bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I pharmacokinetic (PK) study of vorinostat (V) in combination with irinotecan (I), 5-fluorouracil (5FU), and leucovorin (FOLFIRI) in advanced upper gastrointestinal cancers (AGC)
Authors: Fetterly G. J. , Brady W. E. , LeVea C. M. , Litwin A. M. , Zagst P. D. , Prey J. D. , Tarquini M. , Giardina M. K. , Iyer R. V. , Khushalani N. I. 
Published: August 2020

e15540 Background: Currently, advanced AGC has no clear standard regimen. The loss of transforming growth factor-β (TGFβ) response contributes to oncogenesis and has been described in gastric cancer. V, an inhibitor of histone deacetylase (HDAC) can restore TGFβ activity. We hypothesize that the addition of V to a standard chemotherapy regimen, FOLFIRI will result in improved therapeutic efficacy. Methods: AGC (esophagus, gastric, hepatocellular) patients (pts) with adequate organ function, performance status (ECOG 0–1), and 0–1 prior chemotherapy regimens are eligible for this phase 1 study to determine the MTD of V. Treatment consists of standard FOLFIRI (I 180mg/m2, leucovorin 400mg/m2, 5FU 400mg/m2 followed by 46-hr infusion 5FU 2400 mg/m2 q2w) with escalating doses of V given orally daily starting on day 2 (doses 200mg, 300mg, 400mg) in part 1 of the study. Per pre-specified design, initial intra- and inter-patient dose escalation was permitted, but then changed to a standard 3+3 design after observed toxicities. Tumor biopsy pre-Rx and at D13 are being done for TGFβ and survivin expression. PKs for I, SN-38 & SN-38G are being evaluated in part 1. Part 2 examines PK of V at the highest V dose tolerated. Results: 10 pts (7 M, 3 F), with a median age of 52 yr have been treated at 3 dose levels of V in part 1 (2 at 200mg, 5 at 300mg, 3 at 400mg). 2 pts have been given 400mg V in part 2. Major toxicities included neutropenia, leukopenia, fatigue, diarrhea, anemia, and hypoalbunemia. No DLT was noted at any dose level. Of the 8 pts evaluable for response, 2 pts experienced a partial response and 5 pts had stable disease. SN-38 exposure was similar prior to (316–395 ng-hr/mL) and in combination with escalating doses of V (426–469 ng-hr/mL), with a terminal half-life ranging from 7.5–14 hr. Conclusions: V continuously at 400mg/d with FOLFIRI was tolerable in AGC pts. Drug exposure of SN-38 is not affected by V coadministration. The expansion cohort will determine the recommended phase 2 dose. Correlative studies of survivin and TGFβ expression are ongoing. Part 3 will examine intermittent V dosing. This study is supported by an IISP research grant from Merck & Co., Inc. [Table: see text]
Phase II study of efficacy of bevacizumab and erlotinib in inoperable previously untreated hepatocellular carcinoma (HCC)
Authors: Govindarajan R. , Siegel E. , Makhoul I. , Williamson S. 
Published: August 2020

e15557 Background: New treatment options are needed for patients with inoperable and metastatic HCC. Sorafenib, a RAF kinase inhibitor, prolongs the time to progression and overall survival compared to best supportive care (5.5 and 10.7 months respectively). Angiogenesis plays important role in the development and progression of HCC. Erlotinib, an EGFR tyrosine kinase inhibitor that down-regulates expression of Vascular Endothelial Growth Factor (VEGF), and bevacizumab, a monoclonal anti-VEGF antibody, have synergistic activity in arresting angiogenesis. The objective of the study was designed to evaluate the efficacy of the combination of bevacizumab and erlotinib. The pre-determined endpoint for a positive result is a 27 week PFS of > 20%. Methods: A phase II study was conducted for newly diagnosed unresectable or metastatic HCC, Child-Pugh class A or B cirrhosis with bilirubin <2.0 mg/dL, transaminases < 5 x ULN, Platelet count >75,000 K/UL and ECOG PS 0–2 who had no prior systemic therapy and were not candidates for liver transplantation. Erlotinib was administered continuously at a daily dose of 150 mg, and bevacizumab was administered at a dose of 15 mg/kg intravenously every three weeks. Subjects were evaluated for disease progression by RECIST criteria. Results: At the time of analysis, 21 subjects were enrolled (16 Child- Pugh class A, 5 class B). 16 were evaluable. The median age was 60 Yrs.(range 33–81). Four subjects (27%) were progression-free at 27 weeks of enrollment (95% CI 8%- 55%). Median (quartiles) time to progression was 10.3 (9.0–57.1) weeks. The median (quartiles) overall survival (OS) was 59.7 (range 24.6- 92.6) weeks. Grade-3 events observed were (no.): fatigue (4), dehydration (2), hematemesis (1), diarrhea (1), nausea (1), and dyspnea (1). Grade-4 events (no.) observed were: myocardial infarction (1), atrial fibrillation (1), and ventricular tachycardia (1); pulmonary edema (1). Conclusions: The results met the predetermined study end point of progression free survival at 27 weeks of > 20%. The combination of bevacizumab and erlotinib should be further evauated as treatment option for patients with HCC. [Table: see text]
Phase II study of intrabuccally-administered amplitude-modulated electromagnetic fields in patients with advanced hepatocellular carcinoma
Authors: Costa F. P. , de Oliveira A. C. , Meirelles R. , Machado M. M. , Surjan R. , Chammas M. , Bottger B. , Morgan D. , Barbault A. , Pasche B. 
Published: August 2020

