bluuebunny/crossref_metadata_2025_split huggingface dataset:
NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate.
Authors: Strosberg Jonathan R. , Wolin Edward M. , Chasen Beth , Kulke Matthew H. , Bushnell David L , Caplin Martyn E. , Baum Richard P. , Kunz Pamela L. , Hobday Timothy J. , Hendifar Andrew Eugene , Oberg Kjell E. , Lopera Sierra Maribel , Kwekkeboom Dik J. , Ruszniewski Philippe B. , Krenning Eric 
Published: February 2017

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.
Angiogenic gene expression in primary neuroendocrine tumors and their metastases.
Authors: Milosavljevic Tanja , Hall Michael Anthony , Del Valle Luis , Juge Elise , Zabaleta Jovanny , Boudreaux J Philip , Wang Yi-Zarn , Anthony Catherine T. , Woltering Eugene 
Published: February 2017

200 Background: Neuroendocrine tumors (NETs) are neoplasms arising from the cells of the nervous, endocrine and hormonal systems. They most commonly originate in the small bowel (SB) and frequently metastasize to the lymph nodes (LNs) and/or liver (LV). Current treatment of metastatic NETs involves a variety of approaches including antiangiogenic therapies. Our group demonstrated that there are significant histologic and functional differences between the primary NETs and their nodal or organ metastases. We hypothesized that sampling of multiple tumor sites within the same individual will reveal differential expression profiles of angiogenesis-related genes. Methods: Tissue-matched normal and tumor tissue samples were obtained from patients with well differentiated NETs who underwent simultaneous removal of their primary tumor, nodal, and organ metastasis. High quality RNA was extracted from each tumor site using TRIzol and RNeasy Mini kit. Gene expression of 28 well-documented angiogenesis-related genes was assessed using Custom Quantitative RT-PCR array. These gene expression trends were validated by Illumina microarray and TaqMan analysis. Immunohistochemistry (IHC) staining was performed using Avidin-Biotin-Peroxidase complex, with the markers: SSTR2 and FGFR3. Results: Normal SB, LN, and LV gene expression of 28 genes was compared to that of the tumor sample at each tumor site [4-fold change, p ≤ 0.01]. A consistent up-regulation of SSTR2 and SSTR1 was seen in 18/24 (75%) samples. Up-regulation of FGFR3 and SSTR5 was observed in 13/24 (50%) of tumors. TGFA and IGF were consistently down-regulated in 12/24 (50%) and 10/24 (42%) of tumor samples, respectively. Six genes expression trends were validated by TaqMan analysis and Illumina microarray analysis. IHC staining revealed higher SSTR2 and FGFR3 protein expression in all three tumor sites compared to the control. Conclusions: Expression of angiogenesis-related genes varies between the primary tumor (SB) and metastatic sites (LV, LN) within the same individual. We found a positive correlation between SSTR2 and FGFR3 gene and protein expression levels in all three tumor sites.
Pancreatic cancer: Survival in clinical trials versus the real world.
Authors: Sarkar Reith Roy , Matsuno Rayna , Murphy James Don 
Published: February 2017

