bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin effects on clinical outcome in advanced HCC patients receiving sorafenib: Validation study.
Authors: Casadei Gardini Andrea , Faloppi Luca , De Matteis Serena , Foschi Giuseppe Francesco , Silvestris Nicola , Tovoli Francesco , Brunetti Oronzo , Umberto Vespasiani-Gentilucci , Ercolani Giorgio , Valgiusti Martina , Aprile Giuseppe , Fornaro Lorenzo , Saragoni Luca , Frassineti Giovanni Luca , Santini Daniele , Cascinu Stefano , Scartozzi Mario 
Published: September 2018

e15684 Background: In 2015 we published a paper where we have assessed the outcome of patient with HCC treated with metformin(M)and sorafenib(S). The data show that the concomitant use of S and m was associated with a lower PFS and OS respect for patients receiving S alone. The aim of this study was to validate the prognostic significance of m in patients with HCC treated with S. Methods: 280 patients with HCC consecutively treated with S twice daily between March 2008 and August 2016 were included in the study. Patients who had been taking insulin (I) for at least 5 years at the time of the HCC diagnosis were considered “ patients with diabetes treated with I,” whereas those who had been on m at for at least 5 years when HCC was diagnosed were considered “ patients with diabetes treated with M.” Results: In patients treated chronically with m the treatment with S was associated with a median PFS of 1.9 months (95% CI 1.8-2.3) compared to 3.7 months (95% CI 3.1-4.6) for patients without DM2 and compared to 8.4 months (95% CI 5.3-11.4) for patients treatment chronically with I (P < 0.0001). In patients treated chronically with m the treatment with sorafenib was associated with a median OS of 6.6 months (95% CI 4.6-8.7) compared to 10.8 months (95% CI 9.0-13.1) for patients without DM2 and compared to 16.6 months (95% CI 14.5-25.5) for patients treatment chronically with I (P = 0.0001). Metformin effects on clinical outcome were also investigated in relation to ORR. Patients treated chronically with metformin showed a higher percentage of progression at the first CT re-evaluation than those patients treatment with I and patients without DM2 (75.8% vs. 14.7% vs 38,8%, respectively). Considering the overall population, the risk of progression, was higher in DM2 patients taking m compared with patients without DM2 (HR = 1.91, 95% CI 1.28-2.8,). Regarding the risk of survival, similar results were observed (HR = 1.70, 95% CI 1.14-2.55). Conclusions: These results confirm an increased tumor aggressiveness and resistance to S in patients treated with m cronicaly.Molecular alterations in transporter genes or transcription factors involved in m molecular action and pharmacokinetics could contribute to a different response to these drugs combination.
Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs).
Authors: Lung Mei Sim , Hofman Michael , Kong Grace , Thang Sue-Ping , Michael Michael , Hicks Rodney J 
Published: September 2018

e15694 Background:Grade 3 (G3) NETs have a poor prognosis and limited treatment options (usually chemotherapy). PRRT is a potential treatment option if all sites of disease demonstrate high uptake on somatostatin-receptor imaging (SSRI). We retrospectively evaluated the efficacy of PRRT in G3 NETs. Methods: We reviewed records of patients with metastatic G3 NETs (Ki-67 > 20%) who received PRRT at our institution. Patients were treated with up to 5 cycles of PRRT, predominantly 177Lu-DOTA-octreotate. Further maintenance PRRT was administered upon progression if deemed suitable on SSRI. Radio-sensitizing chemotherapy was administered unless contra-indicated. Kaplan-Meier estimate was used to determine median overall survival (OS) and median time to new treatment/death (TNTD) defined from start of PRRT. Subgroup-analysis was performed for patients with Ki67 < 55% and ≥55%. Results: 26 patients with metastatic G3 NET received PRRT; 22 combined with chemotherapy (capecitabine/temozolomide (n = 12), 5-fluorouracil or capecitabine (n = 8), other (n = 2)). 58% were male. The median age was 62 (range 16-78 years). 61% had pancreatic NET, 19% small bowel, 8% lung, 8% unknown primary, 4% rectal. 77% had received at least one line of prior chemotherapy. 54% received prior platinum-based chemotherapy. Median follow-up was 33 months (range 8-83 months). Patients received a median of 4 cycles of PRRT (range 1-15). The estimated median OS from start of PRRT was 18 months: for Ki-67 < 55% (n = 21), 20 months; and Ki-67≥ 55% (n = 5), 9 months. The estimated median TNTD was 12 months: for Ki-67 < 55%, 16 months; and Ki-67≥55%, 4 months. 31% of patients were alive without a change in treatment modality following PRRT. Conclusions: In thispoor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.
Influence of organ location and sex of patient on pancreatic neuroendocrine tumor 5-year survival.
Authors: Botta Gregory P. , Bhangoo Munveer Singh , Sigal Darren 
Published: September 2018

