bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of changes in the glycolytic metabolism on tumor progression and dissemination in gastric cancer.
Authors: Zieker D. , Koenigsrainer I. , Beckert S. , Glatzle J. , Loeffler M. , Taichman R. S. , Koenigsrainer A. 
Published: February 2017

47 Background: Metastases are a frequent finding in gastric cancer patients and are associated with a poor prognosis. Recent data indicate that there might be a link between metabolic changes in the glycolytic system and dissemination in gastric cancer. The enhanced expression of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and its signalling targets CXCR4 and CXCL12 seem to play a crucial role in enabling gastric tumours to develop dissemination. Methods: Microarray analysis was conducted investigating human specimens from consecutive gastric cancer patients with dissemination versus gastric cancer patients without dissemination. Subsequently siRNA-knock- down concerning PGK1 and CXCR4 and transfection (overexpression) of PGK1 was performed. Further, our thesis was investigated in a metastatic nude mouse model simulating human gastric cancer behavior by orthotopic tumour implantation. Tumour growth was detected by PET-MR-imaging and section of the animals. Results: Microarray analysis revealed a significant overexpression of PGK1, CXCR4 and CXCL12 in gastric cancer specimens with dissemination. Further siRNA-knock-down of PGK1 and CXCR4 showed a significant co-regulation on expression and protein level in vitro. The transfection (overexpression) of PGK1 also revealed a significant upregulation of its signalling targets CXCR4 and CXCL12 on expression and protein level. In addition the transfected cells showed a 50-fold distinctive property in the invasion assay compared to cancer cells without PGK1 overexpression. The in-vivo results obtained in the mouse model showed that elevated PGK1 expression increased invasive and metastatic behavior of implanted gastric tumours significantly and PET-MR-imaging and section correlated very well comparing tumour growth and metastasis. Conclusions: The overexpression of the glycolytic enzyme PGK1 and its signalling targets in gastric cancer might be a promising regulation-pathway promoting dissemination. This data may provide new prognostic markers and/or potential therapeutic targets to prevent migration of gastric carcinoma cells and has intriguing connection to an old hypothesis advocated by Otto Warburg for tumour metabolism. No significant financial relationships to disclose.
Patterns of failure in patients with resectable synchronous liver metastases from rectal cancer (SLMRC): An analysis of the outcomes with and without pelvic radiotherapy.
Authors: Butte J. M. , Gonen M. , Ding P. , Goodman K. A. , Wong W. D. , Jarnagin W. R. , Weiser M. R. , D'Angelica M. I. 
Published: February 2017

473 Background: The role of pelvic radiation (RT) remains undefined in the management of patients with resectable SLMRC. A retrospective study of patients with SLMRC treated with and without pelvic RT was performed to determine recurrence patterns (distant vs. pelvic) and survival. Methods: Data from consecutive patients with SLMRC (disease free interval ≤ 12 months) undergoing complete resection of the rectal primary and liver metastases between 1990 and 2008 were identified from a prospective database. Demographics, tumor and treatment related variables were correlated with recurrence patterns. Competing risks analysis was used to determine the risk of pelvic and extra pelvic recurrence. Results: A total of 185 patients underwent complete resection of a rectal primary and liver metastases. One hundred eighty (97%) received CH during their treatment course and 91 patients (49%) received pelvic RT either before (65, 71.4%) or after (26, 28.6%) rectal resection. The 5-year disease-specific survival was 51% for the entire cohort with a median follow-up of 44 months for survivors. Survival was associated with negative liver margin (p<0.001), absence of LVI (p<0.01), and favorable clinical risk score (p=0.001). Overall, 130 patients (70%) recurred; 18 (10%) having pelvic recurrence as any part of their relapse and 7 (4%) having isolated pelvic recurrence. Recurrence pattern did not correlate with survival. Competing risks analysis demonstrated that the risk of any pelvic recurrence was significantly lower than extra pelvic recurrence (p<0.001), independent of the use of RT (Table). Conclusions: Pelvic recurrence after complete resection of SLMRC is uncommon and significantly exceeded by extra pelvic failures. Given the low pelvic recurrence risk in the cohort of patients who did not undergo pelvic RT, these data suggest that with proper patient selection, CH and surgical resection without pelvic RT is appropriate for patients with known SLMRC. [Table: see text] No significant financial relationships to disclose.
Prognostic relevance of genetic aberrations in gastrointestinal stromal tumors.
Authors: Mazurenko N. N. , Beliakov I. S. , Tsyganova I. V. , Bardina E. M. , Anurova O. A. , Gagarin I. M. , Skoromislova E. V. , Arhiri P. P. , Nikulin M. P. , Stilidi I. S. 
Published: February 2017

