT or PET with CT (n = 244) gave additional information in 166 patients (68.0%); it changed the curability in 4 (1.6%), lead to nodal up and downstaging in respectively, 81 (33.2%) and 27 (11.1%) patients, changed the number of or lymph node station of suspected lymph nodes in an additional 58 patients (n = 23.8%), and FNA gave additional information in 34 (13.9%) patients. EUS after PET/CT ”upfront” changed the treatment plan in 90 patients (36.9%), including alteration in the radiation field (86; 35.2%) and curability (4; 1.6%). Conclusions: EUS gave additional information after PET/CT “up front” and altered the radiation field in about one third of the EC patients, suggesting a better yield of “EUS on indication” after PET/CT upfront.
A multi-institutional analysis of duodenal neuroendocrine tumors: Tumor biology rather than extent of resection to dictate prognosis.
Authors: Margonis Georgios A , Samaha Mario , Kim Yuhree , Postlewait Lauren McLendon , Maithel Shishir Kumar , Poultsides George A. , Tran Thuy , Gamblin T. Clark , Berger Nicholas Gerard , Pawlik Timothy M.
Published: February 2017

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Background: Duodenal neuroendocrine tumors (NETs) are rare neoplasms and their management is poorly defined. As such, we sought to evaluate the management and outcomes of patients undergoing resection of duodenal NETs. Methods: Using a multi-institutional database, 132 patients who underwent curative-intent resection for duodenal NETs between 1998 and 2015 were identified. Data on clinical characteristics, comorbidities, procedural details, as well as recurrence-free survival (RFS) were collected and analyzed. Results: Median age was 63 years and most patients were male(52.3%). Two-thirds(66.7%) of patients had symptomatic disease. Most patients presented with abdominal pain(47.8%), while 17(19.3%) patients presented with GI bleeding/anemia. Lesions were located in first/second(94.5%) or third/fourth(5.5%) portion of the duodenum. Median tumor size was 1.7 cm. Local surgical resection(LSR) was performed in 55(42.0%) patients, while 47(35.9%) patients underwent pancreaticoduodenectomy(PD) and 29(22.1%) underwent an endoscopic resection(ER). Most patients had an R0 surgical margin(88.4%)(LSR, 88.7% vs. PD, 95.7% vs. ER, 71.4%; P = 0.02). Among patients who had at least one lymph node examined(n = 86), 49(57.0%) had a metastatic lymph node; lymph node metastasis were more common among patients with tumors ≥ 2cm(OR = 3.21, P = 0.02). Median length-of-stay was longer for PD(11 days) versus LSR(7 days)(P < 0.001). PD patients had more complications(LSR, 52.7% vs. PD, 63.8% vs. ER, 6.9%; P < 0.001). 3- and 5-year RFS was 80.1%, and 69.6%, respectively (site of recurrence: locoregional, n = 8 vs. distant, n = 14). Factors associated with worse RFS included tumor grade(moderate-to-poor: HR 4.12) and presence of metastasis at diagnosis (HR 5.66)(both P < 0.05). PD versus LSR versus ER approach was not associated with RFS (P > 0.05). Conclusions: Recurrence of duodenal NETs was dependent on tumor biology rather than procedure type. PD was associated with a longer hospital stay and higher risk of perioperative complications. For patients with tumors < 2cm, LSR or ER may be appropriate with PD reserved for larger lesions and those not amenable to a more local approach.
Prognostic significance of tumor infiltrating natural killer cells in periampullary adenocarcinoma.
Authors: Lundgren Sebastian , Elebro Jacob , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin
Published: February 2017

267

Background: Adenocarcinomas in in the pancreas and the periampullary region are heterogenous with the shared trait of having dismal prognosis. Despite recent progress in cancer therapy this has not been reflected in better prognosis for this patient group. Research has thus begun to explore the role of the immune system in pancreatic cancer. The aim of this study was to analyze the prognostic value of CD56+ natural killer (NK) cells in periampullary cancer, with particular reference to morphological type. Methods: Immunohistochemical expression of CD56 in lymphocytes and tumor cells was analyzed in tissue microarrays with tumors from 175 consecutive cases of operated periampullary adenocarcinoma, 110 of pancreatobiliary-type (PB type) and 65 of intestinal-type (I type) morphology. Kaplan-Meier and Cox regression analysis, unadjusted and adjusted for sex, age, stage, grade, size, growth in peripancreatic fat, perineural tissue and blood vessels, adjuvant chemotherapy and resection margins, were applied to determine the impact of CD56 expression on 5-year overall survival (OS). Results: A high density of CD56+ NK cells correlated significantly with low T- and N-stage (p = 0.003; p = 0.009), absent lymphatic, vascular and perineural infiltration (p = 0.007; p = 0.006; p = 0.023) and growth in peripancreatic fat (p = 0.016). High density of CD56+ NK cells was associated with a prolonged OS in univariable, but not multivariable, analysis in PB type, but not in I type, tumors (HR = 0.60; 95% CI 0.37-0.98). Interestingly, high density of CD56+ NK cells was a negative predictor of response to adjuvant chemotherapy in patients with PB-type tumors (p for interaction = 0.020). Tumor specific CD56 expression was significantly associated with reduced OS in univariable, but not in multivariable analysis, in patients with PB type but not in I type tumors (HR = 1.65; 95% CI 1.09-2.49). Conclusions: These results demonstrate that stromal CD56+ NK cell infiltration has a significant favorable impact on prognosis in PB type, but not in I type, periampullary cancer. Of note, this beneficial effect was only seen in patients not receiving chemotherapy, indicating that chemotherapy may modulate the beneficial prognostic effect of NK cells.
PD-1/PD-L1 expression and molecular associations in HPB malignancies.
Authors: Mody Kabir , Feldman Rebecca , Reddy Sandeep K. , Reynolds Gina A , McMillan Jessica M , Johnson Elizabeth
Published: February 2017

