bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I evaluation of OXi4503, a vascular disrupting agent, in patients with advanced solid tumours
Authors: Patterson D. M. , Ross P. , Koetz B. , Saleem A. , Stratford M. , Stirling J. , Padhani A. , Asselin M. , Price P. , Rustin G. J. 
Published: March 2020

14146 Background: OXi4500, the active product of OXi4503, is a vascular disrupting agent acting at the colchicine binding site on the β subunit of tubulin. OXi4503 has greater anti-tumour activity in human cancer cell lines, causes a greater reduction in tumour blood flow than combretastatin A4P and has single agent activity in human tumour xenograft models. A phase I trial has commenced to examine the safety, tolerability and pharmacokinetics of OXi4503, with the primary objective being determination of MTD. FDG-PET scans were performed prior to and 28 days after the first infusion of OXi4503. Several other pharmacodynamic endpoints are also being assessed including DCE & BOLD MRI, circulating endothelial progenitor cells and cytokeratin 18. Methods: OXi4503 is administered by 3 weekly iv infusions to a maximum of 6 cycles. Starting dose was 0.06mg/m2. 100% dose escalation in single patient cohorts proceeded to 3.84mg/m2, when cohorts were expanded to three patients and 30% escalation due to emergence of grade 2 drug-related toxicity (thrombocytopaenia). Results: 11 patients have so far received OXi4503 (5F 6M, median age 54, range 33–68); median cycles received was 2 (range 1–4). Common AE’s include hypertension, pyrexia and anaemia. PK profiles show a dose-dependent linear increase in peak plasma concentrations and AUC of both OXi4503 and OXi4500. OXi4500 concentrations at current dosing (5 mg/m2) are close to that seen at the MTD in rats and dogs. DCE-MRI showed significant reduction in Ktrans in one patient (0.24mg/m2). In the 2 patients studied to date, PET images showed a decrease in the standardised uptake value (SUV) in 3 out of 4 metastases for one subject (1.92mg/m2) and in 5 out of 7 metastases for the other subject (3.84mg/m2) demonstrating a reduction in FDG uptake following drug treatment. Of 10 patients assessed, 2 have stable disease and 8 disease progression. Conclusions: OXi4503 has been tolerated at doses up to 5mg/m2 with no DLT observed, but changes in functional activity have been seen in 3 patients. MTD has not been reached and recruitment is ongoing. [Table: see text]
In silico design of novel anticancer antibody mimetic molecules targeting HER2
Authors: Nakajima H. , Tanuma S. , Fujiwara I. , Mizuta N. , Sakaguchi K. 
Published: March 2020

14149 Background: HER2 is a unique receptor molecule for which no ligand has been found and functions as a coreceptor to form homo-and hetero-dimers with other three HER (1, 3 and 4) family members. The dimerization results in the activation of HER tyrosine kinase. This, in turn, promotes the tyrosine phosphorylation of certain proteins, leading to the stimulation of cell proliferation, invasion, and antiapoptosis. The overexpression of HER2 in breast cancer correlates with increased tumor growth and metastatic potential, and thereby poor long-term survival for the patient. A monoclonal antibody against HER2, named trastuzumab, is approved for breast cancer patients, while pertuzumab is currently in phaseIIclinical trial. The two antibodies bind to different epitopes in the extracellular domains of HER2. Trastuzumab binding mainly mediates the antibody-dependent cytotoxicity (ADCC). On the other hand, pertuzumab binding directly inhibits HER2 dimerization with its partner receptors, blocking the growth signaling and inducing apoptosis. Furthermore, the unique binding pockets on HER2 for trastuzumab and pertuzumab have been resolved and provide the important target domains for creation of new anticancer drugs. Methods: Based on these mechanisms, we are trying to design and create both antibodies-mimetic molecules using our in silico methodologies COSMOS (Conversion to small molecules through optimized-peptide strategy) and SARM (Self-assembling regulatory molecule). We design HRAP (HER2 reactive peptide)- SARM and HRAP- SARM- FAB (Fc?-binding peptide). HRAP-SARM may bind to HER2 pertuzumab binding site and sterically interferes with HER2 dimerization and induces apoptosis. HRAP- SARM- FAB is expected to induce both ADCC and apoptosis. Results and Conclusion: In this presentation, we will show the preliminary results and functions of the Ab-mimetics, HRAP- SARM and HRAP- SARM- FAB on human breast cancer cells overexpressing HER2, as compared to those of trastuzumab and pertuzumab. Since those Ab-mimetics are small molecules and cheap, the successful results are sure to promise the revolutionary therapy for refractory breast cancer. No significant financial relationships to disclose.
Orexigenic and cytoprotective effects of a novel adenosine-enriched peptide nucleic acid compound: Implications for clinical application
Authors: D’Olimpio J. T. , Elliston S. , Dediego M. , Sodum R. 
Published: March 2020