49 Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status. Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms. Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression. Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression. No significant financial relationships to disclose.
Effect of catumaxomab treatment in patients with peritoneal carcinomatosis and malignant ascites due to gastrointestinal cancers on survival.
Authors: Ströhlein M. A. , Essing M. M. , Hennig M. , Seimetz D. , Ott M. G. , Heiss M. M. 
Published: February 2017

490 Background: In 2009 the trifunctional antibody catumaxomab was approved for the intraperitoneal (i.p.) treatment of malignant ascites (MA) in EpCAM-positive carcinomas in Europe. Overall survival (OS) results for gastric cancer patients from the pivotal trial showed a significant treatment benefit of catumaxomab in this patient group. We present the results for the gastrointestinal (GI) cancer subgroup from the pivotal trial including long-term survivors. Methods: A total of 86 patients with MA due to GI cancer (gastric, pancreatic, colon, esophagus, rectum carcinoma) were treated with paracentesis plus catumaxomab (59 patients) vs. paracentesis alone (control, 27 patients). The primary endpoint was puncture-free survival; main secondary endpoints were time to next puncture, overall survival and safety parameters. The endpoints were compared between the catumaxomab and the control group using the Kaplan-Meier method and log-rank test. Analyses were performed for the Full Analysis Set (FAS) and the Safety Set (patients who received at least 1 catumaxomab infusion; 95%). Results: For puncture-free survival, a median of 35 days for catumaxomab vs. 14 days for control was observed (p<0.0001, HR: 0.340 with 95 % CI from 0.194 to 0.597, FAS). Time to next puncture resulted in a median of 118 days vs. 15 days (p<0.0001, HR: 0.161 with 95 % CI from 0.069 to 0.378, FAS). Although the study was not powered nor designed for OS, the difference between treatment and control arm was significant for the Safety Set (median: 61 vs. 44 days, p<0.05, HR: 0.553). ADRs were generally mild to moderate, limited to the treatment period and reversible. Conclusions: I.p. catumaxomab is an EMA-approved treatment for patients suffering from malignant ascites. The positive efficacy results were demonstrated in an advanced stage patient population together with a predictable and manageable safety profile. Patients suffering from peritoneal carcinomatosis with malignant ascites due to GI cancers experience a significant survival benefit from i.p. treatment with catumaxomab. [Table: see text]
Biological impact of skip metastasis in patients with gastrointestinal cancers undergoing sentinel lymph node mapping.
Authors: Saha S. , Mozayen M. , Sirop S. , Korant A. , Nalluri S. , Machek O. L. , Manyam M. , Ng P. L. , Nagpal S. , Wiese D. 
Published: February 2017

