bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term survival after multidisciplinary treatment of small-bowel neuroendocrine tumors with synchronous liver metastases. A single-institute experience.
Authors: Bertani Emilio , Fazio Nicola , Chiappa Antonio , Botteri Edoardo , Spada Francesca , Grana Chiara , Ravizza Davide , Cossu Laura , Bonomo Guido , Andreoni Bruno 
Published: February 2017

299 Background: Neuroendocrine tumors (NETs) that originate in the distal jejunum and ileum are commonly diagnosed in stage IV, with liver metastases in 50-75% of cases. The aim of this study was to ascertain the impact of surgery in a consecutive series of patients with small bowel NET and synchronous liver metastases treated at a single institute. Methods: Ninety-one patients managed between 1995 and 2011 were extracted from the institutional tumor registry. All patients had diagnosis by histology of small bowel NET and synchronous liver metastases. Results: Among the 91 patients 28 (30.8%) underwent primary tumor removal and liver metastases resection or intraoperative termal ablation (Group 1), 54 (59.3%) underwent resection of only the primary tumor (Group 2), and the remaining 9 (9.9%) did not receive any surgery (Group 3). After a median follow-up of 64 months an overall survival (OS) of 93.1%, 81.8% and 76.2% at 3, 5 and 8 years was registered for the whole group. Cancer-specific survival (CSS) was 93.1%, 83.3% and 77.6% at 3, 5 and 8 years, respectively. Five-years OS differed significantly according to the surgical approach (96.0% for Group 1 vs 79.8% for Group 2 vs 48.6% for Group 3, p=0.02). During the course of the illness octreotide was administered in 78 patients (85.7%), peptide receptor radiotherapy in 61 (67.0%), systemic chemotherapy in 21 (23.1%), hepatic artery embolization in 17 (18.7%), interferon in 11 (12.1%), molecular targeted agents in 2 (2.2%). For patients who underwent any surgery (Group 1 and Group 2) the multidisciplinary approach was associated with a better OS (85.7% vs 77.2% 5-years OS, p=0.04). In the multivariate analysis only age was associated with OS, HR: 1.05 (C. I.: 1.01-1.10). The results of CSS were comparable to those of OS. Conclusions: In this metastatic setting of small bowel NETs the 5 year OS was as high as 82% with a maximum benefit achievable for patients who had primary tumor resection and liver disease amenable to surgical or thermal ablation. However, the potential impact of age in prognosis should be carefully considered when choosing the treatment to be delivered in such patients.
Continuous-dose regorafenib (REG) in hepatocellular carcinoma (HCC): Phase I safety and pharmacokinetic (PK) study.
Authors: Finn Richard S. , Blumenschein George R. , Tolcher Anthony W. , Leong Stephen , Boix Oliver , Diefenbach Konstanze 
Published: February 2017

300 Background: REG is a novel oral inhibitor of multiple kinases involved in angiogenesis, oncogenesis, and tumor microenvironment. A multicenter, open-label, single-arm phase I dose-escalation study evaluated REG given with a continuous schedule and established 100 mg once daily as the maximum tolerated dose. This study explored the safety and PK of this dose in an expanded cohort of advanced HCC pts. Methods: Adults with advanced treatment-refractory HCC (Child Pugh [CP] A or B) received REG 100 mg daily until tumor progression, unacceptable toxicity, or pt/investigator decision to stop. Safety and PK were primary endpoints. Tumor response was a secondary endpoint. Results: The HCC expansion cohort included 20 pts: male/female ratio: 14/6; 10 Asian, 4 white, 4 Hispanic, 1 black, 1 other; mean age: 56.8 ± 13.5 years; 16 CP A, 4 CP B; 2 stage II, 3 stage IIIA, 1 stage IIIC, 13 stage IV; 14 pts had disease progression at entry; 11 pts had 2+ metastatic sites; 19 pts had received prior sorafenib. Median duration of treatment was 42 days (range 23–329); 2 pts were still on treatment at data cutoff. Two pts died during the study (both due to disease progression). Drug-related AEs were reported in 18 pts (90%). The most common grade 3+ drug-related AEs were hypertension (n=4, 20%), fatigue (n=2, 10%), hand-foot skin reaction (n=2, 10%), pain (n=1, 5%), and hemoglobin, ALT, AST, lipase, and other metabolic/laboratory abnormalities (n=1, 5% each). Nine pts required REG dose modifications, and 2 pts stopped treatment permanently because of drug-related AEs. No drug-related serious AEs were reported. Single-dose PK data (cycle 1, day 1) were available from 18 pts, but only 1 pt was evaluable for steady-state PK samples. Single-dose analysis did not indicate any effect of CP status on REG PK. One pt had a partial response and 6 pts had stable disease; median time to progression was 36 days (range 28-237). Conclusions: Continuous-dose REG 100 mg once daily was well tolerated in pts with advanced HCC that progressed on prior sorafenib. PK data obtained after a single 100 mg dose did not indicate any effect of CP status on the PK of REG or its primary metabolites. Disease control was achieved in 7 pts. Clinical trial information: NCT01117623.
Pretreatment metabolic tumor volume (MTV) as a predictor of survival in borderline resectable pancreatic cancers treated with neoadjuvant therapy.
Authors: Cruz Alex , Chen Dung-Tsa , Fulp William J. , Chuong Michael , Hoffe Sarah , Shridhar Ravi , Rao Nikhil G , Hodul Pamela Joy , Malafa Mokenge Peter , Figura Nicholas , Eikman Edward , Springett Gregory M. 
Published: February 2017

