bluuebunny/crossref_metadata_2025 huggingface dataset:
Effective treatment of 4T1 mammary adenocarcinoma by direct tumor injection and continuous systemic infusion of transferrin receptor antisense in mice
Authors: Head J. F. , Jiang X. , Fort K. A. , Dye V. D. , Elliott R. L.
Published: March 2020

14113

Background: Transferrin receptors (TfR) on the cell surface are the major transporters of iron into cells. Tumor cells often have increased expression of TfR, compared to normal cells. TfR antibodies have been shown to inhibit the growth of tumor cells. We previously reported that human TfR antisense inhibited the proliferation of human breast cancer cell lines in vitro. Methods: In the present study, we used antisense oligonucleotides targeted to the mouse TfR gene to treat the 4T1 mammary adenocarcinoma mouse model. The antisense was either directly injected one time into the tumors or continuously infused systemically for 14 days through subcutaneous implantation of Alzet osmotic minipumps. The control group of mice received Hank’s balanced salt solution. Tumor sizes were measured twice a week. Tumor necrosis and metastasis were examined grossly at autopsy and by microscopy. Results: At 4, 7 and 10 days post- treatment, tumor volumes of treated groups, including direct injection and continuous infusion, were significantly smaller than the control group. At 14 days post-treatment, gross and microscopic pathology showed that the continuously systemically treated mice had significantly less lung metastases than the control group (p<0.001 and p<0.01, respectively). Although the group of mice treated with direct injection received an equal total dosage of TfR antisense as the continuously systemic treated mice, direct tumor injection of TfR antisense did not suppress lung metastasis. Primary tumors had varying degrees of necrosis in the treated and control groups, but there was no statistical difference between groups. Summary: TfR antisense effectively inhibited tumor growth and metastasis of 4T1 mammary adenocarcinoma in mice. Furthermore, continuously systemic administration of antisense was more effective than direct tumor injection.

No significant financial relationships to disclose.
Angiotensin II type 1 receptor antagonist candesartan is an angiogenic inhibitor in MDA-MB 468 human breast cancer cells
Authors: Herr D. , Rodewald M. , Hack G. , Konrad R. , Kreienberg R. , Wulff C.
Published: March 2020

14114

Background: The present study examined the effect of angiotensin II on the regulation of different angiogenesis associated genes in human breast cancer cells and attempted to determine whether administration of At1R blocker candesartan could suppress the angiotensin II dependent gene regulation. Methods: Angiotensin II dependent expression of vascular endothelial growth factor (VEGF), tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), and hypoxia inducible transcription factor 2alpha (HIF-2alpha) as well as administration of angiotensin II and At1R blocker candesartan was analyzed in MDA-MB 468 human breast cancer cells using immunofluorescence and TaqMan-Real-Time PCR analysis. Results: VEGF, TIMP-1, HIF-2alpha and the At1R were expressed in MDA-MB 468 human breast cancer cells. Angiotensin II significantly increased gene expression of VEGF, TIMP-1, and HIF-2alpha in these cells. This effect was completely inhibited by candesartan. Conclusion: It is hypothesized that angiotensin II is involved in regulation of tumor angiogenesis in breast cancer by regulation of angiogenesis associated genes via At1R. These findings are the first evidence for targeting tumor angiogenesis by inhibition of At1R in human breast cancer cells and may lead to new therapeutical anticancer strategies proposing administration of candesartan.

No significant financial relationships to disclose.
Gene expressions of TS and MDR-1 are predictive factors for chemosensitivity and survival in esophageal cancer with fluoropyrimidine-based chemotherapy
Authors: Uchida K. , Hayashi K. , Kudo K. , Kuramochi H. , Yamamoto M.
Published: March 2020