499 Background: As in melanoma and breast cancers, sentinel lymph node (SLN) mapping has been successfully used in gastrointestinal (GI) cancers (Ca) for accurate nodal staging. However, due to variable incidence of skip metastasis between different parts of the GI tract, its usefulness has been questioned for the proper staging. Hence, we aimed to evaluate the rates of skip mets, its mechanism and its biological impact in GICa. Methods: A search of English literature was performed incorporating MEDLINE and Cochrane library database using the following terms: skip metastasis, sentinel node, colorectal, gastric, and esophageal cancer. The following were excluded: comments, case reports, reviews, fewer than 40 patients in the study. The remaining were used for data extraction. Results: Between 2000-2009, 27 studies including 3,589 patients (122 esophageal, 1,185 gastric, 2,113 colon, and 169 rectal cancers) were reviewed. The overall success rate of SLNM was 95% (96.6% in esophageal, 94% in gastric, 94.3% in colon, and 95.6% in rectal cancer). Nodal positivity (positive SLN and/or non-SLN) was 34% in esophageal, 36.6% in gastric, 48.1% in colon, and 41% in rectal cancers. Rates of skip mets were 18%, 14%, 20%, and 15% in esophageal, gastric, colon, and rectal cancers respectively. In patients with skip mets, T3/T4 disease was found in 65%, 44%, and 82.5% of patients with esophageal, gastric and colon cancers respectively. The average tumor size ranged between 3 cm in gastric to 4.4 cm in colon cancer. The most common primary site for skip mets in colon cancer was the right side (50%), and in LN basin 7, 8, 9 in gastric cancer. All node positive (true and false negative) patients were staged as stage III and were treated with adjuvant chemotherapy. Conclusions: Skip mets are common in T3/T4 disease, and in larger tumors suggesting difficulty injecting the dye circumferentially. All node positive patients (true positive and skip mets) are treated with chemotherapy. Hence, skip mets has no real clinical impact on either the staging, treatment, or the outcome of the disease. No significant financial relationships to disclose.
A double-blind, randomized placebo-controlled, phase II study of maintenance enzastaurin (ENZ) with 5-FU/leucovorin (LV) plus bevacizumab (BV) following first-line therapy for metastatic colorectal cancer (mCRC).
Authors: Wolff R. A. , Schepp W. , DiBartolomeo M. , Hossain A. , Stoffregen C. , Nicol S. , Heinemann V. 
Published: February 2017

501 Background: Maintenance therapy is designed to maximize progression-free survival (PFS) and minimize toxicity in advanced CRC. ENZ is an oral serine/threonine kinase inhibitor that targets PKC-b and the AKT/PI3K pathway. Preclinical studies demonstrated synergistic antitumor effects when ENZ was combined with BV. In phase I studies, the combination was well tolerated. This phase II study assessed ENZ with 5-FU/LV plus BV as maintenance therapy for mCRC. Methods: Patients had locally advanced or mCRC, and completed 6 cycles of first-line chemotherapy ≤4 wks prior to randomization. Arm A received a loading dose of ENZ 1,125 mg, followed by 500 mg/d subsequent doses. Arm B received placebo. Both groups received 5-FU/LV (LV 400 mg/m2 IV, 5-FU 400 mg/m2 bolus, 5-FU 2,400 mg/m2 IV) plus BV 5 mg/kg IV, every 2 wks. Patients were treated with 5-FU/LV plus BV plus either ENZ or placebo until disease progression or for 1 yr. Primary endpoint was PFS from randomization. Secondary endpoints were overall survival (OS) from randomization, and OS and PFS from start of first-line therapy. Analysis was done after 50 events (objective or clinical progression). Results: 58 patients were randomized to Arm A (57 treated), 59 to Arm B (58 treated). 82 (70.1%) patients discontinued treatment (Arm A, 42 [72.4%]; Arm B, 40 [67.8%]), the majority due to disease progression. Median cycles were 9 in Arm A, 10 in Arm B. Median PFS in months was 5.8 in Arm A and 8.1 in Arm B (hazard ratio [HR]=1.35, 95% CI: 0.84, 2.16; protocol specified one-sided test, p=0.896). Median OS was not calculable due to high censoring (77.6% in Arm A and 91.5% in Arm B). Median PFS in months from start of first-line therapy was 8.9 in Arm A and 11.3 in Arm B (HR=1.39, 95% CI: 0.86, 2.23; one-sided, p=0.913). More patients developed thrombosis or embolism (TE), including pulmonary embolism, on Arm A (5 [8.8%] patients had grade 3 and 5 [8.8%] grade 4 TE) compared with Arm B (no grade 3 and 1 [1.7%] grade 4 TE). Conclusions: ENZ did not demonstrate an advantage in PFS compared to BV-based therapy alone. Further development of maintenance therapy with ENZ is not recommended for mCRC. [Table: see text]
A population-based study of metastatic colorectal cancer (mCRC) in people age 80 and older: Findings from the South Australian Clinical Registry (SACR) for mCRC.
Authors: Jain K. , Beeke C. , Price T. J. , Young G. P. , Roder D. , Padbury R. , Townsend A. R. , Richards A. , Karapetis C. S. 
Published: February 2017

