bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of sorafenib in symptomatic metastatic medullary thyroid cancer
Authors: Kober F. , Hermann M. , Handler A. , Krotla G.
Published: March 2020

14065

Background: RET receptor tyrosin kinase activity plays a major role in medullary thyroid cancer (MTC) tumor growth. Sorafenib is an oral agent that selectively targets RET tyrosine kinases. Methods: 5 patients (pts) with metastatic MTC with excessive elevation of calcitonin(CTN) serum levels entered this pilotstudy. Hypercalcitonemia-related symptoms were present in all pts (3 severe diarrhea, 2 moderate) and metastasis- related symptoms were present in 4 pts (2 severe pain, 2 moderate). All pts had had prior thyreoidectomy and cervical +- mediastinal lymphnode dissection, 4 pts had prior octreotide therapy, 3 prior chemotherapy. Pts received 800 mg or 400 mg (weight < 50 kg) Sorafenib as a starting dose. According to the protocol, the dose was reduced gradually in 200 mg scale when pts revealed therapy induced side effects to avoid worsening of quality of life. Sorafenib has to be administered at least 3 months, the scheduled duration of therapy was 6 months. Physical examination, calcitonin and CEA levels were monitored every 4 weeks, measurable metastatic lesions were controlled by appropriate means 3 and 6 months after starting therapy. Primary objective was to assess the effect on CTN dependent symptoms, second objectives included assessments of tumor response (RECIST) and biochemical response. Results: After 2–3 months CTN decreased to levels >50% of baseline in all pts, to levels >90% in 2 pts. According to that all pts were free of CTN related symptoms after 4 weeks. In 4 pts CEA levels reacted in a similar way. After 6 months controls of metastatic lesions were classified as CR-1 pt, PR-1 pt, NC-3 pts. 2 pts with severe metastasis-related pain were off analgesics after 3 months of treatment. Due to side effects Sorafenib dosage was reduced to 50% of the initial dose in all patients. Interestingly marked TSH - elevations were observed in 3 pts which indicates a direct influence to the hypothalamic-pituary-axis. Conclusion: Sorafenib has to be considered as an effective teatment of symptomatic, metastatic MTC.

No significant financial relationships to disclose.
A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors
Authors: Avadhani A. N. , Flaherty K. , Rosen M. , Veronese M. L. , Harlacker K. , Johnson S. W. , Sherman E. , Griggs W. , Divgi C. R. , O’Dwyer P. J.
Published: March 2020

14075

Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m2 IV loading, followed by 250 mg/m2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m2), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination.

No significant financial relationships to disclose.
Effects of a proton pump inhibitor (lansoprazole) and food on the bioavailability of enzastaurin administered as single oral doses to healthy subjects
Authors: Welch P. , Musib L. , Darstein C. , Baldwin J. , Ayan-Oshodi M.
Published: March 2020

14076

Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In vitro studies show ENZ solubility is highest at pH 2.0 and decreases with increasing pH. This study examined the effect of increased gastric pH by a proton pump inhibitor (lansoprazole) and the effect of food on the bioavailability of a single oral dose of ENZ in healthy subjects. Methods: In this open-label, three-period, fixed sequence, crossover study, healthy subjects received an oral, 500-mg single dose of ENZ in the fed state, alone (A) and with lansoprazole (B), and in the fasted state alone (C). Lansoprazole was dosed for 5 days, with ENZ administered 2 hours after the 5th dose. A two-week washout occurred between each period. Plasma samples were collected at predose and scheduled timepoints for up to 168 hours post-ENZ dose for pharmacokinetic (PK) characterization of ENZ and its active metabolites. Results: 22 subjects were enrolled in the study with 19 subjects completing all treatment periods. The table summarizes the PK results for enzastaurin and total analytes (enzastaurin + metabolites). ENZ Cmax and AUC(0–8) were unaffected by the administration of lansoprazole, when ENZ was then given in the fed state. Enzastaurin Cmax and AUC(0–8) increased significantly, respectively by 6.8 and 2.8 fold, when ENZ was administered after a standardized breakfast, compared to the fasted state. Median tmax increased from approximately 3 hours in the fed state to 6 hours in the fasted state, indicating slower absorption when ENZ was administered in the fasted state. Conclusions: No significant alterations in ENZ exposures were seen in the presence of lansoprazole, indicating that increased gastric pH did not decrease exposures of ENZ, when ENZ is administered in the fed state. Exposures of ENZ and its active metabolites were significantly enhanced by administration of ENZ after a meal.