e15713 Background: Pancreatic neuroendocrine tumors (PNET) represent a rare tumor histology among patients diagnosed with pancreatic cancer (less than 2% incidence). These tumors arise from the endocrine tissues of the pancreas and can present with a variable clinical course. We sought to examine the overall survival (OS) of patients based upon sex and anatomic location via the SEER database. Methods: Accessing the SEER-Medicare database, we identified 3,242 patients with both Pancreatic Cancer and Neuroendocrine Tumor (NET) histologic validation using ICD-O-3 Codes while excluding Large Cell, Small Cell, and Mixed Endocrine-Exocrine tumors. We then sub-stratified the data to male (N = 1816) and female (N = 1426) sex as well as pancreatic location: Head (Male = 831; Female = 657), Body (Male = 283; Female = 258), or Tail (Male = 701; Female = 510). We excluded PNETs of the pancreatic duct as there were only 2 cases (Male = 1; Female = 1). All comparison tests were run with SEER*STAT 8.3.2 via a Two-Sample t-Test Assuming Equal Variances. OS was analyzed using the Kaplan–Meier method. Results: Overall, both Male and Female patients with PNET have significantly improved 5-Year survival compared with those patients with Pancreatic Adenocarcinoma ((47.47% (n = 3242) vs 6.6% (n = 117,204), p < 0.05). There is no difference in 5-Year OS between Male (44.9%) and Female (50.5%) patients with PNET accounting for all locations. There is a trend towards significance in improved 5-Year OS in Female patients with Tail PNET versus Male patients with Tail PNET (55.8% (n = 510) vs 48.6% (n = 701), p < 0.06). Significantly, Female patients with Tail PNET have a significantly higher 5-Year OS compared to Female patients with Head PNET (55.8% (n = 510) vs 46.9% (n = 657), p < 0.05). There was a trend towards improved 5-Year OS in Female patients with Tail PNET versus those within the Body (55.8% (n = 510) vs 48.6% (n = 258), p < 0.01). Conclusions: Based upon this population study, Female patients with PNET localized to the Tail have a significantly higher 5-Year OS than Female patients with PNET localized to the Head of the Pancreas. These same patients trend towards improved survival when compared with Female patients with Body PNET as well as Male patients with Tail PNET.
A systematic review examining the relationship between progression-free survival and overall survival in adults with untreated metastatic pancreatic cancer.
Authors: Dabbous Omar , Wight Colin , Crathorne Louise , Qadan Ammar 
Published: September 2018