310 Background: A higher initial metabolic tumor burden is associated with lower median survival in locally advanced pancreatic cancer (LAPC), yet the prognostic utility of PET/CT is not defined in the setting of borderline resectable pancreatic cancer (BRPC). Methods: We performed a retrospectivereview of our institutional experience treating BRPC. Initial staging included endoscopic ultrasound as well as pancreatic protocol CT and PET/CT scans. All patients underwent neoadjuvant gemcitabine-based chemotherapy and radiation therapy (RT). RT was delivered using standard fractionation intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). Restaging CT and PET/CT scans were obtained approximately 4 weeks following RT completion. We measured the significance of the pre-treatment and post-treatment SUV maximum and metabolic tumor volume (MTV) 2.5 to 5.0, which was defined as the MTV above a threshold SUV of 2.5, 3.0, 4.0 and 5.0. Cox regression models were used to evaluate the significance between these parameters and disease free survival (DFS) and overall survival (OS). Results: We evaluated a total of 72 BRPC patients. Median follow up was 12.7 months. 56 patients (77%) received induction chemotherapy with gemcitabine, docetaxel and capecitabine (GTX). 43 (59.7 %) underwent surgical resection. Significant predictors for OS in the whole cohort included pre-treatment SUV maximum (p=0.0042), post-treatment SUV maximum (p=0.0183), pre-treatment MTV 2.5 (p=0.0016) and pre-treatment MTV 4.0 (p=0.0111). In addition, the difference between the MTV 4.0 pre-treatment and post-treatment was significant (p=0.0285). In patients who underwent surgical resection, there was a significant correlation between OS with pre-treatment SUV max (p=0.0229) and post-treatment SUV maximum (p=0.0325) but not pre-treatment MTV 2.5 (p=0.0654) nor MTV 4.0 (p=0.0928) nor the differences between each variable pre (0.1482) or post-treatment (0.0959). Conclusions: This is the first study to suggest that pre and post treatment PET activity is prognostic for BRPC.
A phase II study of PD-0332991 in patients with advanced hepatocellular cancer.
Authors: Littman Susan Joy , Knudsen Erik S. , Witkiewicz Agnieszka , Hyslop Terry , Lewis Nancy , Pillai Madhavan V. , Brus Christina , Mitchell Edith P. 
Published: February 2017

321 Background: Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide and the 3rd most frequent cause of cancer-related mortality. Surgical resection & liver transplantation are the main curative options. Most patients present with advanced stage and poor liver function and are ineligible. Cytotoxic drugs give poor response rates and little benefit. The MKI sorafenib has been shown to significantly increase PFS and OS in advanced HCC in 2 rPhase 3 trials. PD-0332991 is an orally available, pyridopyrimidine-derived, selective inhibitor of CDK4/6, that results in the inhibition of RB protein phosphorylation & cell cycle arrest. In preclinical studies, PD-0332991 has cytostatic activity, dependent on RB protein Methods: This is an open-label non-randomized single-institution study for subjects with inoperable, recurrent/refractory advanced HCC. Subjects must have failed or be intolerant of standard first-line therapy, sorafinib. Subjects receive 125 mg PD-0332991 po/d 1-21 of 28-day cycle until disease or clinical progression, unacceptable toxicity, withdrawal of consent or death. Tumor response by CT or MRI using mRECIST v1.1 is q8 w. Subjects are assessed for toxicity per NCI CTCAE, v4.0. Results: 10 pts (8m,2f) have been enrolled. Median age is 61.7 (r32-74) yr. PD-0332991 is well tolerated. The most common toxicities were neutropenia and thrombocytopenia with 3 G3 neutropenia requiring therapy delay. Non-serious AEs were ascites, pain, nausea, vomiting, diarrhea, lightheadedness, anorexia, neuropathy. LFT abnormalities were consistent with underlying ESLD. 3 pts expired due to liver failure before disease progression was observed by RECIST, at 70, 85 and 136 d. 3 subjects developed PD at 3, 5 and 8 m. 2 have received additional therapy. 4 subjects are on therapy, with best PFS being 8 m. Conclusions: PD-0332991 is well tolerated in subjects with HCC and cirrhosis. Primary toxicity is neutropenia and thrombocytopenia consistent with known safety profile of PD-0332991. No unexpected toxicities have been observed. Preliminary responses are encouraging. TTP compares favorably to other drug regimens. Clinical trial information: NCT01356628.
Evaluating malignant intraductal papillary mucinous neoplasm: A population-based study.
Authors: Luu Carrie , Nelson Rebecca A. , Lee Byrne , Singh Gagandeep , Kim Joseph 
Published: February 2017

