bluuebunny/crossref_metadata_2025_split huggingface dataset:
Akt-mediated YB-1 phosphorylation induces resistance for chemotherapy of gastric cancer
Authors: Oki E. , Kakeji Y. , Tokunaga E. , Yoshida R. , Egashira A. , Sadanaga N. , Morita M. , Taguchi K. , Kuwano M. , Maehara Y. 
Published: March 2020

4554 Background: Y-box-binding protein 1 (YB-1), a member of the DNA-binding protein family which contains a cold-shock domain, has pleiotropic functions in response to stimuli of the AKT/PI3K signal pathway. We have previously described a pathway that involves PTEN/AKT/PI3K, thereby mediating chemoresistance in gastric cancer patients. We studied the Akt-mediated YB-1 phosphorylation and resistance to anti-cancer drugs for the treatment of gastric cancer. Methods: Primary gastric carcinoma tissue and the corresponding normal mucosa were both obtained from 81 gastric cancer patients who underwent surgery in the Department of Surgery II at Kyushu University Hospital from the years 1996 to 2000. YB-1 nuclear expression was investigated by immunostaining while AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. LOH of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite markers in the same samples. Results: We found the activated AKT to be associated with an increased resistance to multiple chemotherapeutic agents, including those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). The YB-1 nuclear expression was recognized in some patients and they closely correlated with a high expression of phosphorylated AKT. A high level of AKT phosphorylation (activated AKT) correlated closely with the LOH of PTEN (p < 0.0008), and the prognosis of patients who had LOH of PTEN was significantly poor in comparison to the other patients. Conclusions: The results of this study indicate that AKT activation and LOH of PTEN mediated the YB-1 activation, thus suggesting that they play an important role in conferring broad-spectrum chemoresistance in gastric cancer patients. These findings thus support the carrying out of new clinical trials for investigations of combination chemotherapy using conventional drugs with a new generation of signal transduction inhibitors. No significant financial relationships to disclose.
Combination chemotherapies in advanced gastric cancer: An updated systematic review and meta-analysis
Authors: Wagner A. D. , Grothe W. , Haerting J. , Kleber G. , Grothey A. , Fleig W. E. 
Published: March 2020

4555 Background: Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Methods: Our objectives were to assess the effect of: 1) 5-FU/cisplatin combinations with versus without anthracyclines; 2) 5-FU/anthracycline combinations with versus without cisplatin; 3) Irinotecan versus non-irinotecan containing combination chemotherapies; 4) Docetaxel versus non-docetaxel containing combinations; on overall survival and toxicity. Search strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from DDW, ECCO, ESMO, ASCO until october 2006. Selection criteria: Randomised controlled trials on different combination chemotherapies as above in advanced gastric cancer. Results: 13 trials including in total 2,184 patients (pts) are included in this meta-analysis. Comparison 1) including 501 pts (HR 0.77; 95% CI 0.62–0.95); and 2) including 1,147 pts (HR 0.83; 95%CI 0.76–0.91) both demonstrate a significant survival benefit for three-drug regimens including 5-FU, anthracyclines and cisplatin. Among these, the rate of treatment-related deaths was higher when 5-FU was administered as bolus compared to infusional 5-FU (exact Mantel-Haenszel OR 2.33, p=0.285). Comparison 3) including 536 pts results in a HR of 0.88; 95% CI 0.73- 1.06. The rate of treatment related deaths was 0.7% versus 2.6% in the irinotecan versus non-irinotecan-containing arms (exact Mantel-Haenszel OR 0.275, p=0.166). Comparison 4) 4 relevant trials were identified. A meta-analysis will be performed as soon as the final results of at least 3 trials are available. Conclusions: Three-drug regimens containing 5-FU, anthracyclines and cisplatin achieve superior survival results compared to cisplatin/5-FU or antracycline/5-FU combinations. Among these, ECF (epirubicin, cisplatin and 5-FU) is tolerated best. Combinations including irinotecan demonstrate a non-significant trend towards better survival in this meta-analysis, but have never been compared against three-drug regimens containing 5-FU/cisplatin and an anthracycline. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105]. No significant financial relationships to disclose.
The effects of pasireotide (SOM230) on health-related quality of life in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR
Authors: Kvols L. , Glusman J. E. , Hahn E. A. , Wang E. , Öberg K. , Anthony L. , O’Dorisio T. M. , de Herder W. , Darby C. H. , Wiedenmann, G. B. 
Published: March 2020