14120

Background: Fluoropyrimidines are widely used in chemotherapy regimens for esophageal cancer. To test the hypotheses of whether the relative mRNA expression of the enzyme TS, DPD and MDR-1 were associated with response to in esophageal cancer. We investigated the associations reported between intratumoral TS, DPD and MDR-1 gene expressions and the response with 5-FU based chemotherapy for patients with esophageal cancer. Methods: Twenty six pts with esophageal cancer were treated with 5-FU based chemotherapy (14 pts were treated with chemotherapy only, and 12 pts were chemoradiotherapy). mRNA was isolated from frozen tumor specimens, and relative expression levels of each gene/β-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman®) system. Results: The overall response rate was 50.0%. Each mRNA expression was detectable in 26 patients. TS expressions were significantly lower in the responding tumors compared to the non-responders respectively (P=0.009). There were no significant associations between MDR-1 expression and the response. By setting up a cut-off level for TS and MDR-1 of Median, combining the two gene expression two-dimensionally revealed a relationship with the response (P=0.037). Additionally, MDR-1 expressions were statistically significant predictors of prolonged survival (P=0.0084). Conclusions: These results suggest that intratumoral TS and MDR-1 expressions are prognostic factors for survival after 5-FU based chemotherapy in esophageal cancer.

No significant financial relationships to disclose.
Expression and secretion of VEGF in solid tumor cells is mediated by the mammalian target of rapamycin (mTOR)
Authors: Lackner E. M. , Krauth M. T. , Kondo R. , Rebuzzi L. , Eigenberger K. , Vales A. , Kornek G. V. , Zielinski C. C. , Valent P.
Published: March 2020

14123

Background: Tumor progression and metastasis formation are often associated with enhanced angiogenesis and with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and a mediator of vascular permeability. We here describe that VEGF is produced and secreted by neoplastic cells in various solid tumors and its production mediated through mTOR. Methods and Results: As assessed by ELISA, the VEGF protein was detected in supernatants of cell lines derived from breast cancer (MDA-MB231), pancreatic carcinoma (BxPC-3), lung cancer (A-427), colon carcinoma (HCT8), and cholangiocellular carcinoma (EGI-1). In addition, VEGF was detected in supernatants of primary tumor cells obtained from malignant effusions in various malignancies (breast cancer, n=4; pancreatic cancer, n=1; ovarial cancer, n=1; parotic carcinoma, n=1; oesophageal carcinoma, n=1). In each case, VEGF protein was detectable in neoplastic cells by immunocytochemistry, and was found to accumulate in supernatants of cultured tumor cells over time, suggesting constant production and secretion. Correspondingly, as assessed by RT-PCR, primary tumor cells as well as the cell lines tested were found to express VEGF mRNA in a constitutive manner. Since mTOR is a well known regulator of VEGF synthesis, we applied rapamycin on primary neoplastic cells and on tumor cell lines. Rapamycin (20–200 nM) was found to counteract the production and secretion of VEGF in all tumor cells tested (VEGF in supernatants in cultures supplemented with rapamycin at 100 nM compared to control=100% on day 6: MDA-MB231: 11.8±0.2%; BxPC-3: 23.6±18.8%; A-427: 30.1±3.4%; HCT8 17.2±0.5%; EGI-1 28.4±1.1%; p<0.05). By contrast, neither rapamycin nor VEGF were found to modulate growth of primary tumor cells or the growth of the tumor cell lines tested. Conclusions: Various human tumor cells express and secrete VEGF. VEGF production is mediated through mTOR. These observations may have implications for the design of new treatment approaches attempting to counteract VEGF production/secretion and thus VEGF-dependent angiogenesis and effusion- formation in solid tumors.

No significant financial relationships to disclose.
Prevention of chemotherapy-induced delayed nausea and vomiting with aprepitant in patients recieving highly emetogenic-five day cisplatin regimens
Authors: Joshi A. J. , Singh H. , Chawla S.
Published: March 2020