324 Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly recognized. Due to a paucity of evidence, the management and treatment of IPMN is still under debate. We hypothesize that with increased awareness, the incidence and resection rates for IPMN would increase. Using a population-based cancer registry, we examined incidence, prognostic factors, and survival for IPMN. Methods: Patients diagnosed with invasive IPMN from 1988 to 2009 were identified by the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics, clinical and pathologic factors, and therapies received (surgery and/or radiation) were analyzed. Survival was assessed by Kaplan-Meier method; Cox proportional hazard modeling was used for multivariate analysis. Results: 2,987 patients were identified. Over the study period, there was a decrease in age-adjusted incidence. The overall resection rate was 20.6% with an increase in annual rates of resection. On univariate analysis, age greater than 65 years, tumor location, poorly differentiated tumor grade, higher T stage, and positive lymph nodes predicted worse survival; more recent diagnosis, higher number of lymph nodes examined, and surgery were indicators of improved survival. On multivariate analysis, curative surgery remained predictive of survival. Patients who underwent surgery had median survival rates of 87, 18, and 14 months compared to 6, 7, and 5 months in the no surgery group for stages I, II, and III, respectively. Conclusions: Although recent reports show increasing incidence of IPMN, our study involving a population-based cohort demonstrates decreasing incidence of malignant IPMN. This may be accounted for by increased detection of non-malignant disease. It is imperative that we identify patients with invasive IPMN early so that they may benefit from the survival advantage conferred by curative resection.
Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.
Authors: Ghimire Krishna Bilas , Nepal Barsha , Shah Binay Kumar 
Published: February 2017

327 Background: Development of second primary cancers among gastrointestinal stromal tumor (GIST) patients is not very well studied. This study was conducted to evaluate second primary malignancies in GIST patients using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using MP-SIR session. We analysed secondary cancer rate among adult GIST patients during the period 1992-2009. We also compared the risk of secondary malignancies in pre- (1992-2001) to post-imatinib (2002-2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: There were 2,436 (693 in pre-imatinib era and 1,743 in post-imatinib era) GIST patients reported during 1992-2009 period in SEER database. Among them, 163 GIST patients developed second primary malignancy, which is significantly higher than expected in general population, with observed/expected (O/E) ratio: 1.31, p value = <0.05, (95% CI: 1.11-1.52) and excess risk of 39.76 per 10,000 population. The total number of second primary cancers in GIST in pre- and post-imatinib eras were 69 and 94, p value = <0.0001 with observed/expected (O/E) ratio of 29.18 and 48.22 respectively. The total number of second primary solid tumors in pre- and post-imatinib era was: 59 and 84, p value=0.0008 and O/E ratio: 20.18 vs 43.32 respectively. Conclusions: This study showed overall increased risk of second primary malignancies among GIST patients as compared to general population. There was significantly increased risk of second primary malignancies, especially solid tumors in post-imatinib era. [Table: see text]
Definitive chemoradiation with full-dose gemcitabine for unresectable pancreatic cancer: A single-institution experience.
Authors: Zhou Jessica , Shen Jincheng , Schipper Matthew J , Lawrence Theodore Steven , Feng Mary Uan-Sian 
Published: February 2017