4558 Background: Pasireotide is a novel multi-ligand somatostatin analogue with high affinity binding for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5). This Phase II clinical trial showed that pasireotide is effective in controlling the symptoms of diarrhea and flushing in 27% of patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR. The impact of pasireotide therapy on health-related quality of life (HRQL) was also evaluated. Methods: Patients in this open-label, multicenter study initially received pasireotide 300 μg sc bid which was escalated to a maximum dose of 1,200 μg sc bid until clinical response was achieved. Data are reported for the Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) instrument. FACIT-D comprises the Functional Assessment of Cancer Therapy-General (FACT-G) score, which measures physical, social, emotional and functional well-being, plus a symptom-specific sub-scale which measures HRQL specific to diarrhea. FACIT-D baseline assessment was obtained on day 1 immediately before dosing, and then monthly thereafter. FACIT-D sub-scale and total scores at baseline and after 1, 2, and 3 months of pasireotide treatment are described by categories of clinical response. Results: 45 patients (mean age 61 years; range 40–83) received treatment, and 44 were eligible for the efficacy and HRQL analyses. Functional well-being scores, symptom-specific scores and total FACIT-D scores of non-responders tended to be lower at baseline and during treatment than those of responders. The three sub-scale and summary FACIT-D scores exhibited relatively stable mean HRQL scores and similar patterns of variability in clinical responders and non- responders through the third month of pasireotide treatment. Conclusions: HRQL was stable during treatment with pasireotide in patients with advanced metastatic disease refractory or resistant to octreotide LAR. Additional work in HRQL study design and evaluation of HRQL endpoints in patients with carcinoid disease is indicated, and will further improve our understanding of quality of life in patients with this disease. [Table: see text]
A randomized clinical study of chemoradiotherapy versus radiotherapy in locoregional advanced unresectable esophageal cancer
Authors: Zupanc D. , Roth A. , Kolaric K. , Tometic Z. 
Published: March 2020

4565 Background: To compare the treatment results chemoradiotherapy that include split-course radiotherapy versus continuous radiotherapy for patients with locoregional advanced unresectable esophageal cancer. Methods: The randomized clinical study included 120 patients, of them 107 eligible. The eligible patients with locoregional advanced unresectable esophageal cancer were randomized in two groups. The first group of 55 patients was treated with chemotherapy in combination with split-course radiotherapy and second group of 52 patients received radiation therapy alone.The chemoradiotherapy group was treated with 5-fluorouracil (1,000 mg/m2 i.v. for six hours) and cisplatin (20 mg/m2 i.v.) for four consecutive days at the beginning of each part of therapy plus split-course irradiation (2x20 Gy, 200 cGy daily) separated by a rest of 2 weeks. The patients in radiotherapy group received totally up to 60 Gy, 200 cGy daily. Chemotherapy for clinical recurrence and salvage therapy. Results: The 2-,5-,10- years overall survival rate were 32.2 %, 24.5% and 7.3% in the chemoradiotherapy group and 22.2%,14.5% and 1.9% in the radiotherapy group.Median survival was 15 months in the chemoradiotherapy group and 11.5 months in the radiotherapy group. There was the statistically significant difference (p<0.05) between the groups due to overall survival. The hematological toxicity, nausea and alopecia were more common in the chemoradiotherapy group, but esophagitis and pain in the irradiated region were more common in the radiotherapy group. Conclusions: Chemoradiotherapy with cisplatin, 5-fluorouracil and split-course radiotherapy showed superior results to radiotherapy alone and did not produce any severe side effects in patients with locoregional advanced unresectable esophageal cancer. No significant financial relationships to disclose.
Triple induction chemotherapy and chemoradiotherapy in locally advanced esophageal cancer: Final results of a multicenter phase II trial
Authors: Eisterer W. M. , De Vries A. , Spechtenhauser B. , Kendler D. , Königsrainer A. , Nehoda H. , Lukas P. , Wöll E. , Öfner D. 
Published: March 2020