14125

Background: It has been shown that addition of the NK1 receptor antagonist aprepitant to 5HT3 antagonist plus dexamethasone is more effective than just the 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis due to high dose cisplatin and also that this effect lasts for multiple cycles. This study evaluated whether the antiemetic efficacy of aprepitant could be sustained for 5 day cisplatin regimens. Methods: Patients receiving cisplatin 20mg/m2/day for 5 days (PEB and TCF regimens ) were randomized to one of the following two regimens: (1) aprepitant 125 mg 1 hour before cisplatin on day 1 and aprepitant 80 mg on days 2 and 3 (n = 17); (2) placebo before cisplatin on days 2 to 7 (n = 19). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 7. The primary end point was complete response (no emesis and no rescue therapy) over 7 days following cisplatin in up to six cycles analyzed by a modified intent-to-treat approach. Secondary end point was evaluated using Functional Living Index-Emesis questionnaire. Treatment comparisons were made using logistic regression models and P value calculated using the chi square test due to small sample size. Results: In the acute period, 83% and 56% of patients were without emesis in groups I and II, respectively (P < .01 for group I v group II). In the delayed period upto day 5, the proportion of patients without emesis in groups I and II, was 59% and 32%, respectively (P < .01 for groups I v group II). In the extended period day 6 and 7 the proportion of patients without emesis in groups I and II was 50% and 38% respectively (P< .01 for groups I v II). The distribution of nausea scores in the delayed period beyond day 5 was lower when comparing group I with group II (P < .05 for days 6 and 7). Two serious adverse events of diarrhea were probably attributed to aprepitant. Conclusions: Once daily oral administration of aprepitant was effective and superior in reducing delayed emesis and nausea after 5 days cisplatinum regimen when added to 5HT3 antagonist plus dexamethasone. This benefit persists upto day 7. Confirming and extending previous results aprepitant should be used in triple combination in patients receiving 5 day cisplatin regimens.

No significant financial relationships to disclose.
Genistein combined polysaccharide (GCP) is highly active in both human and canine lymphoma models
Authors: Mack P. C. , Burich R. A. , McCall J. L. , Kent M. S. , Hackman R. M. , Tuscano J. M. , deVere White R. W.
Published: March 2020

14126

Background: The soy isoflavones genistein and daidzein have demonstrated anticancer activity in vitro in multiple tumor types including leukemia/lymphoma, with evidence for a role in chemoprevention. GCP (Amino Up Chemical Co.) is a fermentation product of soy extract and the mycelium of Basidiomycetes, a process which converts soy isoflavones to their aglycone form, greatly increasing intestinal absorption. In humans, GCP has negligible toxicity at potentially active concentrations. We hypothesized that GCP would have significant anticancer activity in hematologic malignancies. Methods: Three human lymphoma cell lines (Jurkat, Raji, and Ramos), a leukemia line (HL60), and four canine lymphoid cell lines (GL-1, CLGL-90, CL1, and CLL-1390) were treated with GCP at doses ranging from 25 to 200 μg/ml. Growth effects were assessed by trypan blue exclusion 5–7 days following a single treatment. Flow cytometry and Westerns were used to measure changes in cell cycling, protein expression and apoptosis. We are conducting a single-agent dose escalation clinical trial in chemo-naïve canines with lymphoma. Results: GCP had striking cytotoxic effects in both canine and human lymphoma cell lines. In all human lines, the 50% inhibitory concentrations (IC50s) were less than 25μg/ml. At 100μg/ml, a concentration achievable in patient plasma, virtually no viable cells remained. Three of four canine lines were sensitive with IC50s in the range of 15–50μg/ml. Substantial G2 cell cycle accumulation was observed, apparent within two hours and maintained for at least 48h. GCP treatment induced apoptosis, as shown by an increase in sub-G1 DNA content and cleavage of PARP and caspase 3. At higher doses, elevated Bcl-2 levels were observed, suggesting a potential mechanism of resistance. These results provided the rationale for a clinical trial in canine patients at UC Davis. One patient with aggressive diffuse large B-cell lymphoma treated at 93 mg/kg/day (dose level 2) had a confirmed partial response. Conclusions: GCP has potent anticancer activity in vitro against lymphoid cell lines, with almost complete cell kill at doses achievable in patient plasma with minimal toxicity. A phase I clinical trial in canine lymphoma will determine whether testing in human lymphoma patients is warranted.