331 Background: Definitive chemoradiotherapy (chemoRT) for unresectable pancreatic cancer has traditionally involved 5-FU-based chemotherapy. We have a long-history of combining gemcitabine and radiotherapy and performed a retrospective review of patients (pts) treated in this manner over the past 13 years. Methods: After IRB approval, the records of pts who underwent definitive treatment with radiotherapy (RT) and concurrent gemcitabine-based chemotherapy at the University of Michigan from February 1999 – May 2012 were reviewed. 193 pts were identified. Mean radiation dose was 40.5 Gy (median 36 Gy, range 24-60 Gy) in 2.2 Gy fractions (range 1.6 to 2.8), and targeted only radiographically apparent disease. 32% of pts received ≥50 Gy, and IMRT was used for 33%. The majority (97.9%) of pts were treated with concurrent full-dose weekly gemcitabine at 1000mg/m2. 48% of pts received at least 1 cycle of chemotherapy prior to chemoRT, and 13% received 2+ cycles. 85% of pts received additional chemotherapy after RT. Cox proportional hazard models were used for survival analysis. Results: Treatment was well-tolerated, with 91% of pts completing RT without a toxicity-related treatment break. With a median follow-up of 10 months, median overall survival (OS) was 13.5 months. 1, 2, and 5 year OS was 57%, 25%, and 5%, respectively. On univariate analysis, pre-treatment CA 19-9 and KPS predicted for OS (p=0.02 and 0.04). Tumor diameter was marginally associated (p=0.06). Age, gender, comorbidities, RT dose, and change in CA 19-9 before or after RT did not predict for OS. With regards to local response to treatment, 1 pt achieved a radiographic complete response (CR) and 30% of pts had a partial response (PR). Distant disease relapse occurred in 52% of all pts, including metastatic disease in the liver in 30%, peritoneum 15%, and lung 14%. 11 pts (6%) had late gastric or duodenal bleeds. Conclusions: Definitive chemoRT utilizing full dose gemcitabine is well-tolerated and achieves survival outcomes which compare favorably with reported series on 5-FU based therapy.
Classification of a VUS in MLH1 using a combination of family segregation studies and protein biochemistry.
Authors: Zbuk Kevin M. , Bell Kathleen , Zhou Anna , Guarne Alba , Aronson Melyssa , Lerner-Ellis Jordan , Pollett Aaron , Palma Laura , Chong George 
Published: February 2017

342 Background: The identification of variants of unknown clinical significance (VUS) presents a challenge for diagnostic laboratories and clinicians working with families with Lynch syndrome (LS). Although a variety of strategies exist to attempt clarification, data from multiple sources is often required before a VUS is re-classified to pathogenic or benign. Methods: We report on the investigation of 2 families with a variant in the MMR gene MLH1, c.2038T>C (p.Cys680Arg). In addition to segregation analysis, and review of published literature, the c-terminal domain of MLH1was cloned, the p.Cys680Arg variant was generated using site-directed mutagenesis and protein expression was induced. In addition, this point mutation was modelled onto the crystal structure of the dimerization domain of MLH1. Results: Both families fit Amsterdam criteria for a diagnosis of LS. All available tumours exhibited MLH1 deficiency and microsatellite instability and all living affected individuals available were positive for MLH1 p.Cys680Arg variant. Protein studies confirmed that p.Cys680 resides in a tight hydrophobic cavity and the p.Cys680Arg mutation disrupts the folding of the C-terminal domain of MLH1. In two families this variant segregated with disease in a total of 12 individuals (>10 meiosis and >1000:1 odds in favor of linkage) and 3 had an MLH1 deficient tumour, supporting a pathogenic role for this variant. Inspection of the crystal structure of MLH1 suggested that the Cys680Arg mutation should severely alter the folding of the dimerization domain. As opposed to the dimerization domain of MLH1 that can be readily produced recombinantly and is stable in solution, the same domain of MLH1 encoding the Cys680Arg mutation was expressed as inclusion bodies, confirming that this mutation causes misfolding of the dimerization domain of MLH1. Conclusions: Our data confirms that the p.Cys680Arg mutation destabilizes the dimerization domain of MLH1, and presumably the DNA mismatch repair proficiency of individuals carrying this mutation. Based on this evidence and family history data, the MLH1 C680R missense variant is classified as pathogenic. This approach may prove useful in the classification of other variants.
A new noninvasive blood-test for the early detection of colorectal cancer.
Authors: Sobhani Iradj , Incitti Roberto , Roperch Jean-Pierre 
Published: February 2017