216 Background: Physicians often use clinical trial data to estimate expected survival for their patients, however clinical trial results may not generalize to a broader population. Given the need for accurate prognostication, we examined whether the survival of clinical trial pancreatic adenocarcinoma patients was similar to “real world” patients. Methods: We conducted a literature search using Pubmed to identify pancreatic adenocarcinoma Phase III trials published between 2005 and 2012. We excluded secondary or pooled analyses, trials with second-line treatments, and non-randomized studies. We compared clinical trial patients to a cohort of patients from the Surveillance, Epidemiology, and End Results (SEER) program, matching for diagnosis year, age and stage of disease. We evaluated for differences in median survival, 1-year survival, and 2-year survival. Results: We identified 27 trials (3 metastatic, 16 mixed metastatic and locally advanced, 3 locally advanced, and 5 resectable) that fit our search criteria, consisting of 8,438 patients. Compared to SEER the median survival was higher in 98% of the individual clinical trial arms by an average of 3.7 months (p = 0.001). The 1-year overall survival rate was higher in 100% of the clinical trial arms by an average of 12.3% (p <.0001). The 2-year overall survival was higher in 76% of the clinical trial arms by an average of 5.1% (p <.0001). The survival differences between SEER and clinical trials were greatest for patients with metastatic pancreatic cancer. Conclusions: We found that clinical trial patients have profoundly improved survival compared to patients in the SEER database, suggesting that clinical trial survival estimates may not generalize to “real world” patients with pancreatic cancer. Patient performance status, underlying comorbidity, and differences in treatment could not be assessed in SEER, though these factors likely explain a portion of the survival differences. These findings suggest that physicians should use caution when extrapolating survival estimates from clinical trials to the real world.
Functional imaging tests and CT scan: Detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up.
Authors: Merola Elettra , Pavel Marianne E. , Panzuto Francesco , Capurso Gabriele , Cicchese Noemi , Rinke Anja , Gress Thomas Mathias , Iannicelli Elsa , Prosperi Daniela , Pizzichini Patrizia , Kump Patrizia , Lipp Rainer , Partelli Stefano , Falconi Massimo , Wiedenmann Bertram , Delle Fave Gianfranco 
Published: February 2017

219 Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), which can be detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to evaluate, in metastatic DNENs FU, the diagnostic yield of FITs associated to Computed Tomography scan (CT) in terms of detecting new distant metastases (primary outcome) and of clinical usefulness (secondary outcome). Methods: Retrospective analysis of stage IV DNENs expressing SSTRs and with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), subsequently it was 68Ga-DOTA- PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-“units”, in which each patient had faced at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathological findings collected for each patient during FU. Clinical usefulness was defined as “appropriate changes” in management (indication to further imaging tests, surgery, biopsy, change in therapy) due to CT and/or FITs. Results: Interim analysis of 381 units (median 3 per patient, range 2-7) obtained from 121 patients included so far (67.8% metastatic since diagnosis). New lesions were detected by CT alone in 82.3% of cases; adding OCT, the diagnostic yield was 9.6%, while adding GaPET 21.7% (P<0.05). CT was responsible in 83.5% of cases of useful changes in patients management; adding OCT, the diagnostic yield was 9.7% (P<0.05), while with GaPET 27.9% (P<0.05). Conclusions: In metastatic DNENs FU, the addition of FITs to CT significantly improves the detection rate of new lesions; this advantage influences clinical practice increasing the clinical usefulness, especially when GaPET is adopted.
The anticancer effects of supinoxin (RX-5902) in pancreatic carcinoma.
Authors: Lee Young , Mazhari Reza , Kim Deog Joong 
Published: February 2017

238 Background: DEAD box RNA helicase DDX5/p68, and its phosphorylated form in particular, may play several important roles in cancer by means of cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Supinoxin also inhibits motility of MDA-MB231 breast cancer cell lines and could potentially prevent metastasis in cancer. Methods: In this study, we first demonstrated anti-proliferative effects in several cell lines originated from pancreas (5 cell lines) with a high level of sensitivity to Supinoxin (IC50 of 18 nM). We also sought to examine the tumor growth inhibition (TGI) and/or tumor growth delay (TGD), and survival benefits of Supinoxin in the human pancreatic carcinoma (MiaPaCa-2) xenograft mouse model. Results: In the MiaPaCa-2 model, at 50 and 70 mg/kg daily (oral, 5 days on/2 days off) for 3 weeks, both doses delayed tumor growth significantly (83% and 339%; P < 0.001). All animals in the high dose showed complete regression (CR) and completing the study as tumor free survival (TFS; Day 65); one animal showed CR and TFS in the lower dose. Gemcitabine (120 mg/kg ip; Q3D for 4 weeks) resulted in TGD of 71% (P < 0.001), with no CRs. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in this tumor model. Conclusions: These data support the potential therapeutic activity of Supinoxin in pancreatic cancer. A Phase 1 study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).
Establishment and validation of prognostic nomograms including HER2 status in metastatic gastric cancer.
Authors: Kawakami Takeshi , Narita Yukiya , Oze Isao , Kadowaki Shigenori , Machida Nozomu , Taniguchi Hiroya , Ura Takashi , Ando Masashi , Ito Seiji , Yatabe Yasushi , Tajika Masahiro , Kito Yosuke , Haraguchi Yutaka , Yasui Hirofumi , Muro Kei 
Published: February 2017