14154 Background: There is a major unmet need for new non-toxic orexigenic and cytoprotective agents that can ameliorate intractable symptoms in cancer such as anorexia, poor wound healing/ulcerations and poor QoL. Underlying causes of these clinical problems include excessive inflammatory/cytokine responses to either treatment related or tumor related processes, or to both at once. AVR118, a novel remarkably non-toxic peptide/nucleic acid formulation has been shown in many anecdotal reports and in small clinical trials, to stimulate appetite, improve fatigue, and assist in more rapidly reversing toxic side effects of chemotherapy, radiation and interferon therapy. It has now been re-characterized to better explain these multiple effects. It binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines expressing A2 receptors, mechanistically involving targeted receptor binding, most likely in the gut and in the functional pathway of orexin A. Methodologies: HPLC, co-chromatography with standards, UV and mass spectrometry. Receptor binding/functional assays in vitro, animal models for anti-inflammatory and wound healing studies. Results: AVR 118 consists of a mix of 14 nucleoside derivatives, including available adenosine at a concentration of 2.1mM in stable solution. Also present is a complex aggregate of peptides showing high proline and tyrosine content. AVR 118 binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines containing A2 receptors and enhances smooth muscle relaxation mediated by A2 and others such as NK2 and NTS1 in vitro. AVR 118 shows 20% enhancement of epithelialization when compared to saline controls in a controlled porcine wound healing model. Conclusions: AVR 118 may prove to play a major role in palliation of anorexia symptoms associated with serious debilitating diseases such as cancer or AIDS and as adjunctive therapy for these patients. [Table: see text] No significant financial relationships to disclose.
Angiogenesis index (AI) as a predictor of tumor burden in lymph nodes in colon cancer (Cca) patients (pts) undergoing sentinel lymph node (SLN) mapping (M)
Authors: Grewal S. , Saha S. , Patel M. , Sehgal R. , Parker R. , Mechetner E. , Wiese D. , Yestrepsky B. , Yee C. , Barber K. 
Published: March 2020

14509 Background: Lymph Node (LN) status is the most important prognostic factor in colon cancer (Cca). Angiogenesis Index (AI) has been studied as a prognostic marker in various solid tumors with conflicting results. Hence, a retrospective analysis was done to evaluate the role of AI as a prognostic marker in Cca. Methods: Pts with Cca who underwent SLNM to determine LN status were included. A portion of tumor was sent for tumor marker analysis including p53, Thrombospondin-1 and CD31 by IHC. AI was derived for each specimen by summing the biomarker specific score for the three tumor markers. AI of -ve 6 was taken as cut off for significance based on previous studies on solid tumors. Metastatic foci in SLNs and non-SLNs were measured in greatest diameter by ocular micrometer; and were added for each pt to estimate overall tumor burden in SLNs and non-SLNs. Results: A total of 111 consecutive pts with Cca were included in the study. SLNM was successful in 100% pts. Pts with distant metastasis (mets) (n=18), Tis (n=1) and skip mets (n=9) were excluded from final analysis. Out of the remaining 83 pts, an AI of -6 or less was found in 22 pts (26.5%) while 61 pts (73.5%) had AI of more than (>) -6. Of the 61 pts with AI > -6, 37.7% pts were SLN +ve while 62.3% pts were SLN -ve (p=0.05)( Table 1A ). Of the 22 pts with AI less than or -6, 45.5% pts were SLN +ve and 54.5% pts were SLN -ve (p=0.65). Size of the metastatic tumor burden in lymph nodes was available in 69.7% of SLN +ve pts. Total average tumor burden for pts with AI > -6 (n=15) was 2.04cm as compared to 1.48cm in pts with AI of -6 or less (n=8)(p=0.66). Average SLN met size was 0.73cm in pts with AI > -6 and 0.63cm in pts with AI of -6 or less (p=0.66)( Table 1B ). Conclusions: AI did not correlate with nodal positivity or tumor burden in LNs in pts with Cca. LN status remains the most important prognostic marker in Cca. Further larger trials are required to determine the role of AI as a prognostic marker in Cca. [Table: see text] [Table: see text] No significant financial relationships to disclose.
Outcome of colorectal cancer (CRC) patients resected for brain metastases (BM)
Authors: Zanon E. , Aprile G. , Tuniz F. , De Pauli F. , Iaiza E. , Pella N. , Saman M. , Skrap M. , Fasola G. , Piga A. 
Published: March 2020