No significant financial relationships to disclose.
A novel therapeutic strategy for ER-negative human breast cancers, targeting AP-1 activity
Authors: Sakaguchi K. , Nakajima H. , Fujiwara I. , Mizuta N. , Magae J.
Published: March 2020

14129

Background: While agents targeting estrogen receptors are the most effective in adjuvant therapy for human breast cancers expressing estrogen receptor(ER), breast cancers lacking ER are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Although a transcription factor, AP-1, is known to be related to tumor malignancy including metastasis, invasion and drug-resistance, it remains to be elucidated how AP-1 plays in development and expression of malignant characters of human breast cancers. Methods and Results: Here, we used MX-1, a human breast cancer cell line lacking ER and several ER positive cell lines, to clarify the roles of AP-1 and the therapeutic efficacy of ascochlorin, a newly developed prenylphenol antibiotic on ER-negative breast cancer. We found that MX-1 exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos and Fra-1 when compared with conventional ER-positive human breast cancer cell lines. Consistent with this study in vitro, histological study on human breast cancer tissues suggests that ER-negative cancers express high Fra-1 protein, and that paclitaxel- sensitive cancers express low Fra-1 protein. The ascochlorin, which inhibits AP-1 through the Erk signaling pathway, suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Moreover, administration of ascochlorin elongated life span of mice intraperitoneally implanted with murine mammary carcinoma cells. Conclusions: Our results suggest that AP-1 is an effective clinical target molecule for the treatment of ER-negative human breast cancer, and that ascochlorin is promising therapeutic agent for these refractory breast cancers.

No significant financial relationships to disclose.
A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results
Authors: Renshaw J. S. , Patnaik A. , Gordon M. , Beeram M. , Fischer D. , Gianella-Borradori A. , Lin C. , Mendelson D.
Published: March 2020

14130

Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes from parent to daughter cell and have been linked to tumorigenesis. Aurora kinase A is commonly amplified in solid tumors and has been established as an oncogene. Aurora B is often overexpressed and leads to defects in mitosis and increased tumor invasiveness. AS703569 is an orally available, highly potent inhibitor of aurora kinases A and B and several other kinases. AS703569 has been shown in vitro and in tumor xenograft models to inhibit proliferation and to trigger apoptosis of several tumor types. We report on the initial results of a phase I study of AS703569 in patients with solid tumors. The study objectives are to determine for each of 2 different dosing regimens the MTD and to evaluate safety, PK and pharmacodynamic effects. Methods: This is a phase I, two arm, dose-escalation study. Cohorts of 3 patients ≥18 years old with advanced solid tumors are being assigned to one of 2 dosing regimens. The dose escalation follows a modified Fibonacci scheme. The starting dose level is 6 mg/m2 p.o. per 21-day cycle divided in 2 or 3 doses (regimen 1: dosing on days 1, 8 or regimen 2: dosing on days 1, 2, 3). Patients with stable disease or response will be offered additional cycles. Results: A total of 15 patients have been included to date. The tumor types represent a typical widespread in phase I trials, including 3 cases of uterine/cervical cancer and 2 cases of breast cancer. The first 2 cohorts of 3 patients on dose level 1 (regimen 1 and 2) have been treated with no dose-limiting toxicities (DLTs) or serious adverse events (SAEs). Dose-escalation is proceeding for both regimens with 9 patients treated on dose level 2, 6 in regimen 1 where due to a DLT (likely disease-related and unlikely related to AS703569) the cohort was expanded, and 3 in regimen 2. Thus far, only two patients were withdrawn from the study due to disease progression and one patient withdrew consent. Two patients are ongoing at 4+ cycles and one at 3+. Conclusions: Treatment of patients in this phase I study of the aurora kinase inhibitor AS703569 at dose level 1 and 2 has been well tolerated over several cycles. Dose escalation is ongoing and analysis of PK and pharmacodynamics will be reported.