e15573 Background: Over the past few years we have identified tumor-specific frequencies for several common forms of cancer. The goal of this study was to assess the tolerability and effectiveness of electromagnetic fields amplitude-modulated at tumor-specific frequencies and administered by means of an intrabuccal spoon-shaped probe in patients with advanced hepatocellular carcinoma (HCC). Methods: From October 2005 to July 2007, patients with advanced HCC and Child-Pugh A or B were recruited in a phase II study. Three daily 60 min outpatient treatments were administered until disease progression or death. Imaging studies were performed every eight weeks. The primary efficacy end point was progression-free survival ≥ 6 months. Secondary efficacy end points were progression-free survival and overall survival. Results: A total of 41 patients were enrolled, 17 had Child-Pugh A, 20 Child-Pugh B disease. The median age was 64.0 years. Seventeen patients (34.1%) were progression-free for more than 6 months. Median progression-free and overall survivals were 4.8 months (95% CI 2.3–6.0) and 6.9 months (95 CI 4.8–11.1). As of December 2008, four patients are alive and two patients, who are still undergoing therapy, remain progression-free for 30.4 and 30.7 months, respectively. Four patients had partial response (9.8%) and sixteen had stable disease for at least 12 weeks (39.0%) according to the RECIST criteria resulting in 48.8% disease control. All responses were confirmed by independent review. There were no NCI grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient grade 1 fatigue. Conclusions: In patients with advanced HCC and impaired hepatic function, treatment with amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of anti-tumor effects, which are long-lasting in some patients. No significant financial relationships to disclose.
A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma
Authors: O'Neil B. H. , Williams-Goff L. W. , Kauh J. , Bekaii-Saab T. , Strosberg J. R. , Lee R. , Deal A. M. , Sullivan D. , Sebti S. M. 
Published: August 2020

e15574 Background: HCC is a deadly disease with few effective treatments. It is characterized by frequent MEK/ERK activation in the absence of RAS or RAF mutation. AZD6244 is a specific inhibitor of MEK that can be administered orally. Methods: Multi-center, single-arm study with a two-stage design utilizing RR as primary endpoint. Patients had advanced or metastatic HCC not amenable to surgical therapy or who failed locoregional therapy. Pts with Childs-Pugh A and compensated B were eligible. No prior systemic therapy was allowed. A pre-treatment biopsy was performed for p-ERK analysis. AZD6244 was administered orally at a dose of 100 mg bid. Results: 19 patients were enrolled, completing the first planned stage. One patient withdrew during cycle 1 with grade 2 AEs and is not evaluable. One patient is too early for evaluation. Another was removed from study for toxicity prior to evaluation. Two patients exhibited clinical progression and were removed from study without imaging (both assigned response of PD). Of 16 evaluable patients, PR + CR was 0%, SD 37.5%, PD 62.5%. Toxicities were generally low grade and included nausea (75%), transaminitis (63%), Alkaline phosphatase (50%), vomiting (50%), fatigue (44%), diarrhea (44%) and skin rash (44%). Grade 3–4 toxicity included transaminitis (38%), hyperbilirubinema (25%), and hypokalemia (13%). Median TTP was 8 weeks (95% CI: 6.6, 11.1). Conclusions: The study has been stopped at the interim analysis due to lack of radiographic response. Time to progression is not suggestive of significant prolonged stable disease. AZD6244 is well tolerated, but appears to have minimal activity in advanced HCC. Analysis of ERK phosphorylation status in biopsy samples is ongoing. No significant financial relationships to disclose.
BRSK2 expression as a prognosis marker in pancreatic cancer patients
Authors: Lou Dr. W. , Niu G. 
Published: August 2020