[Table: see text]

No significant financial relationships to disclose.
MAP4/OP18 mRNA expression predicts progression in patients treated with vinorelbine plus carbolpatin in advanced lung cancer patients in a Multicenter trial
Authors: Galan J. , del Barco S. , Mendez M. , Esquerdo G. , Huarriz M. G. , Bandres E. , Gil M. C. , Paules A. B. , Gayo J. , Garcia- Foncillas J.
Published: March 2020

14088

Background: Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. MAP4 and stahmin have been previously reported as potential markers of resistance to treatment based on microtubule-destabilizing agents. Methods: In this multicenter study, we have used quantitative PCR to analyse expression of MAP4, stathmin, beta-tubulin III, BRCA1 and ERCC1 in mRNA isolated from peripheral blood samples of 51 non-small-cell lung cancer patients treated with vinorelbine/carboplatin. Results: In a preliminary set, 29 patients with stage IIIB and IV were analyzed. Lower levels of MAP4/OP18 mRNA expression are statistically related with response to vinorelbine-based treatment (p=0,029). This significant relationship is maintained in a second analysis after third cycle of treatment (p=0,032). Higher levels of MAP4/op18 were associated with a lower TTP (p=0,05). Conclusions: Our preliminary results suggest that the ratio MAP4/OP18 may be a good predictor of response for patients with non-small-cell lung cancer treated with vinorelbine-based chemotherapy.

No significant financial relationships to disclose.
Phase I/II trial of OncoVEXGM-CSF combined with radical chemoradiation (CRT) in patients with newly diagnosed node-positive stage III/IV head and neck cancer (HNC)
Authors: Coffin R. S. , Hingorani M. , McNeish I. , Sibtain A. , Hamilton B. , Love C. , Nutting C. , Harrington K.
Published: March 2020

14095

Background: OncoVEXGM-CSF is a second generation oncolytic herpes virus expressing GM-CSF which has previously completed a Phase I study with evidence of anti-tumor activity. Combination of OncoVEXGM-CSF with CRT has additionally demonstrated significant pre-clinical anti-tumor activity. Methods: Patients (pts) with newly-diagnosed node-positive stage III/IV HNC were enrolled in cohorts of 4. Patients received radiotherapy (70 Gy/35 fractions to gross disease, 50 Gy/25 fractions to elective areas) with concomitant cisplatin (100mg/m2 days 1, 22, 43). Four doses of intranodal virus were given on days 1, 22, 43 and 64 as follows: Cohort 1 - 106, 106, 106, 106; Cohort 2 -106, 107, 107, 107; Cohort 3 - 106, 108, 108, 108 pfu/ml. Patients underwent neck dissection 4–6 weeks after the last dose. Endpoints were safety, viral replication and anti-tumor activity. Results: Eight pts have completed the protocol. Nodal stages were N2a (2 pts), N2b (3), N2c (2), N3 (1). Compliance with the CRT schedule was 100%. In Cohort 1, 1 pt received only 3 doses of virus because of early complete response (CR). In Cohort 2, 1 pt received 3 doses and 1 pt 2 received doses because of early CR. Neck dissection was undertaken as planned in all but 1 pt. CRT-related toxicities were not exacerbated by OncoVEXGM-CSF. Non-CRT-related toxicities were mild (grade 1–2 fever and injection site pain). No dose-limiting toxicities were seen. In pts in whom nodal biopsy was possible during treatment, evidence of viral replication was seen. Clinical responses in the primary site (7 pts) and nodal disease (8 pts) were impressive which anecdotally appeared to be greater than would be expected with chemoradiation alone. Pathological CR was confirmed at the primary tumour site in 6 pts and in the neck in 3 pts after neck dissection. Extensive tumour necrosis was seen in all injected nodes. Extensive staining for OncoVEX was also seen including in adjacent uninjected nodes demonstrating considerable intratumoral virus spread. Conclusions: Combination of OncoVEXGM-CSF and CRT is well tolerated with promising anti- tumor activity. Recruitment to the final dose-escalation cohort has now been completed.

No significant financial relationships to disclose.
Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)
Authors: Suttle B. , Jones S. , Dowlati A. , Tan A. , Mauser C. , Taber K. , Gibson D. , Arumugham T. , Lager J. J. , Burris H. A.
Published: March 2020

14118

Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (>20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of > 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text]

No significant financial relationships to disclose.
Phase I study of ECO-4601, a novel Ras pathway inhibitor
Authors: Kavan P. , Melnychuk D. , Langleben A. , Baker S. D. , Bangash A. , Gauthier C. , Ranger M. , Gourdeau H. , Harvey M. D. , Falardeau P. , Batist G.
Published: March 2020

14128

Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing.