24 Background: It remains unclear whether human epidermal growth factor receptor 2 (HER2) status is an outcome-associated biomarker independent of known prognostic factors for metastatic gastric cancer (MGC). There are few reports on nomograms in MGC, while several studies have been published on nomograms for other cancer types. This retrospective study aimed to develop nomograms that combine HER2 status and other prognostic factors for predicting survival outcome of individual patients with MGC starting first-line treatment. Methods: We used a training set of 838 consecutive patients with MGC starting first-line chemotherapy between 2005 and 2012 in Aichi Cancer Center Hospital (ACC) to establish nomograms that calculate the predicted probability of survival at different time points; overall survival (OS) at 1 and 2 years. The covariates analyzed in this model by Cox proportional hazard models included HER2 status, Eastern Cooperative Oncology Group performance status (PS), history of gastrectomy, serum lactic acid dehydrogenase (LDH), and serum alkaline phosphatase levels (ALP). Nomograms were independently validated using data on 269 consecutive patients with MGC who underwent first-line chemotherapy between 2010 and 2012 in Shizuoka Cancer Center Hospital (SCC). Missing covariate data were estimated using multiple imputation methods. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-index. IHC3+ or IHC2+/ISH+ tumors were defined as HER2-positive. Results: Patient characteristics were as follows: median age, 64 vs. 66 years; ECOG PS 0/1/2, 34%/51%/15% vs. 45%/44%/11%; prior gastrectomy, 42% vs. 39%; 1/ > 1 metastatic sites, 56%/44% vs. 43%/57%; high LDH, 76% vs. 27%; high ALP, 22% vs. 26%; and positive/negative HER2 status, 10%/45% vs. 7%/53%, respectively. At a median follow-up of 12.3 (ACC) and 11.6 (SCC) months, 782 and 248 patients had died, and median OS was 12.5 and 12.4 months (P= 1.00), respectively. The nomograms were capable of predicting an OS with a c-index of 0.68 and 0.58. Conclusions: These nomograms may provide objective and approximate prediction of OS for individual MGC patients in clinical settings.
Hypertension as a predictor of outcome and treatment response to cetuximab: A retrospective analysis of NCIC CTG CO.17.
Authors: Sud Shelly , O'Callaghan Christopher J. , Jonker Caleb , Karapetis Christos Stelios , Price Timothy Jay , Tebbutt Niall C. , Shapiro Jeremy David , Van Hazel Guy A. , Pavlakis Nick , Gibbs Peter , Jeffery Mark , Siu Lillian L. , Gill Sharlene , Wong Ralph , Jonker Derek J. , Tu Dongsheng , Goodwin Rachel Anne 
Published: February 2017