514 Background: Life expectancy is increasing and more patients (pts) with mCRC are presenting at an advanced age (>80). Optimal management approach for this group of pts is not well defined as they are under-represented in clinical trials. Methods: The SACR for mCRC collects data on mCRC pts diagnosed after 1/2/2006. We examined cancer characteristics, treatments administered and outcomes for pts aged >80 yrs. Comparison was made with pts <80 yrs. Results: Data from 1737 mCRC pts has been entered to date of which 522 (30%) pts were aged ≥ 80. Key patient characteristics and treatments are reported in the table. The majority had grade 2 tumours. Grade 3 differentiation was reported in lower proportion of pts ≥80 yrs than the younger group (18% v 26%, p < 0.001). Only 23.6% of pts >80 received chemotherapy (CT). Of these, 63% received single agent CT (mostly capecitabine) while 37% received combination CT as first line treatment. In contrast, 67% of pts <80 received CT, 73% of which received combination CT and 27% single agent (majority capecitabine) as their first line CT. Pts aged ≥ 80 had fewer liver resections and were also less likely to receive radiotherapy or monoclonal antibodies. Median survival was 7.1 mths for >80 yrs v 17.4 mths for <80 yrs, p < 0.001. Median survival for pts treated with chemotherapy was 19 mths for >80 and 21.7 mths for <80, p = 0.141. Pts without any treatment had a poor survival regardless of their age (median survival 2.9 mths >80 yrs v 2.4 mths <80 yrs). Conclusions: Older pts (≥ 80 yrs) were less likely to receive intervention for their mCRC and had poorer survival. However, survival for selected elderly pts, who received CT, was similar to those <80, despite most receiving single agent therapy. [Table: see text] [Table: see text]
A randomized phase II study of modified OPTIMOX1 or FOLFOX in advanced colorectal cancer.
Authors: Mikami C. 
Published: February 2017

519 Background: A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) is a standard first-line regimen for advanced or unresectable colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity, but the OPTIMOX1 (stop and go) approach offers a reasonable strategy. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX4 or modified FOLFOX6 (+/− bevacizumab), a simplified leucovorin and fluorouracil regimen with normal-dose oxaliplatin. Methods: Previously untreated patients were randomly assigned to either FOLFOX administered every 2 weeks until progression (arm FOL) or FOLFOX for six cycles, maintenance without oxaliplatin for six cycles, and continued every six cycles until progression (arm OPT). Results: Sixty patients (arm FOL [n=35], arm OPT [n=33]) were enrolled. The median number of treatment cycles was 10 (range, 3-28) in arm FOL and 12.5 (range, 1-32) in arm OPT. Cumulative dose of oxaliplatin was 850 mg/m2 in arm FOL and 552.5 mg/m2 in arm OPT. Median progression-free survival was 8.5 months in patients allocated to arm FOL compared with 15 months in patients allocated to arm OPT. Response rates evaluated by RECIST criteria were 50% with arm FOL and 64% with arm OPT. National Cancer Institute Common Toxicity Criteria grade 3 toxicity was observed in 37.1% of the patients in arm FOL and 24.0% of patients in arm OPT. Grade 3 sensory neuropathy was observed in 22.8% of the patients in arm FOL and 6% of patients in arm OPT. Conclusions: Our modified OPTIMOX1 regimen may be effective and safe treatment to prevent oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients. No significant financial relationships to disclose.
Evaluation of predictive factors of response of preoperative chemoradiotherapy (CRT) for rectal cancer biopsy specimens collected one week after the start of therapy.
Authors: Suzuki T. , Sadahiro S. , Maeda Y. , Tanaka A. , Okada K. , Ogoshi K. , Kamijo A. , Murayama C. 
Published: February 2017