[Table: see text]
The use of gene array analysis to determine down-stream molecular expression patterns of trastuzumab (T) treatment
Authors: Welle S. , Welt S. , Shay T. , Lanning C. , Horton K. , Kostyal D.
Published: March 2020

14135

Background: Breast cancers expressing the HER/2 amplicon are more aggressive and are associated with a poorer prognosis. HER/2 over-expression has been correlated with expression of proteins responsible for invasion, metastases, rapid growth, angiogenesis and apoptosis. However, it is unknown if T treatment of HER/2 over-expressing tumors reverses these phenotypes. Methods: BT 474 and SK-BR3 breast cancer cell lines contain the HER/2 amplicon. Under growth conditions demonstrating inhibitory effects of T by MTT and 3H-Thymidine incorporation, (0.25–50 micrograms/ml for up to 9 days), RNA extracts from treated and un- treated cells were analyzed and compared by whole human genome, gene array analysis. Results: Specific gene products reported to be up-regulated in HER/2 over-expressed breast cancer lines or responsible for aggressive behavior were assessed for down regulation by T treatment including: topoisomerase II, heregulin, egfr-1,2,3 and 4, p27, ki67, mapKinase, akt, caspase-3, caspase-7, caspase-9, bcl-2, veg-f, veg-f receptor, p38, sapk/jnk, erk1/2, LGALS1 galectin-1, LGALS3 galectin-3, proline-4-hydrolase P4HA2, FN1 fibronectin -1, CDH3 p-cadherin, laminin receptor protein -1, pro2605 and insulin like growth factor binding protein-3. No significant change in these mRNA levels were observed due to T treatment. In contrast, over 1000 other gene were found to be specifically and significantly up or down regulated including the down regulation of S100 Calcium binding protein associated with increase metastatic potential. Conclusions T treatment does not reverse the expression of a large array of proteins conferring poor prognostic features on HER/2+ tumor. The use of gene array analysis to study T induced gene expression is a robust method to assess downstream protein expression patterns mediated by antibody binding to receptor.

No significant financial relationships to disclose.
Spontaneous tumor apoptosis, caspase 3 and the survival outcome in medulloblastoma patients treated by postoperative radiotherapy and chemotherapy
Authors: Santek F. , Markulin-Grgic L. , Kusec R.
Published: March 2020

14136

Background: The role of apoptosis in neurooncology is still an unexplored area. Only a small number of studies which have combined clinically relevant data and treatment modalities, with the apoptotic activity have been published. Methods: The influence of spontaneous tumor apoptosis and its potential regulators caspase 3, BAX, p53 and bcl-2 was analyzed in 30 medulloblastoma patients with a long follow-up period, after the treatment at the Clinic of Oncology and Radiotherapy by postoperative radiotherapy with or without postirradiational chemotherapy. The mean apoptotic and mitotic index ratio (AI/MI) was measured in all tumor samples obtained by the initial neurosurgical procedure. Results: Significantly different survival groups of adequately treated patients were found only if the apoptotic indexes measured by the morphometrical analyzes (AIM) had been correlated with the TUNEL-essay results (AIT) in the same tumor sample, (log rank test=2.0287, p=0.04). The mean apoptotic index measured in the described combined way had slightly higher values AIM+T=38.2±20.3 (median=32.0), than when measured only by morphometrical analysis AM=23.9±24.9 (median=15.0). In the multivariate analysis according, the most relevant variables were the disease free interval (p<0.001) and the number of CT cycles (0.005<p<0.01). Further parameters of significance were the modality of postoperative radiotherapy, and the general condition of patients measured according to the WHO grading system at the end of treatment (p<0.001) as well as on the late controls, ater completion of the treatment (p<0.001) Conclusions: Our expirience in evaluating the metodology of apoptotic index measurement has confirmed the advantage of combined method of detection of the apoptotic index AIM+T over the use of each of the described methods alone. The apoptotic index has shown a significant influence on survival of the medulloblastoma patients only when divided with the mitotic index MI. Using clinical data of our medulloblastoma patients, the index of apoptosis alone as a prognostic factor has not appeared to be of significant relevance.

No significant financial relationships to disclose.
An open, pharmacokinetic (PK) and mass balance study of 14C-AZD2171, incorporating DCE-CT evaluations
Authors: Reid A. H. , Tang A. , Spicer J. , Gallerani E. , Mears D. , Settatree S. , Yap T. A. , Puchalski T. , Harrison M. , De-Bono J. S.
Published: March 2020