256 Background: Adrenergic receptor stimulation is involved in development of hypertension (HTN), and is implicated in progression and dissemination of metastases in tumour types such as colon cancer (CRC). Adrenergic antagonists, such as beta-blockers (BB), demonstrate inhibition of invasion and migration in CRC cell lines and have been associated with decreased mortality in advanced CRC. We examined the association of baseline HTN (BHTN) and use of BB on overall (OS) or progression-free survival (PFS) of pts with pre-treated, chemotherapy refractory, metastatic CRC (mCRC). We also examined BHTN and BB use as predictors of Cetuximab (CET) efficacy. Methods: Using data from NCIC CO.17 (CET vs. BSC), we coded BHTN and use of anti-HTN meds (Rx), including BB, for 572 pts. Chi-square test assessed association between these variables and baseline characteristics. Univariate and multivariate analyses of OS and PFS by BHTN diagnosis and BB use were performed using Cox regression models. Results: Pts with BHTN (149/572) and those using BB (60/572) were older, had diminished performance status, and higher creatinine levels. BHTN, BB use and anti-HTN Rx were not prognostic for OS and PFS, though a trend was noted between BB use and improved PFS (HR 1.38 [0.97- 1.96], p= 0.077). BHTN and BB use were not significant predictors of CET benefit. However, pts with BHTN tended to have a stronger treatment effect in PFS from CET (interaction p = 0.074). Conclusions: In chemo-refractory mCRC, BHTN and BB use are not significant prognostic factors. BHTN and BB use are also not predictive of CET benefit, though pts with baseline HTN may benefit from a stronger treatment effect with CET. Patients with chemo-refractory mCRC may be biologically selected and the impact of BB use in earlier lines may therefore still warrant investigation. [Table: see text]
Expression and prognostic significance of human epidermal growth factor receptors 1, 2, and 3 by histological type in periampullary adenocarcinoma.
Authors: Elebro Jacob , Warfvinge Carl Fredrik , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin 
Published: February 2017

258 Background: Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumors with dismal prognosis. The human epithelial growth factor receptor family consists of four closely related members EGFR (HER1) - HER4. HER-targeting drugs have a beneficial effect on survival in several types of cancer, but the benefits have been modest in pancreatic cancer and the prognostic value of HER-expression remains unclear. The aim of this study was therefore to examine the expression and prognostic value of EGFR, HER2 and HER3 in periampullary cancer, with particular reference to histological subtype. Methods: Immunohistochemical expression of EGFR, HER2 and HER3 was analyzed in tissue microarrays with 175 periampullary adenocarcinomas consecutively operated at the University hospitals of Lund and Malmö, Sweden, 2001 – 2011, with follow up data on RFS and OS for up to 5 years. Results: The expression of EGFR and HER2 was similar in pancreatobiliary (PB) and intestinal (I) type tumors but HER3 was more often highly expressed in I-type tumors (52% vs 21%, p < 0.001). In PB-type tumors there were no associations between expression of HERs and clinicopathological parameters or survival. In I-type tumors, high EGFR expression was associated with larger tumors and high expression of HER3 was inversely associated with growth in peripancreatic fat (p = 0.003) and T-stage (p = 0.006). HER2 expression was not associated with any clinicopathological parameter. In I-type tumors, high expression of EGFR was associated with shorter OS and RFS in univariable Cox regression analysis (HR = 2.74, CI 1.32-5.69 for OS and HR = 2.58, CI 1.23-5.38 for RFS) but not in multivariable analysis. HER2 expression was not prognostic. High HER3 expression was associated with a prolonged RFS in univariable (HR = 0.45, CI 0.21-0.95) but not in multivariable analysis. Conclusions: High EGFR expression is an unfavorable prognostic factor and high HER3 expression a favorable prognostic factor in I-type periampullary cancer. Expression of HERs in PB-type tumors had no evident prognostic value. The prognostic value of HERs in periampullary cancer thus differ by histological subtype.
Risk factors of gastric carcinogenesis in underlying gastric mucosal atrophy.
Authors: Song Ji Hyun , Kim Sang Gyun , Jin Eun Hyo , Lim Joo Hyun , Yang Sun Young 
Published: February 2017