e15724 Background: The majority of pancreatic cancers are diagnosed in advanced stages with a median survival of 3 to 5 months. From 2005 to 2012, the US Food and Drug Administration approved 41 oncology drugs; surrogate endpoints were used in 84% of the trials providing the basis of approval. The aim of this systematic review was to evaluate the relationship between PFS/TTP and OS in metastatic pancreatic cancer. Methods: A systematic literature review used the Centre for Reviews and Dissemination principles to identify studies that reported median PFS or TTP and OS. We searched Medline, Medline In-Process, and Embase, with the following additional limits: English language and published 1/1990 to 7/ 2016. Selection criteria, defined a priori, included chemo, immuno or targeted therapy, randomized controlled studies (Phase 2 or 3) in patients with metastatic pancreatic cancer. Studies were assessed for quality using the Cochrane Risk of Bias tool and the Jadad scale. Studies were excluded if full-text articles were not available, and if patients received chemotherapy plus radiotherapy or surgery. Correlation analyses and weighted linear regression were used to assess the association between median PFS/TTP and median OS. The distributions of median PFS/TTP and OS were examined using scatterplots. Results: 1,691 studies were identified. After screening by title and abstract, 212 full articles were assessed, of which 28 studies (evaluating 6,734 patients) met the selection criteria. The mean median PFS/TTP and OS were, respectively, 3.82 months (range 1.2 to 6.8 months), and 7.06 months (range 2.5 to 11.9 months). The correlation coefficient was 0.837; 95% CI (0.734-0.903) indicating a very strong positive correlation between median OS and median PFS/TTP. Regression analysis indicated that median PFS/TTP was a highly significant predictor of median OS = 2.177 + 1.247 * median PFS/TTP (p < 0.001). Conclusions: The analysis demonstrates a very strong positive correlation of median PFS/TTP with median OS for the treatment of metastatic pancreatic cancer, which reinforces the hypothesis that PFS or TTP is a useful surrogate endpoint for OS in this cancer setting.
Relationship between diagnostic interval and pancreatic ductal adenocarcinoma (PDAC) resectability: A single-center retrospective analysis.
Authors: Deshwar Amar , Torto Deirdre , Sugar Elizabeth , Laheru Daniel A. , Yarchoan Mark 
Published: September 2018

e15738 Background: PDAC often presents with nonspecific symptoms and the workup for suspected PDAC is not standardized. While surgery remains the only curative therapy, only 20% of PDAC is resectable due to local extension or metastasis. We examined the relationship between diagnostic interval of PDAC and surgical resectability. Methods: We performed a retrospective chart review of patients evaluated for PDAC at the Center for Pancreas Cancer at Johns Hopkins in 2014. Data were collected on the patient, diagnostic, and treatment time intervals (defined as days between first symptoms to medical presentation, presentation to diagnosis, and diagnosis to treatment), diagnostic tests performed, and the type of initial treatment. Asymptomatic patients diagnosed incidentally, or those for whom initial medical presentation was unclear, were excluded from our analysis. Results: Of 453 charts reviewed, 116 patients met our inclusion criteria. The median patient interval was 14 days (IQR 6-30), the median diagnostic interval was 22 days (IQR 8-46), and the median treatment interval was 26 days (IQR 15-35). The median number of diagnostic tests performed was 8 (IQR 6-11). At the time of diagnosis, 7 patients (6%) had stage 1, 53 (46%) had stage 2, 24 (21%) had stage 3, and 32 (28%) had stage 4 disease. A total of 38 patients (33%) received upfront surgery for treatment of PDAC and 78 (67%) received nonsurgical treatment. Non-white individuals had lower odds of receiving surgery (Adjusted Odds Ratio [aOR]: 0.09, 95% Confidence Interval [CI]: 0.01, 0.74, p = 0.024). After adjusting for age, sex, race and diagnostic clinic, the odds of receiving surgery significantly increased for individuals with a patient interval of 1 month or less (aOR: 3.47, 95% CI: 1.003, 12.0, p = 0.010) and with a diagnostic interval of 2 months or less (aOR: 15.3, 95% CI: 1.90, 122, p = 0.019). Conclusions: A patient interval of less than 1 month and a diagnostic interval less than 2 months for symptomatic PDAC were associated with an increased probability of upfront surgical treatment. These data indicate that extended intervals prior to PDAC diagnosis may reduce the odds of obtaining a potentially curative treatment.
Effect of Redd1 loss on proliferation and metastasis of pancreatic cancer cells with KrasG12D-LOH by inhibiting glycolysis.
Authors: Hu Mingyue , Huang Peilin , Ma Yu , Ling Sunkai , Li Yuan , Chen Baoan , Xu Yueshuang 
Published: September 2018