521 Background: Preoperative CRT is the standard therapy for advanced rectal cancer. It has been reported that not only local recurrence but also distant metastasis are few in patients (pts) with remarkable histologic response. However, no definitive predictive factor has been established. The aim of this study was to determine whether biopsy collected before and one week after the start of CRT has significance as a predictive factor. Methods: Subjects were 72 pts with cT3/T4NxM0 rectal cancer who underwent preoperative CRT (40 or 45 Gy in 20 or 25 frs. with oral UFT or S-1 based chemotherapy). Pathologic response was assessed based on tumor regression grade (TRG) and tumor reduction rate (TRR) was calculated from barium enema images. Biopsy specimens were evaluated by proliferative index (Ki67), apoptosis and its related p53/p21 immunological staining and H-E staining. Results: For biopsy specimens collected before the start of CRT, a significant increase in TRR was observed in p21 positive pts (p = 0.04), but no factor related to the histological response. For biopsy specimens collected one week after the start of CRT, TRR were 50±13% for p21 positive pts and 40±14% for negative pts, 51±13% for apoptosis positive pts and 41±14% for negative pts, and 53±11% for pts with moderate effect recognized on H-E staining and 40±14% for pts with mild effects, respectively. The difference between positive and negative pts was significant (p<0.01, p<0.01, and p<0.01, respectively). The percentages of pts with moderate or higher histological effect (TRG 1 and 2) were significantly high in pts who were p21 positive, apoptosis positive, and had a moderate effect on H-E staining (p=0.01, p=0.04, and p<0.01, respectively). In other words, for biopsy specimens taken before the start of CRT, p21 was the only predictive factor, however, for biopsy specimens collected one week after the start of CRT, apoptosis and the effect recognized on H-E staining were also predictive factors in addition to p21. Conclusions: In CRT for rectal cancer, biopsy samples collected one week after the start of therapy increases the number of reliable predictive factors of response. No significant financial relationships to disclose.
Tolerance of full-dose sorafenib (S) combined with irinotecan (I; weekly, two on, one off) and cetuximab (C) in previously treated patients with advanced colorectal cancer (CRC).
Authors: Dasari A. , Rudek M. A. , Arcaroli J. , Powell R. W. , Carducci M. A. , Laheru D. , Wright J. J. , Hidalgo M. , Messersmith W. A. , Azad N. S. 
Published: February 2017

522 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways are qualified targets in CRC, and are both inhibited by S. Preclinical evidence suggests S may also overcome cetuximab resistance. We previously reported (2008 GI Symposium, abstr#435) excessive toxicity of this combination with I 120 mg/m2 days (d) 1,8,15,22 every 42 d; the study was amended with an alternative I dose/schedule and the phase I results are presented. Methods: Patients (pts) with advanced, pretreated CRC irrespective of KRAS mutation status with ECOG PS 0-2 and good organ function were eligible. The original dose/schedule of I was combined with C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S PO daily with dose level (DL) 1 = 200mg QD, DL2=200 mg BID and DL 3=400 mg BID. 2/4 pts had DLTs: grade (g) 3 fatigue and febrile neutropenia. The dose/schedule were amended to I 100 mg/m2 d1, 8 of 21d cycles (c) without changing S or C. As with the original design, there was a C/S lead-in for 2 weeks in c1, thus c1 (DLT window) was 5 weeks (w). Results: In the original design, 5 subjects were recruited; after the study amendment, 13 additional pts were recruited (3, 3 and 7 pts respectively at amended DL1, DL2 and DL3). Overall, median age was 56.5 yrs, M: F 12:6 and colon: rectal cancer 16:2. All patients are evaluable and 3 are still on treatment (10+ - 20+ w). At the amended I dose/schedule, there were no further DLTs. Any c g3 toxicities included constitutional (fatigue:2, dehydration:1), gastrointestinal (nausea:1, vomiting:2, diarrhea:1), metabolic (hypomagnesemia:2 including one with tetany; hypokalemia:3), elevated ALT:1 and neutropenia:1. G 4 toxicities included neutropenia:1, thrombocytopenia:1. Two pts (one KRAS MT) had partial response with one pt (KRAS WT) on treatment for >44 w. 10 pts had stable disease (5–20+ w). PK/PD analysis is ongoing. Conclusions: The recommended phase II dose is I 100 mg/m2d1,8; C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S 400 mg PO BID. The regimen is tolerable in advanced, pretreated CRC. Due to the limited responses and current phase III studies with S in CRC, there are no plans to open the phase II portion at this time. No significant financial relationships to disclose.