14530 Background: Advances in systemic treatment for metastatic CRC confer survival advantage, allowing patients to reach a median survival of almost 2 years. As a consequence of this remarkable life extension, the incidence of BM from CRC, though still low, is increasing over time. The presence of BM is considered an index of poor prognosis, even when surgical resection is possible. Methods: To determine if an aggressive approach to BM from CRC could provide patients with clinical benefit or survival advantage, we retrospectively collected data from 29 CRC patients who underwent neurosurgical resection of BM between March 1998 and July 2006. Results: The median age at the time of surgical procedure was 65 years, median ECOG PS was 1, and the majority of patients (26 out of 29) had concomitant metastases at other sites. Lung and liver metastases were both common. Median number of previous chemotherapy regimens was two, with almost all of the patients being exposed both to oxaliplatinum and irinotecan-based regimens. After resection, 30 Gy of external whole-brain radiotherapy were administered to the majority of the patients. At the time of the analysis, 26 out of 29 patients had died, with a median survival time after brain metastasectomy of 210 days (8–682). Only 2 patients died within a month from surgery. We did observe prolonged survival for patients who received post-surgical radiotherapy (Kaplan Maier, p=0.033). Although death due to encephalic progression was reported for the patients with brain as the sole metastatic site, intracranial disease progression was not a clear predictor for poor survival in the whole cohort (p>0.05). Conclusions: Surgical resection of BM from CRC, whether followed by radiotherapy or not, is a feasible and safe technique, offering a chance of prolonged survival. Patients who received radiotherapy after complete neurosurgical resection have a better outcome. No significant financial relationships to disclose.
Early analysis of toxicity and surgery in patients treated with cetuximab single agent followed by 5-fu, cetuximab and pelvic radiotherapy as neo-adjuvant treatment for operable, locally advanced rectal cancer (rc)
Authors: Bertolini F. , Zironi S. , Malavasi N. , Dealis C. , Bertoni F. , Losi L. , Chiara S. , Sonaglio C. , Luppi G. , Conte P. F. 
Published: March 2020

14531 Background: Pre-operative chemo-radiotherapy in locally advanced RC has been used to improve local control and to facilitate sphincter-sparing surgery for distal tumors. Cetuximab, an anti EGFR monoclonal antibody, has proved efficacy in advanced colorectal cancer. Methods: Study design provided: 1) tumor biopsy to confirm diagnosis and to measure tumor biomarkers (EGFR, TS, p53, MAP kinase, Ki 67, p21, bcl-2; immunological cell profile at the tumor level: CD45RO, CD68, CD56 CD4+/CD25+, CD31, HLA-A, -B and -C), 2) Cetuximab single agent (400 mg/sqm loading dose, then 250 mg/sqm weekly) for 3 doses, 3) a second biopsy to evaluate tumor biomarkers, 4) Cetuximab 250 mg/sqm weekly plus 5FU (225 mg/sqm in continuous infusion) concomitantly with RT (50 Gy), 5) surgery. Tumor biomarkers are measured again on tumor specimen in non pCR patients (pts). 66 pts with resectable uT3/uT4 N0/+ RC will enter the study. Primary aim is: toxicity and activity (pathologic complete response). Secondary aim is: evaluation of biological parameters, rates of sphincter sparing surgery and disease free survival. Results: Up to now 29 pts are valuable for toxicity (M/F= 22/5; median age: 61; range: 35–74). Ultrasound staging at diagnosis is: uT3N0: 7; uT3N1: 20; uT4N1: 2. Four pts (14%) withdrew neo-adjuvant treatment after 1 administration of Cetuximab: 2 for hypersensitivity reactions (1 G3; 1 G4), 1 for progression and 1 for purulent arthritis. Twenty-two pts (75%) presented acne-like rash; treatment with Cetuximab was interrupted or reduced in 4 pts (14%): in 2 for acne-like rash grade 3 (NCI-CTC) and in 2 pts for refuse. Grade 1–2 gastro-intestinal toxicity (unrelated to Cetuximab) was observed in 13 pts (proctitis: 4; diarrhoea: 9); in 1 case: diarrhoea G4. Twenty pts are valuable for surgery: 18 pts (90%) underwent conservative surgery. Two pts (10%) experienced post-surgical complications: 1 anastomotic fistula and 1 colonic necrosis. Conclusions: Pre-operative treatment with 5FU, Cetuximab and pelvic RT is well tolerated and does not increase surgical complication rate. An update on efficacy data and biological markers evaluation will be presented at the meeting. No significant financial relationships to disclose.
Bevacizumab (BV) related adverse events among various age groups of elderly patients with advanced colorectal cancer
Authors: Raman A. K. , Lombardo J. C. , Chandrasekhar R. , Fakih M. G. 
Published: March 2020