28 Background: Atrophic gastritis and intestinal metaplasia were considered as premalignant lesions. The prevalence of chronic atrophic gastritis is very high in Korea. The aims of this study were to evaluate the risk factors of gastric carcinogenesis in underlying gastric mucosal atrophy. Methods: A total of 10187 subjects underwent upper gastrointestinal endoscopy for health checkup between 2003 and 2004 were enrolled in this retrospective cohort study. Follow-up endoscopy was performed between 2005 and 2014. Atrophic gastritis and intestinal metaplasia were assessed according to the Kimura-Takemoto classification by endoscopy. Helicobacter pylori (Hp) was evaluated by serum IgG antibody. Results: The number of atrophic gastritis was 3716 (36.5%) in baseline endoscopy, and 2146 were undergone follow-up endoscopy (82.8±38.3month); 1139 showed aggravation of atrophy and 1007 showed no change. A total of 71 subjects were diagnosed as gastric neoplasms (34 adenoma, 37 carcinoma). Age (HR = 1.019, 95%CI 1.010-1.028), alcohol intake (HR = 1.002, 95%CI 1.001-1.002), Salt intake (HR = 1.295, 95%CI 1.038-1.617) and Hp infection (HR = 1.584, 95%CI 1.220-2.057) were associated with aggravation of mucosal atrophy. The risk factors for gastric neoplasm in underlying mucosal atrophy were age (HR = 1.041, 95%CI 1.004-1.079), alcohol intake (HR = 1.003, 95% CI 1.001-1.005), Salt intake (HR = 2.553, 95% CI 1.141-5.712), Extent of mucosal atrophy (HR = 2.375, 95% CI 1.201-4.695 in C3-O1; HR = 4.255, 95% CI 1.612-11.229 in O2-O3), and intestinal metaplasia (HR = 2.599, 95% CI 1.286-5.251). Conclusions: Hp was a risk factor for aggravation of atrophy, but not for gastric neoplasm. Salt intake, extent of mucosal atrophy, and intestinal metaplasia were important risk factors for gastric neoplasm.
The influence of venous thromboembolism on prognosis of esophageal cancer patients.
Authors: Amada En , Takeuchi Hiroya , Kato Fumihiko , Kawakubo Hirofumi , Fukuda Kazumasa , Nakamura Rieko , Takahashi Tsunehiro , Wada Norihito , Kitagawa Yuko 
Published: February 2017

29 Background: Venous thromboembolism (VTE) is sometimes found in esophageal cancer patients who underwent surgical treatment. VTE contains deep vein thrombosis, pulmonary embolism and catheter-related thrombosis. Our previous study revealed that pre-therapeutic plasma fibrinogen level, C-reactive protein level, adenocarcinoma histology and neck lymph node dissection are the risk factors for venous thromboembolism in patients[Surg Today, 2015]. However, the correlation between VTE and prognosis is not clear in esophageal cancer. We hypothesized that VTE may have an impact on prognosis of esophageal cancer patients. Methods: One hundred and seventy-two patients who underwent radical esophagectomy from March 2008 to December 2012 in our hospital were reviewed in this study. The existence of VTE was assessed from the neck to the pelvis with computed tomography at the initial visit and after neo-adjuvant chemotherapy (NAC) and 6thpostoperative day. The patient and tumor characteristics, neo-adjuvant chemotherapy were compared between patients with VTE (VTE group) and those without VTE (non-VTE group). The primary outcome is disease-free survival (DFS) and the secondary outcome is overall survival (OS). Results: Twenty-one VTE events among 172 patients (12%) were observed. Six of which occurred preoperatively and were considered to be associated with NAC, 14 were detected postoperatively and one occurred just after inserting a peripherally inserted central catheter preoperatively. The VTE group and the non-VTE group have homogenous characteristics in patients’ backgrounds and tumor features. We found no significant difference in median DFS and OS between two groups. However, in patients with pathologically N 0 or 1(7thedition of UICC TNM classification, n = 157), the median DFS was significantly shorter in VTE group compared with non-VTE group (41 months versus 64 months, p = 0.04). The recurrence risk increased 50.9% in VTE group in comparison with non VTE group (p = 0.048). By using logistic regression analysis, we found that existence of VTE is an independent risk factor with Odd’s ratio 2.964 (p = 0.026). Conclusions: Our study suggests that VTE may be the risk factor for recurrence in esophageal cancer patients.