e15603 Background: The prognosis of pancreatic cancer remains dismal because of difficult early diagnosis, low resection rate and aggressive biological behavior. The research of factors related to oncogenesis, tumor infiltration and metastasis is valuable. AMPK(AMP-activated protein kinase)family is a group of regulators on the cellular energy metabolism which are sensitive to the cytoplasmic change of AMP/ATP ratio. As a member of AMPK, BRSK2 is found to be expressed in human pancreatic cell line and facilitate the tumor cell survival on glucose starving. In order to examine the expression of BRSK2 in human pancreatic cancer and explore the underline clinical implication, human pancreatic tissue was examined immunohistochemically Correlation of tumor biological behavior, prognosis and BRSK2 expression was examined. Methods: Seventy nine resected tumor specimens were collected. Immunochemical staining method was used to examine the expression pattern of BRSK2 translated protein. Semi-quantitative analysis was employed to compare the expression intensity and content of BRSK2 in tumor issues, peri-tumorous tissue and normal pancreatic tissue. Possible relationship of tumors differentiation, TNM stage, presence or absence of vessel and neural infiltration were explored with BRSK2 expression. The correlation of BRSK2 expression profile and patients survival was explored. Results: BRSK2 was weakly expressed in normal pancreatic tissues and peri-tumor tissues, including the islet and minor ducts. BRSK2 was strongly expressed in pancreatic cancer tissues, the expression intensity was correlated with extent of lymphatic metastasis, distant metastasis, TNM staging and neural invasion. Tumors with lymphatic metastasis, distant metastasis, neural invasion and later TNM stages showed stronger expression of BRSK2. The expression of BRSK2 in pancreatic cancer was closely correlated to the prognosis of patients, those with higher expression pattern showed bad prognosis. Conclusions: BRSK2 is up-regulated in pancreatic cancer; the expression of BRSK2 is correlated with tumor biological behavior and patient's prognosis. No significant financial relationships to disclose.
Phase I study of docetaxel, oxaliplatin, and capecitabine as first-line therapy to patients with advanced gastroesophageal cancer
Authors: Schønnemann K. R. , Andersen M. , Yilmaz M. , Jensen H. A. , Vestermark L. W. , Pfeiffer P. 
Published: August 2020

e15613 Background: Previously, epirubicin, cisplatin, and 5-FU (ECF) were often recommended as first line therapy to patients (pts) with advanced gastro-esophageal cancer (GE). If cisplatin is substituted by oxaliplatin (E) and 5-FU by capecitabine (X) this regimen can easily be administered with comparable efficacy and lower toxicity. In addition, recent studies have shown that efficacy can be improved by adding docetaxel (T) to CF. We therefore initiated a phase I trial of docetaxel, short-time infusion of oxaliplatin and continuously capecitabine (TEX) as first line therapy to establish the recommended dose for further therapy. Methods: Pts were enrolled in cohorts of 3 at each dose level ( Table ). All pts had non resectable histologically GE adenocarcinoma. No pts had received prior chemotherapy. Therapy was given day 1 with escalating doses of docetaxel (60 mg/m2to 75 mg/m2, as a 60 minutes infusion), capecitabine (1000 to1250 mg/m2/day continuously) and oxaliplatin (85 to 130 mg/m2 as a 30 minutes infusion). Cycles were repeated every 3 weeks for a maximum of 8 cycles. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first TEX cycle and defined as non-hematological toxicity grade ≥ 3, neutropenia grade 4 or febrile neutropenia more than 7 days. Results: From June 2007 to July 2008, 16 consecutive pts were treated with escalating doses of TEX. Median age was 59 years (43–74), median performance status was 1 (0–1). At dose level 5, two of 4 pts had DTL (1 pt had grade 3 vomiting and nausea and 1 pt had grade 3 nausea, vomiting and diarrhea). In addition 3 of 4 pts had neutropenia grade 4 without fever at dose level 5. Presently, 12 pts are still alive. Conclusions: First line taxotere, oxaliplatin and capecitabine every 3 weeks is easily administered in an out-patient setting but with substantial GI and haematological toxicity at dose level 5. An additional 6 pts will be included at dose level 4 to confirm tolerability at dose level 4. [Table: see text] No significant financial relationships to disclose.
Primary gastroenteropancreatic poorly differentiated neuroendocrine carcinoma: Clinico-pathologic analysis of 68 cases
Authors: Bukhari M. H. , Byron E. , Strosberg J. R. , Nasir N. A. , Henderson-Jackson E. , Bui M. , Hakam A. , Domenico C. , Kvols L. , Nasir A. 
Published: August 2020