e15741 Background: Aerobic glycolysis, regulated by mammalian target of rapamycin (mTOR) pathway, plays an important role in pancreatic carcinogenesis. Regulated in development and DNA damage response (Redd1) constitutes an important regulator of mTOR signaling. Previously, we observed that the loss of heterozygosity (LOH) status of Kras mutations (e.g. KrasG12D) is associated with an increased Redd1 expression. Here, we investigated the functional relevance of Redd1 in the context of KrasG12D-LOH. Methods: Murine KrasG12D-LOH/KrasG12Dpancreatic cancer cells isolated from genetically engineered mice were used in this study. The glycolysis dependence was detected by CCK8 assays after treated by glycolysis inhibitor 2-Deoxy-D-glucose (2-DG). Redd1 expression was down-regulated using shRNA transfection. Cell proliferation was determined by CCK8 and colony formation assays. Cell invasion and migration was measured by transwell and wound-healing assays. The levels of lactic acid and ATP were tested by ELISA kit. Genes related to glycolysis and mTOR signal were evaluated by western-blot and quantitative RT-PCR. Results: Compared with KRASG12D pancreatic cancer cells, the viability of KRASG12D-LOH cells decreased significantly in the presence of 2-DG. After Redd1 suppression, the proliferative and invasive potentials of KRASG12D-LOH cells decreased significantly when compared with blank group and negative group. The levels of lactic acid and ATP were also reduced by Redd1 down-regulation. Furthermore, the signal activity of mTOR pathway and Pkm2 and Hk2 expression were reduced dramatically, while Tsc1 and Tsc2 expression were unaffected. Conclusions: The LOH status of KRASG12D renders the pancreatic cancer cells additive to glycolysis, which further affect the proliferative and invasive potentials via the function of Redd1/mTOR. These data underscore the importance of KRASG12D-LOH in regulating cancer glucose metabolism.
Phase two clinical trial of combination oxaliplatin, irinotecan, and cetuximab for patients with locally advanced or metastatic pancreatic cancer.
Authors: Abdou Yara , Friend Sarah Cooke , Patt Yehuda Z. , Gan Christine , Lee Fa-Chyi 
Published: September 2018

e15781 Background: Pancreatic cancer remains a leading cause of cancer death with limited treatment options. After promising results from a retrospective chart review of the combination of irinotecan, oxaliplatin, and cetuximab (OIC), a prospective phase II trial was conducted to determine the efficacy and safety of this novel combination regimen in patients with advanced pancreatic cancer. Methods: Patients aged 18 and older, with a performance status of 0-2, and a life expectancy of minimum 12 weeks were eligible if they had confirmed locally advanced or metastatic pancreatic cancer. Patients were treated with intravenous irinotecan at 90 mg/m2, oxaliplatin at 60 mg/m2, and cetuximab at 250 mg/m2on day 1 of a 14-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1 criteria. The secondary endpoints included progression free survival (PFS), overall survival (OS), and tolerability of the regimen. Results: 60 patients were enrolled and 58 were evaluable; of these, 78% had metastatic disease and 22% had locally advanced cancer at time of enrollment. 41.4% of patients had received at least one prior line of cytotoxic chemotherapy. The ORR and DCR were 6.9% and 58.6%, respectively (complete response n = 1; partial response, n = 3; stable disease, n = 30). The median PFS was 3.6 months [95 % confidence interval (CI): 2.24-4.31], and median OS was 4.8 months [95 % CI: 3.68-6.25]. The most common grade 3 or 4 toxicities were hypokalemia (20.7%), fatigue (17.2%), abdominal pain (15.5%), hyperglycemia (13.8%) and dehydration (13.8%). Conclusions: OIC on a two-week regimen was well tolerated and demonstrated a high disease control rate, encouraging further investigation of this regimen in advanced pancreatic cancer. Clinical trial information: NCT00871169.
A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer.
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Kleiner David E , Alewine Christine , Figg William Douglas , Steinberg Seth M. , Levy Elliot B , Krishnasamy Venkatesh P , Wood Bradford J. , Citrin Deborah E. , Jones Jennifer C , Greten Tim F. 
Published: September 2018