No significant financial relationships to disclose.
Increased detection and contrast enhancement of small malignant lung nodules in mice by a tumor-targeting nanoimmunocomplexed contrast agent
Authors: Freedman M. T. , Pirollo K. F. , Chang E. H.
Published: March 2020

14131

Background: Lung cancer screening with CT results in the detection of many small lung nodules, few of which are cancerous. As a result many patients are followed to assess nodule growth. Contrast enhanced MRI and CT are used to determine whether small nodules are hypervascular or hypovascular, differentiating between nodules that are more/less likely to be malignant. For nodules 7 mm and larger, contrast enhancement has few false negatives, but a moderate number of false positives leading to unnecessary biopsies. Reported here is a new method of delivering contrast agent that transfers it directly into the cancer cells. This delivery system is a nano size immunoliposome complex containing gadopentetate dimeglumine which is targeted to the transferrin receptor on the cell. Methods: Syngeneic mouse model of lung metastases is used. Mouse renal carcinoma cells are tail vein injected into female BALB/c mice. For small lung nodules (1–4 pixels), the animals are imaged 7–9 days post inoculation. Images are obtained with a 7T MRI using RARE sequences. Results: Comparisons of pixel intensity were made between the pre- and post contrast images and between the novel and standard contrast agents. Using the complex, nodules as small as 2 pixels (200 μm) in size can be visualized and have greater pixel intensity. Conclusions: A novel carcinoma specific nanocomplexed MR contrast agent shows improved enhancement when compared to standard MR contrast. This agent is on the path towards clinical testing. It could help determine which small nodules identified on screening CT have a high or low probability of malignancy. Specific targeting to carcinoma cells should result in fewer false positives. This novel imaging contrast agent should enable detection, and earlier confirmation of malignancy, in nodules substantially smaller than currently possible.

No significant financial relationships to disclose.
Implication of human epidermal growth factor receptor-2 (HER-2) over expression in treatment of breast cancer in developing countries—report on 250 cases from Bangladesh
Authors: Hossain M. , Rahman S. , Alam A. , Qamruzzaman C. , Hossen M. , Hai M. , Reza M.
Published: March 2020

14139

Background: Carcinoma breast is the second most common malignancy in Bangladeshi women. Though HER-2 over expression has profound effect on prognosis of breast cancer, no published data is available about this among Bangladeshi patients. Our aim in this study was to see HER-2 status in Bangladeshi patients, and their relation with other prognostic parameters. Implication of this molecular marker in management of breast cancer in poor country like ours remains controversial, keeping in mind the exorbitantly high cost of Trastuzumab. Methods: This prospective study was conducted in the department of Oncology at Bangladesh Medical College Hospital, National Institute of Cancer Research and Hospital and Ahsania Mission Cancer Hospital Bangladesh, from January 2003 to December 2006. Total 250 women with breast carcinoma were enrolled; biopsy specimens were tested by immunohistochemistry to detect HER-2 status. For recommending treatment with Trastuzumab, patients with 3+ immunohistochemistry results were considered HER-2 positive. Fluorescent In Situ Hybridization (FISH) testing facility was not available. These findings were correlated with age, ER/PR and nodal status. The practical application of marker in terms of use of Trastuzumab was analyzed. Results: Age of patients ranged from 19.75 years to 72 years, mean age was 49.75 years. HER-2 was over expressed in 38.4 % (96) cases and their mean age was 42.92 years compared to 47.61 years in HER-2 negative cases. HER-2 positive cases tended to have higher rates of lymph node metastases (44 out of 96) compared to HER-2 negative (46 out of 154) cases (45.8 % vs 29.87 %). ER/PR was positive in 64 % cases. HER-2 over expression was inversely related to ER / PR expression. Of the HER-2 positive cases, 11.45 % (11 out of 96) afforded treatment with Trastuzumab. Conclusions: HER-2 is over expressed in almost 38 % of breast carcinoma patients in Bangladesh. This expression is associated with relatively young age, lymph node metastasis and lack of ER / PR expression. Only 11.45 % of patients with HER-2 over expression afforded Trastuzumab though 38 % of cases over expressed HER-2.