4568 Background: Surgery is the standard treatment for patients with resectable esophageal carcinoma, but 5-year survival rates rarely exceed 20%. Neoadjuvant chemoradiotherapy (CRT) may lead to downstaging of the tumor and thus improve the possibility of complete oncologic resection. Docetaxel (Dx) showed considerable activity in combination with hyperfractionated radiotherapy and only moderate toxicity. We evaluated a triple neoadjuvant regime including Dx in patients with locally advanced esophageal adenocarcinoma (AC) or squamos cell carcinoma (SCC). Methods: 24 patients (pts) with AC (n=8) or SCC (n=16) medically fit, no prior therapy, ECOG-performance status = 2 were included. Pts received 2 cycles of cisplatin (Cis) 15mg/ms2 d1–5, 5-fluorouracil (5-FU) 750mg/m2 continuous infusion (CI) d1–5, and Dx 75mg/m2 d1 repeated every 29 days followed by radiotherapy (RT) 39.6 Gy total dose (daily fraction 1.8Gy) concomitant to Dx 15mg/m2 on days 1, 8, 15, 22 and 5-FU 300mg/m2 CI on the days of RT followed by resection or definitive RT up to 59.6 Gy in case of inoperability. Results: See table . Grade 3/4 toxicity (n/%): neutropenia 10/43%, diarrhea 4/18%, alopecia 2/9%; deep vein thrombosis 1/5%, blurred vision 1/5%, fever 1/5%, pulmonary embolus 1/5%, arterial hypertension 1/5%. 1 pt died 39 days post resection due to fatal anastomical bleeding. 6/16 operated pts (37%) showed morbidity (anastomical stenosis/insufficiency, fistula, nervus recurrens palsy). 4/22 pts (18%) died 7- 25 months after therapy due to metastatic disease. At a median follow-up of 12 months 18 pts (82%) are alive, median survival has not been reached yet. Conclusions: Triple induction CT and CRT with Dx, Cis, and 5-FU is safe, feasible, and effective with CPR in 31%, downstaging in 81% and R0-resection in 100% of pts. Main toxicities are neutropenia (43%) and postoperative morbidity (37%). A follow-up phase II trial of triple induction therapy in combination with an EGFR-directed antibody is planned. [Table: see text] No significant financial relationships to disclose.
Cervical squamous cell carcinoma of the esophagus-a unique series of limited resection and free jejunal graft interposition after neoadjuvant RCTx in 94 patients
Authors: Ott K. , Lordick F. , Feith M. , Bartels H. , Fink U. , Stein H. J. , Molls M. , Biemer E. , Siewert J. 
Published: March 2020

4572 Background: The treatment of cervical squamous cell carcinoma (SCC) is discussed controversial. A limited resection of the cervical esophagus and reconstruction with a free jejenunal graft interposition using a microsurgical technique has been evaluated in our department. Methods: From 1986–2006 94 patients with the initial staging uT2–4, N any cM0 (75 male, 19 female; age 56+9.6, range: 19–74 years) with cervical SCC of the esophagus were treated with limited esophageal resection and reconstructed with a free jejunal autograft in combination after neoadjuvant RCTx within phase II studies. The median follow up is 23 months (0.1–120). Results: Laryngectomie had to be performed in 13 patients (14%). Recurrent nerve palsy on one side was found in 15/77 (19.5%) and on both sides in 13/77 (17%). Complications occurred in 70 (75%) of the patients, 47% of the patients had more than one complication. Reoperations were necessary in 29 patients (31%). The 30-day mortality was 2/94 (2.1%). Median survival is 29.9 months (1-, 3 and 5-year survival rates: 81%, 43%, 41%). 27/94 (29%) patients showed complete tumor regression (ypT0) after RCTx. Prognostic factors are complete tumor regression (p=0.007), ypT-(p=0.006), the R-category (p=0.018), but not the ypN-category (p=0.06). Neither the occurrence of complications (p=0.57) nor reoperation (p=.89) are associated with survival. The complete resection rate was 76 % (71/94). Median survival is 34.3 months, median recurrence free survival is 21.4 months for the R0 resected patients. 30/71 (42%) had a recurrence (locoregional in 27% (19/71), distant metastases in 10% (7/71) and a combination of both in 6% (4/71). Conclusions: Limited resection of the esophagus and reconstruction by a free jejunal graft after neoadjuvant RCTx is highly sophisticated and complex. Despite a high complication and reoperation rate the results are excellent with a low mortality and a good prognosis. This approach seems to be appropriate for cervical SCC in oncological centers with an infrastructure providing interdisciplinary management. Comparable data for cervical SCC of the esophagus without the inclusion of hypopharyx carcinoma do not exist in literature so far. No significant financial relationships to disclose.
Surrogate endpoints for overall survival (OS) in advanced pancreatic cancer (APC): Analysis of randomized clinical trials (RCTs) exploring gemcitabine (G)-based combinations
Authors: Milella M. , Bria E. , Carlini P. , Cuppone F. , Gelibter A. , Nisticò C. , Ruggeri E. M. , Terzoli E. , Cognetti F. , Giannarelli D. 
Published: March 2020