14140

Background: AZD2171 is an oral, highly potent and selective VEGF signaling inhibitor in clinical development. Methods: Patients with solid metastatic tumors received a single radiolabeled oral dose of 14C- AZD2171 45 mg; blood samples and all excretions were collected for evaluating the PK and metabolic profiles. After sufficient radioactivity recovery, patients started once-daily oral dosing with AZD2171 30 mg. The primary objective of the study was to determine the rates and routes of excretion of AZD2171 using 14C-AZD2171. Efficacy (RECIST), safety and tolerability were secondary objectives. The potential effects of AZD2171 on DCE-CT vascular parameters were also explored. Results: Six patients received treatment and remained on study for 64–171 days. In 5/6 patients, the amount of radioactivity recovered in the urine and feces samples within 168-hours post- dosing ranged from 84.8–93.0%; the analogous amount in the remaining patient was only 34.1%. In all patients, mean radioactivity recovered was 58.8% in feces and 20.8% in urine. Radioactivity appeared to be confined to plasma. Three patients (2 renal cell carcinoma; 1 mesothelioma) had a best RECIST response of stable disease (SD); 1 patient had a confirmed reduction in max tumor diameter of 10% to <30%. Two patients had progressive disease and 1 patient was non-evaluable. The most common adverse events (AEs) were diarrhea (n=5) and hypertension (n=3); no grade 3 or 4 AEs occurred more than once. There was evidence of reductions in DCE-CT parameters post treatment, particularly perfusion, permeability surface product (PSP) and positive enhancement integral. For each of these parameters, a decrease from baseline outside the baseline reference range was recorded for 3 patients (including 2 with SD) at 1 month after the start of daily dosing of AZD2171. Overall, within-patient variability (W-PV) was generally low for all DCE-CT parameters measured and was consistently lower than between-patient variability. The W-PV was largest for PSP (18%) and lowest for mean transit time (7%). Conclusions: The primary route of AZD2171 elimination appears to be hepatic. AZD2171 was well tolerated and clinically meaningful disease stabilization was seen. Changes in tumor vascular parameters were detected by DCE-CT.

[Table: see text]
Tolerance of avastin in metastatic colorectal cancer—a single institute Kuwait Cancer Control Centre experience
Authors: Vyas V. , Awadi S. A. , Khodary A. E. , Nemec J. , Muralidharan K. C. , Delvadiya M. D.
Published: March 2020

14156

Background: Bevacizumab is being used in combination with five fluorouracil(5-FU) based chemotherapy like FOLFIRI, FOLFOX, and capecitabine, since its inception in the treatment of metastatic colorectal cancer one year ago. Methods: a retrospective analysis was carried out to assess the toxicity profile of bevacizumab. Results: total 36 patients received bevacizumab in combination with various 5-FU based regimens .Twenty one were males 15 were females. A total of 288 cycles have been administered. Toxicities included change in medication for uncontrolled hypertension and mild epistaxis in 3 cases. One patient with intact primary in sigmoid colon developed perforation, peritonitis and she died subsequently. Conclusions: Conclusion- this preliminary results indicate that bevacizumab in combination with 5-FU based chemotherapy was tolerated. Extra precaution is required in cases of intact primary tumours.

No significant financial relationships to disclose.
The study of the relationship between Notch signal transduction pathway and polycomb protein Bmi1 in colorectal caner cells
Authors: Zhang H. , Ye Y. , Xu F. , Zhou J. , Wang S.
Published: March 2020

14501

Background: As is known the polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function. However, the potential molecular mechanism of BMI1 act as a cancer stem cell factor may also promote cancer development is unclear. In this study we demonstrated for the first time that Notch signal transduction pathway regulating expression of Bmi1 in colorecta caner cells and investigate the Notch1 mRNA and Bmi1 mRNA level in human colorectal cancer samples and their correlation with clinicopathological parameters of colorectal cancer. Methods and Results: We assessed Notch1 and Bmi1 mRNA in 50 cases of colorectal cancer and adjacent normal tissue by RT-PCR. The immunohistochemistry was used to determine the expression of ICN and in the 50 tissues of colorectal cancer and normal mucosa. Bmi1 SW480 cells were treated with DAPT (g-secretase inhibitor) at different times. MTT assay and flow cytometry were used to measure the proliferation and apoptosis of SW480 cells. The expression of ICN, Bmi1 were measured by western blot. Notch1 and Bmi1 mRNA level were increased in colorectal cancer compared with adjacent normal mucosa (P<0.05), the median values were 1.97-fold, 1.88-fold, respectively. It was found that overexpression of Notch1 and Bmi1 was related to differentiation and lymph nodes metastasis in colorectal cancer (P<0.05). The correlation between Notch1 and Bmi1 mRNA level, ICN and Bmi1 protein level are significant at the 0.01 level. Treating SW480 with DAPT, resulted in significant growth inhibition, apoptosis induction and downregulation of ICN and Bmi1. Conclusion: Our results show that overexpression of Notch1 and Bmi1 may play a critical role in the development of colorectal cancer. Notch1 signal transduction pathway regulating expression of Bmi1 in colorectal cancer cells.Blockade of Notch1 signal pathway can inhibit proliferation and accelerate apoptosis of colorectal cancer. [Key words] Colorectal cancer; BMI1; Signal transducers and activators of transcription3; Western blotting