No significant financial relationships to disclose.
Changes in the kinase expression panel of K562 human leukemia after Avemar treatment
Authors: Telekes A. , Rásó E.
Published: March 2020

14143

Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x105 cell/ml), were treated with Avemar (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the kinase expression pattern Kinase OpenArray™ plates were used, having over 500 kinase genes with controls in quadruplicates in each plate. Changes in expression was declared if the average value was over 1 (2-fold change in mRNA copy number) and the standard deviation was relatively small (2xSTDEV = AVERAGE). Results: We have found 16 kinases which expression has temporary or durative (maintained for 24 hour after washing) decreased (e.g.: CCL2, ABR, FLT1, EphB6, TGFa) and 30 which expression has increased (e.g.: CPT1B, IRE1, ITK, RON, LTK, EphB2, FASTK). Conclusions: Our result demonstrated that many of the kinases which expression was altered by Avemar treatment is known to participate in cell cycle, cell migration, apoptosis and signal transduction. Thus, our results might shed light on the main mechanism(s) of action of Avemar and raise the possibility to identify the active substance(es) of this natural extract.

No significant financial relationships to disclose.
Manifestations of cardiovascular toxicity associated with the approved tyrosine kinase inhibitors
Authors: Verbois S. L. , Saber H. , Benson K. A. , Morse D. E. , Justice R.
Published: March 2020

14152

Background: Since 2001, 5 tyrosine kinase inhibitors (TKi’s; imatinib, erlotinib, sorafenib, sunitinib and dasatinib) have been approved for hematologic and solid tumor indications including, CML, ALL, GIST, RCC, pancreatic and NSCLC. While individual agents are designed to inhibit the TK activity of specific targets, “cross-talk” with non-target TKs (e.g., ABL, EGFR, VEGFRs, KIT, KDR, CSF1R, PDGFRs, RET, the SRC family, EPHA2, RAF, and FLT3) is extensive. The relationship between inhibition of individual kinases and the toxicity profile of each drug is unclear. Methods: Following from the observation of cardiovascular (CV) toxicity in clinical settings (pre- and post- marketing) and from the original non-clinical toxicologic evaluations, a new “class-related” review of non-clinical toxicological findings was conducted. To compare the non-clinical and clinical CV findings, the Adverse Event Reporting System (AERS) was searched for all events, excluding those of non-CV nature and those unlikely to be drug-related (e.g. hemorrhagic events were excluded from the initial analyses). Individual patient reports were not reviewed in full, therefore definitive attribution of disease related events can not be made. Results: While variable in expression, the non-clinical signs of toxicity included cardiac and vascular inflammation, cardiac degeneration and hypertrophy, decreased cardiac function (e.g. LVEF decreases), alterations in blood pressure, and QT prolongation. Clinical reports for the TKi’s have included hypo- and hypertension, conduction abnormalities and arrhythmias, cardiac hypertrophy and changes in cardiac function (LVEF and CHF). Conclusions: It is not possible at this time to relate the CV toxicities associated with the TKi’s to a specific pattern of TK inhibition. CV toxicity has been observed both clinically and non-clinically and warrants further investigation.

No significant financial relationships to disclose.
Combined therapy for rectal cancer in the elderly
Authors: Bohac G. C. , Hartshorn K. , Cheng D.
Published: March 2020