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Background: Cholangiocarcinoma (CC), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC) are all devastating malignancies. Limited data exists about PD-1 and PDL1 expression in these cancers. We assessed expression of PD1/PDL1 in a large cohort of patients with hepato-pancreatico-biliary (HPB) cancers and explored the existence of accompanying genomic mutations associated with expression of PD-1/PD-L1. Methods: 524 patients with HPB cancers (354 PDAC, 58 HCC, 54 intrahepatic (ICC), 18 extrahepatic (ECC), and 40 gallbladder (GBC)) were included in the study and tumors tested centrally at a CLIA lab (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (next generation sequencing, Illumina TruSeq), protein expression (immunohistochemistry [IHC]) and gene amplification). PD-1 (SP142 antibody) and PD-L1 (MRQ-22 antibody) status was tested in all samples. Two-tailed Fisher's exact test was performed to test where proportions of positive results were different by subgroup (p²0.05). Results: Among those with PDAC, HCC, ICC, ECC, and GBC, rates of PD1 expression on tumor infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells is detailed in the Table. In PD-1+, compared with PD-1- HPB cancers, mutations in the following were more prevalent, though not statistically significant: BRCA2, ATM, CTNNB1, and PIK3CA. Among all theranostic biomarkers tested, TOP2A expression (IHC) was significantly increased in PD-L1+ versus PD-L1- tumors (82% vs 60%; p=0.0083). Conclusions: HPB tumors express PD-L1 at a frequency of 4-18%, and PD-1 at a frequency of 29-45%. A statistically significant association of mutations with PD-1+ or PD-L1+ tumors was not identified in this group of tumors. PD-L1 expression associates with TOP2a expression, a marker of proliferation and also anthracycline sensitivity. Further evaluation of this correlation and PDL1/PD-1 + anthracycline combination therapy may be warranted. [Table: see text]
Phase II study of fixed dose-rate gemcitabine plus S-1 as second-line treatment in advanced biliary tract cancer.
Authors: Kobayashi Satoshi , Sugimori Kazuya , Morizane Chigusa , Kojima Yasushi , Ueno Makoto , Morimoto Manabu , Ohkawa Shinichi
Published: February 2017

301

Background: Cisplatin plus gemcitabine (GC) is considered as standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). However, no standard therapy is established for second-line setting. Some clinical studies showed that gemcitabine was more effective if administered by the fixed dose rate method, and S-1 had anti-tumor effect as second-line chemotherapy for BTC. We evaluated the efficacy and safety of combination therapy of fixed dose-rate gemcitabine and S-1 after failure of GC or gemcitabine alone. Methods: This study was a single arm phase II study, and primary endpoint was response rate (RR) with MinMax two stage design to test the hypothesis that RR was more than 7%. Number of patients needed was 35 with a power of 90% and two-sided α value of 0.05. Patients received gemcitabine (1,000 mg/m2, div, over 100 minutes, day 1) and S-1 (40 mg/m2 twice daily, oral, day 1-7), every two weeks until disease progression or intolerable adverse events. Results: Forty patients were enrolled from July, 2011 to Nov., 2014. Of 23 patients in the first stage, two patients showed response and proceeded to the second stage. Overall response rate was 7.5%. Overall survival, progression-free survival and disease control rate were 7.7 months, 2.6 months, and 47.5%, respectively. Common adverse events were anemia (97.2%), thrombocytopenia (66.7%), leukopenia (47.2%), neutropenia (41.7%), anorexia (39.0%) and fatigue (37.8%). Grade 3–4 adverse events were leukopenia (19.5%), neutropenia (19.5%), anemia (14.6%), thrombocytopenia (7.3%) and anorexia (4.8%). Biliary tract infection led to death in two patients; however, these were reported as not related to this study treatment. Conclusions: Fixed dose-rate gemcitabine plus S-1 was tolerable as second-line settings in BTC; however, its activity was modest for patients refractory to the standard gemcitabine. Clinical trial information: UMIN000005918 Clinical trial information: UMIN000005918.