No significant financial relationships to disclose.
Minimal effect of initial TNM stage on follow-up intensity for rectal cancer patients
Authors: Ode K. , Virgo K. S. , Longo W. E. , Audisio R. A. , Johnson F. E.
Published: March 2020

14508

Background: For rectal cancer patients, the risk of recurrence after curative-intent treatment is directly related to initial tumor stage. It is often assumed that more intensive follow-up is worthwhile in patients with high TNM stage lesions, while less intensive follow- up is sufficient for those with low TNM stage cancers. We carried out a survey of members of the American Society of Colon and Rectal Surgeons (ASCRS) to determine the surveillance strategies they use after primary curative-intent treatment for their own patients. This report describes the variation in surveillance intensity ascribable to initial TNM stage. Methods: We created a series of 4 vignettes succinctly describing generally healthy patients with rectal carcinoma (stage I treated with local excision, stage I treated with radical surgery, stage II treated with radical surgery, and stage III treated with radical surgery ± adjuvant therapy). We mailed a questionnaire based on the vignettes to all 1,795 members of ASCRS. Evaluable replies were entered into a computer database. The effect of TNM stage on follow-up intensity was analyzed using repeated-measures ANOVA. Results: There were 566 responses (32%), among which 347 (61%) were evaluable. The most frequent surveillance modality was office visit. In post-operative year 1 for patients with stage I lesions treated with local therapy, 3.8 ± 1.4 office visits (mean ± SD) were recommended, decreasing to 1.5 ± 0.8 in year 5. For patients with stage III lesions treated with radical surgery ± adjuvant therapy, 4.0 ± 2.8 office visits were recommended in year 1, decreasing to 1.7 ± 1.2 in year 5. Similar results were generated for all commonly used modalities on the questionnaire (3 blood tests, 2 endoscopic procedures, 8 imaging studies). Conclusions: The intensity of post-operative surveillance following curative-intent treatment for rectal cancer varies minimally by TNM stage. Because of this, a randomized trial of alternate follow-up strategies may be feasible without stratification according to stage. We will present the schema of such a trial at the meeting.

No significant financial relationships to disclose.
High serum YKL-40, but not plasma VEGF and serum HER2, as a prognostic biomarker of short survival in patients with metastatic colorectal cancer
Authors: Nicolaisen N. , Johansen J. S. , Pfeiffer P. , Christensen I. J. , Qvortrup C. , Nielsen S. E. , Glimelius B. , Keldsen N. , Fokstuen T. , Jensen B. V.
Published: March 2020

14517

Purpose: To evaluate the prognostic value of plasma VEGF, serum YKL-40 and HER2 before, during and after chemotherapy in patients with their first manifestation of metastatic colorectal cancer (mCRC). Patients and Methods: Prospective, longitudinal study of 105 patients (60 men and 45 women, median age 65, range 36–79 years, PS 0–2) from 7 centers referred with their first manifestation of mCRC. The patients were treated with Oxaliplatin 130 mg/m2 day 1 and Capecitabine 2000 mg/m2 days 1–14 every 3 weeks. Median follow-up was 1.8 years. 92 patients had progression and 62 died. The biomarkers were determined by ELISAs. Results: Pretreatment plasma VEGF (median 90 ng/l, range 3–2622, 37% had high level >137 ng/l) and serum YKL-40 (102 μg/l, 28–692, 40% had higher level than the age-corrected 95th percentile in healthy individuals) were significantly (p<0.001) elevated in the patients compared to normal levels. Serum HER2 was not elevated (7.90 μg/l, 3.6–92, 6% had high level >15 μg/l). Pretreatment serum YKL-40 was higher in patients who died compared to those alive (115 vs. 75 μg/l, p=0.004). No differences in plasma VEGF (97 vs. 85 ng/l, p=0.27) and serum HER2 (8.0 vs. 7.4 μg/l, p=0.16) were found. Univariate Cox analysis showed that plasma VEGF and serum HER2 before treatment or during follow-up could not predict progression-free and overall survival. Pretreatment serum YKL-40 (log transformed, scored as a continuous variable) was in a univariate analysis a prognostic biomarker of overall survival (HR=1.8, 95% CI: 1.3–2.6, p=0.0006), but not of progression- free survival (p=0.81). Multivariate Cox analysis (age, sex, number of organs with metastasis, pretreatment serum YKL-40 (continuous variable)) showed that serum YKL-40 (HR=1.8, 95% CI: 1.3–2.6, p=0.001) and possible the number of organs with metastasis (p=0.06) were independent predictors of overall survival. During follow-up, a high serum YKL-40 (log transformed continuous variable and landmark time) predicted shorter time to progression (HR=1.5, 95% CI 1.1–2.1, p=0.01) and overall survival (HR=1.7, 95% CI 1.2–2.4, p=0.005). Conclusion: Serum YKL-40 is a prognostic biomarker of overall survival and during follow-up also of progression-free survival in patients with mCRC.