e15786 Background: Durvalumab is a human IgG1 monoclonal antibody directed against PD-L1. Tremelimumab is a selective human IgG2 monoclonal antibody against CTLA-4. Several studies have documented an increase in peripheral antitumor immunity following radiation. The hypothesis of this study is that the effect of immune checkpoint inhibition (ICI) can be enhanced by radiation in pancreatic adenocarcinoma (PAC). Methods: Patients with histologically confirmed metastatic PC with primary in-situ or metastatic SBRT-amenable disease are being enrolled to this pilot study. Primary objective to determine safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone (Cohort A), or combined durvalumab and tremelimumab (Cohort B)] in combination with stereotactic body radiation therapy (SBRT) at two different schedules (8Gy/single fraction or 25Gy in 5 fractions). Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 accessible for biopsy. No limit to the number of prior chemotherapy regimens; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active autoimmune disorders. Results: N = 24 patients with chemorefractory metastatic PC have so far been enrolled; M/F = 13/11; Median age = 61. Treatment was well tolerated. No DLT encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. 5/24 pts had early discontinuation ( < 4 wks) due to rapid PD. No objective responses have been seen. 5 pts (21%) had SD as best response. Conclusions: Immune checkpoint inhibition in combination with SBRT in advanced pancreatic cancer is safe and feasible. Preliminarily no objective responses have been seen for these schedules of SBRT with durvalumab. The study is continuing with evaluation of SBRT with dual checkpoint inhibition (durvalumab and tremelimumab). Clinical trial information: NCT02311361.
Outcomes of elderly patients with muscle invasive bladder cancer (MIBC) treated with cystectomy or radiation therapy (RT): A surveillance epidemiology and end results (SEER) database analysis.
Authors: Tripathi Abhishek , Friderici Jennifer , Preston Mark A , Trinh Quoc-Dien , Mouw Kent , Beard Clair , Bellmunt Joaquim , Stewart James A. , Kibel Adam S. , Harshman Lauren Christine 
Published: September 2018

e16001 Background: Cystectomy and RT are both utilized in the management of MIBC. Elderly pts are more likely to be treated with non-surgical approaches that include RT. Using the SEER database, we evaluated outcomes in elderly pts with MIBC. Methods: Inclusion required pts ≥75 years with MIBC (T2-4, N0-3, M0). Cohorts were based on treatment received: cystectomy; RT; TURBT or no treatment. A propensity score was developed to address differences in treatment allocation according to age, race, sex, T and N stage, tumor location, and year of diagnosis. Propensity-adjusted competing risks analysis compared cancer specific mortality (CSM) between cohorts. Results: We identified 8506 pts with MIBC treated from 2007-2012. Of the 8423 pts with adequate treatment data, 26% had cystectomy (2196), 21% underwent RT (1752), 49% received TURBT alone (4128), 3% (262) received no treatment, and 1% (85) received both RT and cystectomy. Compared to RT, cystectomy cohort had a significantly higher proportion of pts < 80 yrs (49% vs. 25%) and was surgically staged with a higher degree of node + (22% vs. 4%) and ≥T3 disease (58% vs. 17%; all P < 0.001). At median follow-up of 10 mo (0-71), 48% (1061) of cystectomy pts and 61% (1064) of RT pts had died. MIBC was the leading cause of death (31% cystectomy, 39% RT). On propensity adjusted analysis, RT was associated with significantly worse CSM (HR: 1.62; 95% CI: 1.45-1.82) compared to cystectomy. Patients treated with TURBT or no treatment had the worst outcomes (5 year CSM: 71% each). Conclusions: Even in elderly pts with competing morbidities, MIBC accounted for more deaths than other causes. In this SEER cohort, non-surgical approaches involving RT were associated with significantly worse outcomes compared to cystectomy. However, worse performance status, less concurrent chemotherapy use, discrepancies between pathologic and clinical staging, use of lower dose RT, or lack of completion TURBT could not be examined and could have contributed to worse outcomes in the RT cohort. These results highlight the need for aggressive management of fit elderly patients with cystectomy or multimodality BPT.