e15616 Background: Primary gastro-entero-pancreatic poorly differentiated neuroendocrine carcinomas (GEP-PDNECAs) are highly aggressive neoplasms with a very poor prognosis. This study was conducted to evaluate the immuno-morphological spectrum of GEP-PDNECA, and patient survival with systemic platinum and etoposide therapy. Methods: Under an IRB-approved protocol, clinico-pathologic data were collected on 68 adult patients with GEP-PDNECA who had undergone biopsy / resection at MCC or outside institution. Data sources: Pathology archives, consultation files, tumor registry and social security index. All available slides were reviewed and tumors were histologically sub-typed. Subsequently, clinico-pathologic data and patient survival were analyzed. Results: Patients: 41 M/27 F. Age: 25–76 yrs (mean 42 yrs). Sites: Colo-rectum 39, pancreas 19, small intestine (SI) 4, stomach 3, colon/SI/pancreas 3. 63 of 68 (93%) patients presented with lymph node/distant metastases. Of 68 tumors 37 (54%) were classified as small cell carcinoma (SCCA), 16 (24%) large cell carcinoma (LCCA), 5 (7%) mixed small and large cell (MSLCCA) and 10 (15%) poorly differentiated carcinoma with neuroendocrine features (PDCA-NEF). Tumors were positive for chromogranin in 38/65 (55%), synaptophysin in 62/67 (92%), and CD56 in 17/21 (81%) cases. One marker was positive in 22/68 (32%), 2 in 40/68 (59%) and all 3 were positive in 9/68 (13%) cases. Fifty eight of 68 (85%) patients were treated with platinum and etoposide. Overall survival at 1, 3 and 5 years was 85%, 40% and 24% respectively. Patient survival was independent of age (r= -0.1022), sex (r= -0.909) and histologic subtype (r= - 0.1028) (p= 0.128) but was related to distant metastases (r=0.306; p=0.0383). Conclusions: Diagnosis of GEP-PDNECA can be based on histo-morphologic features and expression of neuroendocrine markers. Synaptophysin was the most sensitive marker; however, a panel of 2 or 3 neuroendocrine markers (Syn, Cg and CD56) may be more useful to avoid under-diagnosis of GEP-PDNECA, especially in the metastatic setting. Although survival of GEP-PDNECA patients following platinum and etoposide in our series was relatively favorable, there is need for novel therapies to improve patient survival. No significant financial relationships to disclose.
Serum lactate dehydrogenase (LDH) level as a prognostic factor for the patients with advanced gastric cancer
Authors: Lee H. , Yuh Y. , Kim S. 
Published: August 2020

e15621 Background: Though serum LDH level is frequently elevated in the patients with advanced gastric cancer, its clinical significance is still elusive. Moreover, the relationship between the change of serum LDH level after chemotherapy and the response to the treatment has not been studied, yet. We analyzed serum LDH level as a prognostic factor for the patients with advanced stomach cancer. Methods: We assessed serum LDH level before chemotherapy for the patients who were planned to receive palliative chemotherapy. We re-assessed their serum LDH level at the time when the response to chemotherapy was evaluated after 2–4 cycles of treatment. The survival duration and the response to chemotherapy for the patients with low serum LDH level were compared to the survival duration and the response to chemotherapy for the patients with high serum LDH level. The relationship between the change of serum LDH level and the response to the treatment was evaluated, too. Results: Total 118 patients were entered into this study and 114 patients were evaluable for their response to chemotherapy. Pre-treatment serum LDH level was normal in 88 patients and elevated in 30 patients. The response rate in the patients with high serum LDH level was significantly higher than the response rate in the patients with normal serum LDH level (34.5% versus 15.3%, p < 0.05). However, the patients with normal serum LDH level lived longer than the patients with high serum LDH level (median: 378 days versus 206 days, p < 0.001). The normalizing of the elevated serum LDH level after chemotherapy was related to the good response to treatment (response rate 50.0% versus 18.8%, p < 0.05). Conclusions: For the patients with advanced gastric cancer, high serum LDH level was related to better response to chemotherapy but shorter survival duration. The normalization of elevated serum LDH level after chemotherapy was related to good response to treatment. No significant financial relationships to disclose.
Analysis of association between carcinoid heart disease and mesenteric fibrosis in patients with midgut carcinoid tumour
Authors: Desai K. , Bhattacharya S. , Srirajaskanthan R. , Morgan-Rowe L. , Toumpanakis C. , Meyer T. , Caplin M. 
Published: August 2020