No significant financial relationships to disclose.
Heparanase and Survivin—potential markers of aggressiveness of colon cancers
Authors: Hoffmann A. C. , Hoffmann C. , Danenberg K. D. , Lenz H. J. , Danenberg P. V.
Published: March 2020

14524

Background: Survivin is an inhibitor of apoptosis and specifically expressed in several human cancers. Heparanase seems to play an important role in cancer metastasis, angiogenesis and regulation of COX-2 expression. The purpose of this pilot study was to evaluate whether there is a difference in the level of survivin and heparanase expression in paraffin-embedded tissue from patients with colon cancer with and without metastasis. Methods: Paraffin-embedded tissue samples were obtained from 32 patients with primary colon tumors with (n = 15) and without liver metastases (n = 17) at the time of diagnosis. After laser capture microdissection direct quantitative real-time reverse transcriptase PCR (RT-PCR, TaqMan™) assays were performed in triplicates to determine survivin and heparanase gene expression levels. Gene expression was normalized with beta-Actin. Decision tree analysis was used to assess whether higher levels of these genes are associated with the existence of metastasis. Results: Neither survivin nor heparanase gene expression alone showed a significant relationship with the pM-Stage, although the detection levels of heparanase showed a tendency towards significant correlation with the existence of liver metastasis (p = 0.06). Decision tree analysis was used to split patients into two groups based on cut-off values of gene expression most closely associated with the pM-stage. The groupings determined by this analysis were significantly differently correlated with metastasis by Spearman’s test (p=0.03). Conclusions: Our results show that high expression levels of both survivin and heparanase in paraffin- embedded tissue are significantly correlated with the pM-Stage in this patient cohort. In conclusion, using intratumoral survivin and heparanase gene expression levels might be useful to identify patients at risk for liver metastasis. Prospective and larger clinical studies are warranted to validate our preliminary findings.

No significant financial relationships to disclose.
Postgraduate medical education homogenizes follow-up strategies after primary therapy for rectal cancer patients
Authors: Patel U. , Ode K. , Virgo K. S. , Audisio R. A. , Longo W. E. , Johnson F. E.
Published: March 2020

14533

Background: The pedagogical literature suggests that continuing medical education (CME) is valuable, but objective evidence of its value has proved difficult to obtain. We investigated how self-reported surgeon age affects self-reported surveillance strategies utilized by expert surgeons following their own patients with rectal carcinoma after curative-intent treatment. We reasoned that, if there were no significant differences in strategies among surgeons of various ages, the homogenization would be ascribable to CME. Methods: We surveyed the 1,795 members of the American Society of Colon and Rectal Surgeons (ASCRS) using a questionnaire based on 4 succinct vignettes describing idealized patients treated with curative intent for TNM stages I-III rectal carcinoma. The surgeons were asked how often they use 14 specific surveillance modalities (office visit, 3 blood tests, 2 endoscopic procedures, 8 imaging studies) during years 1–5 after surgery. The motivation underlying their surveillance practices was analyzed using a menu of 12 possible factors and a Likert scale of 1 (lowest effect on motivation) to 10 (highest effect). We assessed the effect of surgeon age on follow-up intensity, controlling for TNM stage and year post- treatment, using repeated-measures ANOVA. One-way ANOVA was used to analyze the effect of surgeon age on motivation. Results: Of the 566 responses, 347 were considered evaluable. There were no significant differences among age strata (30–39, 40–49, 50–59, and = 60) in surveillance practices for any of the 4 vignettes. Only one motivating factor differed significantly among age strata: psychosocial support for the patient; surgeons = 60 were motivated more strongly (Likert score 6.9; p < .05) by this factor than younger surgeons (Likert score 5.8). Conclusions: CME contributes to homogenization of this important aspect of clinical management among ASCRS surgeons.

No significant financial relationships to disclose.
Phase I/II study of S-1 combined with triweekly irinotecan for advanced or recurrent colorectal cancer
Authors: Kakeji Y. , Oki E. , Yoshida R. , Ikeda K. , Ohta M. , Honboh T. , Egashira A. , Sadanaga N. , Morita M. , Maehara Y.
Published: March 2020