4575 Background: G-based combinations often result in an improved overall response rate (ORR) in APC; this improvement in ORR, however, seldom translates into a significant OS advantage. We therefore evaluated the appropriateness of ORR and progression-free survival (PFS) as surrogate endpoints for OS in RCTs comparing single-agent G and G-based combinations as first-line treatment for APC. Methods: Phase III trials reporting ORR or PFS and OS data were considered eligible. Potential correlations were explored according to a linear regression model considering both the actual outcome (ORR or PFS and OS) for each single arm and the calculated relative risk (RR) for each outcome in paired comparisons. Correlation was estimated according to Pearson’s (r) and R2 coefficients (parametric) and Spearman’s (Rho) coefficient (non-parametric). A model to calculate the target sample size to correctly identify 0.4, 0.7, and 1.5 mos benefits in OS was derived as well. Results: Nineteen (6,288 pts) and 17 (4,882 pts) RCTs were identified for the ORR/OS and PFS/OS correlation, respectively. When considering ORR rates and medians, ORR did not significantly correlate with OS (r=0.23, R2=0.06, p=0.14; Rho=0.16, p=0.33), while PFS showed a strong linear correlation (r=0.75, R2=0.56, p<0.0001; Rho=0.90, p<0.0001). Similarly, when considering RRs, ORR did not significantly correlate with OS (r=-0.17, R2=0.03, p=0.46; Rho=-0.18, p=0.44), while PFS showed a strong linear correlation (r=0.91, R2=0.82, p<0.0001; Rho=0.59, p=0.01). Based on these data, we derived a sample size model (beta-coefficient=0.75) to calculate how many patients would be necessary to demonstrate a significant OS advantage of 0.4, 0.7 and 1.5 mos, respectively, using PFS as a surrogate endpoint; according to this model, 0.5, 1, and 2 months improvements in PFS would be necessary to translate into the target OS advantages, requiring 2,370, 678 and 222 pts, respectively. Conclusions: In APC, ORR does not seem to correlate with OS. Conversely, PFS could be a reliable surrogate endpoint for survival in this setting, although the detection of relatively small differences in PFS would require a remarkably large sample size. No significant financial relationships to disclose.
Volumetric 3D CT analysis - an early predictor of response to therapy
Authors: Schwartz L. H. , Curran S. , Trocola R. , Randazzo J. , Ilson D. , Kelsen D. , Shah M. 
Published: March 2020

4576 Background: Evidence suggests that changes in unidimensional measurements (using RECIST criteria) may not accurately reflect actual changes in tumor size, and do not correlate well with other biomarkers of response, tumor progression, or patient outcome. We evaluated changes in tumor volume of target lesions with volumetric CT, and compared them with response assessments derived from RECIST criteria. Methods: We evaluated target lesions, including lymph node, liver, peritoneal and lung metastases in 25 patients with metastatic gastric cancer or gastroespohageal junction adenocarcinoma treated on a phase II clinical trial with irinotecan, cisplatin and bevacizumab. All patients underwent thin-section multidetector CT at baseline and 6-week follow-up for 10 cycles. Target lesions were measured unidimensionally and volumetrically, using validated automated and semiautomated segmentation algorithms. For initial analysis, correlation was made with the RECIST response using a cut-off value of 65% volume change. A ratio of change in RECIST measure to volume measure was calculated at time of maximal clinical response for each patient, as well as for responders versus non-responders. Results: 18 of 25 (72%) patients showed a clinical response. Of these 18 responders, 5, 6, 4, and 3 were identified as responders using RECIST criteria after cycles 1, 2, 3, and 4, respectively. Using a cut-off of 65% volume change, 14 of these responders were indentified after cycle 1, and 4 were identified after cycle 2. Using a cut-off value of 65%, volume measurements identified responders a mean of 50.3 days earlier than did RECIST criteria. There was a statistically significant (p<0.01) change in ratio of volume measurement change to RECIST measurement change for responding versus stable patients. Conclusions: Volumetric change in tumor size appears to predict clinical response earlier than do RECIST criteria in the majority of cases. Changes in volume are more sensitive because they exhibit a wider dynamic range. Ratios of size changes volumetrically appears to better discriminate RECIST responders from those with stable disease. Further work is needed to define the biologically relevant cut-off value for volume change, and to correlate volume change with other biomarkers. No significant financial relationships to disclose.
18-FDG-PET and somatostatin receptor scintigraphy (SRS) can predict disease progression and survival in patients with metastatic endocrine tumors: Results of a prospective study
Authors: Raoul J. , Devillers A. , de Lajarthe A. , Cuggia M. , Boucher E. , Garin E. 
Published: March 2020