348 Background: Colorectal cancer (CRC) remains a major medical problem in the world. Its early detection impacts the prognosis and the cost of treatment. Fecal occult blood test is a current noninvasive screening method for CRC detection in asymptomatic average risk individuals. It detects less than 50% of cancers and yields a high number of “normal” colonoscopies. The dysregulation of DNA methylation has been recognized as playing a crucial role during CRC development. The aim of the study was to develop a CRC-specific methylated DNA test in serum. Methods: First, the GoldenGate Methylation microarray containing 1,505 CpG loci within 807 cancer-related genes was used to study methylation patterns in CRC patients. We performed such assays on 9 tissues (4 CRC, 4 normal autologous tissues, 1 polyp), 17 blood and urine pooled samples (7 CRC, 6 polyps, 4 normal) and 20 stool samples (7 CRC, 3 polyps, 10 normal). The clinical status of each sample was assessed by colonoscopy and/or pathology findings. Among methylated genes detected in tumour tissue, stools, and blood, NPY, PENK and WIF1 genes were selected taking into account their high degree of methylation. We then carried out a clinical validation by quantitative multiplex methylation-specific PCR (QM-MSP) in two phases: firstly on 30 tissues (15 CRC, 15 homologous normal tissues) and secondly on 193 serum samples (32 CRC, 161 normal). Results: For to obtain the best accuracy of QM-MSP test, we defined for both biological sources a cumulative methylation index (CMI) by adding of the methylation percentage of each gene. At the CMI of 20.0% on tissues, our QM-MSP test allows to diagnose the CRC with the highest accuracy (100% of specificity and 100% of sensitivity). From sera, the CMI has been standardized at 2.0% giving a sensitivity and specificity for detecting CRC of 94.4% and 59.4% respectively (NPV of 92.1% and PPV of 67.8%). Conclusions: We developed a QM-MSP-based analysis of NPY, PENK, and WIF1 methylated genes in serum. This test classified correctly and with a high accuracy the healthy individuals and colon cancer patients. We propose here new sensitive serum-based epigenetic biomarkers as an effective and simple new noninvasive test for CRC screening in the average and high risk populations.
Prognostic and predictive value of CA19-9 in metastatic colorectal cancer.
Authors: Narita Yukiya , Taniguchi Hiroya , Komori Azusa , Nitta Sohhei , Yamaguchi Kazuhisa , Kondoh Chihiro , Kadowaki Shigenori , Takahari Daisuke , Ura Takashi , Andoh Masashi , Muro Kei 
Published: February 2017

354 Background: CA19-9 has been approved by FDA as a tumor marker in pancreatic cancer. The prognostic and predictive value of CA19-9 in metastatic colorectal cancer (mCRC) is still unclear. Moreover, CA19-9, a sialyl Lewis A antigen, acts as an adhesion factor of cells lining the blood vessels, but the association between the CA19-9 value and the effect of bevacizumab (BV) has not been reported. Methods: We conducted a retrospective review of 239 patients undergoing first-line chemotherapy by oxaliplatin-based regimens at a single institution from April 2005 to December 2009. The relationship between the CA19-9 value at baseline and the various clinicopathological factors and survival data was analyzed. Results: Median age was 62 years (range 23–83 years). 133 patients had a baseline CA19-9 value above the normal upper limit (>50 U/ml, high group), 86 had ULN (<50 U/ml, normal group), and 20 had below measurement sensitivity (example of Lewis antigen negativity, low group). The rate of KRAS MT and BRAF MT was high in the CA19-9 high group (KRAS MT 41.0%/BRAF MT 10.7%) as compared with the CA19-9 normal group (KRAS MT 22.7%/BRAF MT 0%). The high CA19-9 value in all the cases was a poor prognostic factor compared with the normal value (HR: 1.61, 95% CI: 1.28–2.04, p < 0.001). In multivariate analysis, the high CA19-9 value was an independent prognostic factor (HR:1.45, 95% CI: 1.10–1.91, p = 0.0082). Moreover, in the CEA normal group (<5 ng/ml), the high CA19-9 value was a poor prognostic factor as compared with the normal CA19-9 value (HR: 1.90, 95% CI: 1.00–3.62, p = 0.049). In the CA19-9 normal group, the median survival time (MST) with BV was longer than that without BV (53.2 vs 28.4 months, HR: 0.47, 95% CI: 0.30–0.93, p = 0.030). Furthermore, in the CA19-9 high group, MST with BV was longer than that without BV (20.6 vs 16.6 months, HR: 0.65, 95% CI: 0.44–0.97, p = 0.033). Conclusions: The CA19-9 value before chemotherapy in mCRC is an independent prognostic factor and intercorrelated with KRAS/BRAF MT. Bevacizumab exhibits clinical activity in mCRC patients, regardless of CA19-9 value.