14541

Background: A dose-escalation study of irinotecan (CPT-11) combined with S-1, an oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced or recurrent colorectal cancer. Methods: The subjects were untreated patients with inoperable advanced or recurrent colorectal cancer aged 20–75 years. S-1 was administered orally at 80 mg m-2 day-1 from day 1 to 14 of a 21-day cycle and CPT-11 was given intravenously on day 1 at an initial dose of 80 mg m-2 day-1, stepping up to 150 mg m-2. The treatment was repeated every 3 weeks, unless disease progression was observed. Results: In the phase I portion, only one of six patients at level 1 (80 mg m-2 of CPT-11) developed DLT, grade 3 diarrhea. No other serious adverse reactions occurred (either hematological or non- hematological), and all patients at levels 2 (100 mg m-2) to 5 (150 mg m-2) could receive therapy safely on an outpatient basis. The final RD was determined to be 150 mg m-2. In the phase II portion, fourteen patients including three patients in the final RD phase I portion were evaluated. The median treatment course was six (range: 2–17). The incidences of severe (grade 3–4) haematological and nonhaematological toxicities were 41.7 and 8.3%, respectively, but all were manageable. The RR was 50% (7 of 14, 95%CI: 23.0–77.0%), and Disease Control Rate (PR + SD) was seen in 71.4%. MST is not reached. Conclusions: Our phase I/II trial showed that S-1 combined with CPT-11 achieved a high response rate and could be given safely on an outpatient basis. These findings suggest that the therapy has potential as first- line treatment for inoperable advanced recurrent colorectal cancer. The updated analysis will be presented at the meeting.

No significant financial relationships to disclose.
Phase I trial of neoadjuvant concurrent chemoradiotherapy with S-1 and weekly irinotecan in locally advanced rectal cancer
Authors: Ahn J. , Choi H. , Cheon S. , Shin S. , Keum K. , Min B. , Baik S. , Kim N. , Jeung H. , Roh J. , Chung H.
Published: March 2020

14543

Background: S-1 is a novel, orally administered 5-FU analogue and is known of radiosensitizer. The aim of this study was to establish the feasibility and efficacy of S-1 in combination with weekly irionotecan with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. Methods: Clinical stage T3–4 or N+(on MRI) rectal adenocarcinoma patients received weekly irinotecan 40mg/m2(day1,8,15,22,29) and S-1 at dose levels of 40, 50, 60 and 70mg/m2 (5days a week from day 1 to 38) according to phase I methodology. Concurrently conventional RT was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 50.4 (45 + 5.4)Gy. Surgery was performed 4–8 weeks following completion of chemoradiation. Results: A total 16 patients (10M/7F, median age 46 years, ECOG PS0–1) were enrolled between August 2005 and July 2006. One pt withdrew the consent during CCRT. Dose-limiting toxicity (DLT) occurred at 50mg/m2 of S-1 in one of six pts (G4 cerebral infarction). At dose of 60, 70mg/m2 of S-1, no DLT occurred. G3/4 toxicties were rare. Fifthteen pts underwent surgery and R0 resection was achieved in 13 pts. Four pts (25.0%) had a pathological complete response. Conclusions: The recommended dose (RD) for further study is S-1 70mg/m2 with irinotecan and radiotherapy. Neoadjuvant S-1/irinotecan/RT is feasible and well tolerated. Phase II trial is being conducted.

No significant financial relationships to disclose.
Assessment of influence of hepatitis B or C virus (HBV or HCV) infection on occurence of colorectal liver metastasis (CLM)
Authors: Takahashi S. , Kinoshita T. , Saito N. , Sugitoh M. , Ochiai A.
Published: March 2020

14559

Background: Rare occurrence of CLM was reported in patients (pts) with HBV or HCV infection, or liver cirrhosis (LC). However, it is obscure whether HBV or HCV infection itself influence occurrence of CLM irrespective of liver cirrhosis (LC). The aim of this retrospective study was to evaluate correlation between HBV or HCV infection and occurrence of CLM. Methods: Subjects of this study were colorectal carcinomas treated by curative resection at our institution between Nov ’92 and Dec ’01 and fulfilled the following criteria; TNM Stage I-III, histologically confirmed colorectal adenocarcinoma, having definitive results of preoperative tests for HB surface antigen (HBsAg) and HCV antibody, and no LC. Results: A total of 1040 pts met the recruitment criteria. Eleven and 60 pts were positive for HBsAg and HCV antibody respectively. Both HBsAg and HCV antibody were negative in the remaining 969 pts. Comparing characteristics between the infection group and the non-infection group, stage (I/II/III: 19/31/21, 305/306/358), lymph node metastasis (present/absent: 51/20, 607/362), histological type (well, mod/por, others: 62/9, 895/74) depth of tumor (T1,T2/T3,T4: 21/50, 358/611), and preoperative CEA level (ng/ml: 6.5±7.5, 9.2±24.6) did not differ between two groups significantly by the chi-square test (stage, lymph node metastasis, histological type, and depth of tumor) and Mann-Whitney’s U test (CEA). Hepatic function of the infection group was slightly worse than those of the non-infection group by student t-test; alb (g/dl: 3.8±0.5, 4.0±0.4, p<0.01), t-bil (mg/dl: 0.8±0.4, 0.7±0.3, p<0.01). When correlations between hepatic recurrence-free survival and clinicopathological factors were examined, depth of tumor (T3.T4), lymph node metastasis, and alb < 3.8g/dl were the independent poor prognostic factors by the Cox regression model. HBV or HCV infection did not correlate with hepatic recurrence-free survival, recurrence- free survival, or overall survival. Conclusions: HBV or HCV infection does not influence on occurrence of CLM.