e15650 Background: Valvular heart disease in patients with carcinoid syndrome is due to development of fibrosis and endocardial thickening in the heart. The most accepted theory relating to development of heart disease is secretion of serotonin (5- hydroxy tryptamine) by the tumour or metastases. Mesenteric fibrosis develops as a result of peptides e.g.TGF beta released by local metastases. Both complications cause significant morbidity and mortality in patients with carcinoid syndrome. Aim: to evaluate the relationship of carcinoid heart disease and mesenteric fibrosis. Methods: We analysed retrospectively all patients (n=200) who had metastatic (liver metatstasis) neuroendocrine tumour and carcinoid syndrome with the primary clearly identified within the small bowel or caecum. We aimed to evaluate clinically symptoms of mesenteric ischemia and small bowel obstruction and also radiological presence of desmoplasia and small bowel dilatation. All patients underwent clinical and echocardiographic cardiovascular assessment to determine the presence of carcinoid heart disease. Results: Of 200 patients 42 had echocardiographic evidence of carcinoid heart disease. 4 patients had evidence of both mesenteric desmoplasia and carcinoid heart disease. 38 patients had carcinoid heart disease alone. Of the remaining 158 patients who had no evidence of carcinoid heart disease, 24 of them had evidence of desmoplasia and/or clinical evidence of sub-acute bowel obstruction where no other cause could be found. The remaining 134 patients had none of these complications. Comparing the relationship of Carcinoid heart disease and mesenteric fibrosis using two tailed exact Fisher's test, p value is 0.45, demonstrating they are statistically independent. We are currently assessing the effect on mortality. Conclusions: Carcinoid heart disease and mesenteric fibrosis (and its effects) are important determinants in morbidity and mortality of patients with midgut neuroendocrine tumour. Although carcinoid heart disease and mesenteric fibrosis are part of the same patho-physiologic process affecting patients with midgut neuroendocrine tumour, the results suggest that progression of these complications is independent of each other. No significant financial relationships to disclose.
Use of fermented mistletoe (viscum album L.) extract from oak tree (quercus) as supportive treatment for patients with pancreatic cancer
Authors: Stauder G. M. , Matthes H. , Friedel W. E. , Bock P. R. 
Published: August 2020

e15656 Background: To evaluate safety and efficacy of supportive treatment with fermented mistletoe extract Iscador Qu (from oak tree, quercus) (ISC-Qu) in a cohort of patients that received conventional adjuvant chemo- and/or radiotherapy (conv-th) alone (control) or additionally ISC-Qu (test group). Methods: Multicenter, comparative, non- interventional cohort study with parallel groups. Unselected, standardized, anonymized data from medical records meeting the eligibility criteria were followed until last visit or death. All endpoints were adjusted to baseline imbalance, therapy regimen and other confounders. Results: 270 patients (75 ISC-Qu/195 control) from 17 oncological centers. The treatment with ISC-Qu started before (16.7%), during (75.0%), or after (8.3%) the conv-th (mainly with gemcitabine) and usually lasted until last visit or death. The period of aftercare was median 20.3 (test group) and 10.1 months (control). Isc-Qu was applied by sequential dose escalation from 0.01 mg up to 20 mg, 2–3 injections per week (s.c.). Safety: Only 14.7% of the patients developed local ADR to ISC-Qu, there was no life- threatening ADR. Efficacy: There was a significant and relevant prolongation of overall survival: hazard ratio, HR (95% CI) = 0.35 (0.21- 0.58), p < 0.001; estimated relative risk reduction = 65%. The number of ADR to conv-th (odds ratio, OR = 0.20, p = 0.006, risk reduction 80%) and the estimated risk for disease or therapy related symptom persistence were significantly reduced in the test group with ISC-Qu. Conclusions: The results show reliable safety and an important effect of supportive ISC-Qu treatment on overall survival in patients with pancreatic cancer of any stage. [Table: see text]