14546 Background: Hypertension (HTN), arterial thrombosis (ATE), venous thrombosis (VTE), and gastrointestinal perforation (P) are known BV related adverse events. The incidence of these events in different age groups of elderly patients (= 65 years) has not been well described. This study aimed at identifying the incidence of HTN, ATE, VTE, and P among three age groups: 65–69, 70–74 and =75 years. Methods: A retrospective chart review of CRC patients = 65 yrs treated with BV based chemotherapy during the period of January 2004 - July 2006 at Roswell Park Cancer Institute was performed. The incidence of grade (G) 3–4 HTN, ATE, VTE, and P was calculated. Results: Sixty patients = 65 yrs received BV during the study period: 20 patients were 65–69, 19 were 70–74, and 21 were = 75 years of age. The median age was 73 (range 65–90). Eight (13.3%) patients developed G3–4 arterial thromboembolic events, 7 (11.6%) developed G3–4 venous thromboembolic events, 10 (16.6%) developed G3 HTN, and 2 (3.3%) had a bowel perforation. The incidence of ATE was the highest in the = 75 age group (4/21, 19%) when compared to the 70–74 age group (2/19, 11%) and the 65–69 age group (2/20, 10%). Similarly, G3 HTN was more common in the = 75 years age group (6/21, 29%) when comparison to the 70–74 (2/19, 11%) and the 65–69 (2/20, 10%) age groups. VTE were evenly distributed in all 3 age groups while one P occurred in the 70–74 and = 75 age groups respectively. The trend of increasing incidence of ATE and HTN did not reach statistical significance using Odds Ratio analysis (SAS exact logistic regression method), likely due to the small sample size. Conclusion: The incidence of ATE and HTN is increased in the elderly population, especially in patients = 75 yrs. BV based therapy needs to be investigated further in this population to determine if BV clinical benefits outweigh the associated risks. No significant financial relationships to disclose.
Phase I/II study of irinotecan, UFT, and leucovorin with hepatic arterial infusion in colorectal cancer patients with unresectable liver metastases: Preliminary results
Authors: Yamaguchi T. , Matsumoto H. , Takahashi K. , Yasutome M. , Mori T. 
Published: March 2020