No significant financial relationships to disclose.
Serum p53 antibodies is a postoperative predictive biomarker after curative resection in colorectal cancer patients
Authors: Takeda A.
Published: March 2020

14567

Background: Because alternations of the p53 tumor suppressor gene are the most commonly observed and can occur early in the carcinogenic process, the accumulation of mutant p53 often leads to the production of p53 antibodies in the sera. The aim of this study is to evaluate the clinical usefullness as early detection marker and as a predictive biomarker of serum p53 antibodies in primary colorectal cancer. Methods: Serum samples are obtained before treatment and from time to time postoperatively and stored - 800C until assay. We employed the newly produced quantitative p53 antibodies ELISA Kit (MESACUP anti-p53 Test, MBL, Japan) to determine the presence of p53 antibodies in 311 patients with colorectal adenocarcinoma compared with the conventional two markers of CEA and CA19–9. Post operative clinical course and the long time survival were evaluated in sero-positive patients after resection. Results: The sensitivities of serum p53 antibodies, CEA and CA19–9 were 32.9%, 36.0% and 23.1%, almost equivalent to CEA and significantly higher than CA19–9. No obvious correlations were evident between the status of serum p53 antibodies and values of two markers, resulting in independent of the other markers. The sensitivity rate of CEA turned up as promotion of pathological stage, but the presence of serum p53 antibodies was more significantly associated with stage 0,I,II. One hundred-nine patients who showed preoperatively sero-positive patients were monitored for at least one year after resection. There was a significant correlation between operative curability and postoperative absence of serum p53 antibodies. Most of repeatedly positive patients treated as curative resection developed recurrence within one year in stageIIandIII. Repeatedly detected patients for serum p53 antibodies have a significantly poor prognosis compared with changed negative patients after curative resection in stageIIandIII. Conclusions: Serum p53 antibodies is easy and convenient, non- invasive, detectable many times and not necessary for surgical specimens for assay. Surveillance of p53 antibodies is rapid and readily facilitated test, which appears to be useful as a new tool for early diagnosis and as a postoperative predictive marker for colorectal cancer patients.

No significant financial relationships to disclose.
Cetuximab and irinotecan (CPT11) salvage treatment for colorectal cancer (CRC) in progression after two or more chemotherapy (CT) lines: The POLONORD Group experience
Authors: Fagnani D. , Bertolini A. , Menatti E. , Duro M. , Luchena G. , Ardizzoia A. , Zavallone L. , Filipazzi V.
Published: March 2020

14575

Background: Cetuximab is a monoclonal antibody blocking the Epidermal Growth Factor Receptor (EGFR), that showed activity in advanced CRC. His safety and therapeutic profile in clinical practice is still carefully evaluating. Methods: 7 Italian Oncology Units (PoloNord Group) treated, from December 2004 to December 2006, 72 patients (pts) affected by metastatic (mts) CRC, in progression after two or more previous CT lines, with Cetuximab + CPT11 ± Fluorouracil (5FU). Cetuximab initial dose was 400 mg/m2, followed by 250 mg/m2 as weekly infusion; dose adjustments based on cutaneous toxicity. Median courses: 12 (range 2–59). CPT11 and 5FU was administered according centres favourite schedules. We evaluated pts for safety, objective response (RO), progression free survival (PFS) and overall survival (OS) Results: Pts characteristics: M/F 48/25; median age 64 years (range 39–74); previous chemotherapy lines: 2–6 (Oxaliplatin and CPT11± 5FU); EGFR positive: 72. Mts sites: liver 56%, lung 21%, peritoneum 10%; 13% of pts had two or more mts sites. Safety: 8/72 (11%) pts showed G3–4 toxicity (WHO): cutaneous 5 pts; vomiting 1 pts, and neutropenia 3 pts . No allergic reactions. 4/72 pts stopped therapy to unacceptable toxicity, while 53/72 pts to disease progression. RO in 68/72 pts were: 9 RP (13%), 14 SD (21%) and 45 PD (66%). 6/14 SD pts showed tumor markers (CEA/Ca19.9) reduction. No pts had surgery option after treatment. Median PFS from start of therapy in 58/72 pts was 4 months (range 1–15). Median OS from diagnosis of mts disease in 67/72 pts was 28 months (range 7–81). Conclusions: According to safety and control disease reporting by international trials, our experiences showed that, also in clinical practice, Cetuximab + CPT11 is a valid option for the treatment of advanced, pretreated CRC.

No significant financial relationships to disclose.