4577 Background: Appropriate treatment for metastatic endocrine tumors (MET) depends on the aggressiveness of the disease. We wanted to know whether PET and SRS can predict early disease progression and patient survival. Methods: A prospective exploration protocol was applied for new cases of untreated MET diagnosed between September 2003 and January 2006 who gave their written informed consent. Explorations included: computed tomography (CT), SRS, PET, review of histological data (WHO grade, p53 and Ki67 IH); CT was repeated every three months to assess: disease-free survival (PFS), the risk of early (first 6 months) progressive disease (PD6m)and overall survival (OS). Results: The series included 38 patients (60±15y) with a primary digestive tract (n=24), lung (n=2) or unknown (n=12) tumor. Histologically, 4 patients had a high-grade tumor and 34 a low-grade tumor. Visual analysis of PET and SRS was positive in 15 and 27 patients respectively. The 2-year OS and DFS were 73% and 45%; 16 patients had PD6m. PET exhibited an excellent positive predictive value for PD6m (14/15 PET+ and 2/23 PET- were PD6m) and was correlated with DFS (p<0.0001; at 2 yr 75% DFS for PET- and 0% for PET+) and OS (p<0.0001; at 2 yr 95% vs 42%) even when considering only low-grade tumors. Positive SRS was associated with DFS (p<0.001) and OS (p<0.03). Among patients with positive PET, the SRS-positive patients had a better DFS than the SRS-negative patients. At univariate analysis DFS and OS were correlated with: PET, SRS, WHO grade, Ki67 and p53. At multivariate analysis only PET was predictive of DFS. Conclusions: PET and SRS exhibit excellent predictive value for rapid tumor progression. There results are correlated with DFS and OS even for histologically low-grade tumors. Tumors progressed within 6 months in 14/15 patients with a positive PET. These explorations should be included in the initial work-up for MET. No significant financial relationships to disclose.
NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract or gallbladder carcinoma: Phase II results
Authors: McWilliams R. R. , Foster N. R. , Quevedo F. J. , Marschke R. F. , Kugler J. W. , Friedman E. L. , Jaslowski A. J. , Sande J. R. , Alberts S. R. 
Published: March 2020

4578 Background: Gemcitabine is commonly used in patients with cholangiocarcinoma with a response rate of 20–30% and median overall survival of 6–10 months. Pemetrexed’s mechanism of action and tolerability in patients with hepatic dysfunction makes it a potential agent for cholangiocarcinoma. Methods: Patients with unresectable, previously untreated biliary tract cancers were eligible for participation. Patients received pemetrexed 500 mg/m2 IV over 10 minutes and gemcitabine 800 mg/m2 IV at 10 mg/m2/minute on days 1 and 15 of an every 4 week schedule with vitamin B12 and folate supplementation. The primary end-point is 6-month survival with a planned accrual of 59 patients. Results: 58 eligible patients are included in this analysis. 93% had metastatic disease. Median age was 61 (range: 40 - 81). Median follow-up was 6.5 months (range: 3.3 - 23.2). Median of 3 cycles of treatment was given (range: 1 - 10). Reasons for stopping treatment included disease progression (57%), adverse events (20%), refusal (17%), death on- study (4%), and other medical problems (2%). 6-month survival was 52% (95% CI: 40 - 68%). Median survival was 6.3 months (95% CI: 5.4 - 8.0 months) and median time-to-progression was 3.8 months (2.4 - 5.0). 46 of 58 patients (79%) experienced at least one grade 3+ AE (at least possible attribution), and 26 patients (45%) experienced at least one grade 4 AE (at least possible attribution), most of which were due to grade 4 neutropenia. Conclusions: This study shows similar results to what would be expected with gemcitabine alone. The addition of pemetrexed, as with other agents, has not significantly enhanced the activity of gemcitabine. Supported by NIH Grant CA25224- 18. [Table: see text] No significant financial relationships to disclose.