14549 Background: To determine the maximum-tolerated dose (MTD) and to evaluate the efficacy and tolerability of combination chemotherapy of irinotecan (CPT-11), UFT and leucovorin (LV) with hepatic arterial infusion (HAI) in colorectal cancer patients with unresectable liver metastases. Methods: Patients who had unresectable liver metastases from colorectal cancer were treated concurrently with intravenous CPT-11 on day1 of each 14-day treatment cycle with dose escalation, with orally UFT and LV on day 1–7 of each cycle, and with HAI of 5-FU on day 8–14 of each cycle. The primary objective of this phase I study was to determine the MTD of biweekly intravenous CPT-11 and UFT/LV with HAI of 5-FU. In the phase II study, the primary endpoint was to determine the response rate. Results: In the phase I study, the recommended dose of CPT-11 for phase II study was 140 mg/m2 combined with UFT 300 mg/m2/day, LV 75 mg/body/day and 5-FU 2,000 mg/body/week. Sixteen patients were enrolled onto the phase II study. The six patients treated at the recommended dose during the phase I study also included in the phase II analysis (n = 22). Median number of liver metastases was 12 (range, 3 to 35). Median size of maximum diameter was 6.3 cm (range, 2.0 to 12.0 cm). The most common adverse event was neutropenia. The complete and partial response rate totaled 81.8%. Median survival time has not been reached yet. Eleven patients (50.0%) were ultimately able to undergo liver resection. Conclusions: The combination chemotherapy of CPT-11 and UFT/LV with HAI was safe, well tolerate and effective in current population of the patients with unresectable liver metastases from colorectal cancer. Updated toxicity and response data will be available in the spring of 2007. No significant financial relationships to disclose.
A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens
Authors: Zoran P. , Tarabar D. , Doder R. 
Published: March 2020

14555 Background: This is a phase II study combination of capecitabine plus bevacizumab for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. Methods: The dose of capecitabine was 1000 mg/m2, administered twice daily for 14 days every 3 weeks. Bevacizumab was given at a dose of 5mg/kg on day 1 as i.v. infusion every 3 weeks. Treatment was repeated until the occurrence of disease progression or unaccepted toxicity. Results: Twenty-eight patients were enrolled. Of 28 patients, the overall response rate was 14.3% and the disease control rate was 42.9%. With a median follow-up period of 7 months, median time to progression and overall survival duration were 3 months and 14 months, respectively. The 1-year survival rate of all patients was 60.7%. The most common treatment-related grade 3/4 hematological toxicities included leukopenia/neutropenia in 4 patients and thrombocytopenia in 3 patients. Nonhematologic toxicities attributable to bevacizumab included bleeding in 3 patients, hypertension in 4 patients, thromboses in 3 patients, proteinuria in 5 patients, and gastrointestinal perforation in 1 patient. Conclusions: This drug regimen was well tolerated and combination of bevacizumab and capecitabine shows potential as third line chemotherapy in heavily pretreated patients with metastatic colorectal cancer. No significant financial relationships to disclose.
Matrix metalloproteinase-1 is differentially expressed in signet ring cell, and intestinal colorectal carcinomas histotypes
Authors: Calascibetta A. , Gebbia V. , Cabibi D. , Martorana A. , Aragona F. , Rausa L. , Sanguedolce R. 
Published: March 2020

14564 Background: Signet ring cell colorectal carcinoma ( SRCC) pure is an infrequent and highly malignant variant of colorectal cancer, while this histological component is present in 30% of all colorectal carcinomas. In our previous studies we compared the E- Cadherin, β- Catenin, Fibronectin, Ki 67 and Thymidylate Synthase (TS) expression of SRCC, the intestinal type of colorectal carcinoma (ICRC) to try to explain the pathogenesis, the aggressiveness and the low 5 Fluorouracil (5FU) responsiveness of these tumours. We found that all SRCCs had very low levels of all markers and were in the post- mitotic phase of the cell cycle. To understand their high metastatic capability we assessed the SRCC expression of Matrix Metallo Proteinase-1 (MMP1), a proteolytic enzyme, suspected to play an important role in the progression of various cancer and compared it to the ICRC one. Methods: We tested MMP1 expression immunohistochemically on formalin-fixed, paraffin-embedded samples of 32 SRCC and 70 ICRC. Differences in the distribution of the study variables, and associations between variables were assessed by means of the ?2 test. Results: SRCC showed a high expression of MMP1 over all in the invasion front of the tumour and in the neoplastic embolus rather then the ICRC (p<0.001). Conclusions: As MMPs seem to play important role in tumour invasion and metastasis, recently they have gained attention as targets for new anticancer therapy strategies. MMPs inhibitors have been shown to prevent tumour spread both in vitro and in vivo and to inhibit tumour angiogenesis and some of them are being developed for clinical use. In these study we demonstrated that SRCCs showed a different MMP1 expression pattern from the ICRC one, for this reason an anti-MMP therapy should be advisable in these patients, because of their bad prognosis. No significant financial relationships to disclose.