14504

Background: Neoadjuvant or Adjuvant Chemoradiotherapy (CRT) plus surgery is the standard of care for treatment of Stage II/Stage III rectal cancer. Previous studies of practice patterns have evaluated SEER data using single dose chemotherapy as a surrogate for having ever been treated. No study to date has evaluated the use of CRT along with surgery to determine the ability of elderly patients with rectal cancer to complete prescribed therapy. Methods: A retrospective study of all patients treated for Stage II/III rectal cancer identified by Tumor Registrar from January 1, 1987 to June 1, 2006 at the Boston VAMC and Boston Medical Center were analyzed. Data was extracted from computerized records and paper charts. Statistical analysis was performed with SAS software. The primary endpoint was to determine if younger (<70 yr) and older (>=70yr) patients were equally likely to complete CRT and surgery without having a dose of chemotherapy or radiation reduced, held, or delayed. Secondary endpoints were to determine if older and younger age groups were equally likely to receive CRT and a multivariate analysis of factors (age, having received neoadjuvant therapy, number of comorbidities, stage of tumor) had an effect on these outcomes. Results: A total of 266 patients were identified and included in the study. The likelihood of completing CRT and surgery without a dose being held, delayed or reduced was statistically similar among patients age 70 and older (16.1%) as among younger patients (23.9%) (Chi-square 2.16 p=0.1414). However, older patients were far less likely (58.24%) than younger patients (76%) to receive CRT (Chi-square 8.79 p=0.003). A multivariate analysis of factors associated with completion of CRT without a dose being held, delayed or reduced identified only the number of comorbidities (one or more) OR=0.383 (95% CI 0.186–0.790) as statistically significant. In addition, multivariate analysis of factors associated with receiving CRT identified having received neoadjuvant therapy OR=5.397 (95% CI 2.303–12.60) and age >=70 OR=0.424 ( 95% CI 0.201–0.898) as statistically signficant. Conclusion: Elderly patients with rectal cancer are less likely to be prescribed CRT than younger patients. However, elderly patients who are prescribed to receive CRT appear to be able to tolerate the therapy as well as younger patients.

No significant financial relationships to disclose.
A systematic review on the efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma
Authors: Sim J. , Yan T. D. , Black D. , Morris D. L.
Published: March 2020

14506

Background: Liver recurrence after hepatectomy for colorectal liver metastases (CRLM) is common and associated with a reduced survival if not treated aggressively. The objectives of this systematic were to critically appraise the quantity and quality of current clinical evidence and demonstrate the efficacy of repeat hepatectomy for CRLM. Methods: Electronic searches for relevant studies published in peer-reviewed medical journals on repeat hepatectomy for recurrent CRLM prior to September 2006 were performed on six databases. The reference lists of all retrieved articles were manually searched for further identification of potentially relevant studies. All relevant articles identified were assessed with application of selection criteria. The quality of each included study was assessed. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies. Results: Seventeen studies with more than 20 patients were included for quality appraisal and data extraction. These 17 studies consisted of two multi- institutional, one bi-institutional and 14 single-center observational studies. The overall perioperative morbidity rate ranged from 7–30% and mortality rate varied from 0–5%. The rates of intra-abdominal abscess, wound infection, bile leak, hepatic failure and pleural effusion ranged from 2.4–23%, 2.4–11%, 0.8–10%, 0–4.5% and 2.4–9.5%, respectively. The overall median survival since initial hepatectomy was 26 to 73 months. The overall median survival since the repeat hepatectomy ranged from 23 to 56 months, with 3- and 5-year survival of 24–68% and 21–49%, respectively. The median disease-free survival ranged from 9 to 52 months, with 3- and 5-year disease-free survival of 16–68% and 16–48%, respectively. After repeat hepatectomy the rates of disease recurrence in the liver and at an extra-hepatic site were 15–67% and 27–64%, respectively. Conclusions: The current literature suggests that repeat hepatectomy is associated with a prolonged survival for recurrent CRLM. Although all studies were observational case series, repeat hepatectomy is justified in selected patients, as there is a lack of evidence for alternative treatment.

No significant financial relationships to disclose.
Trans-arterial chemoembolization (TACE) of liver metastases (LM) from colorectal cancer (CRC) adopting irinotecan-eluting beads: Results of a phase II clinical study
Authors: Fiorentini G. , Aliberti C. , Giovanis P. , Tilli M. , Rossi S. , Benea G.
Published: March 2020

14525

Background: Patients with LM from CRC have a poor prognosis with survival rates of 31% at 1 year and 2.6% at 3 years. Surgery is feasible in a minority of patients and most them received systemic chemotherapy. Irinotecan (IRI) is an active drug in the treatment of advanced CRC. The advantage of delivering chemotherapy by hepatic arterial infusion is the achievement of high-dose of the drug in the target . TACE is a combination of local drug infusion with selective embolization of the feeding arteries of the liver metastases. DC bead is a new embolic microsphere product that can be loaded with IRI before administration in TACE. The purpose of this study is to assess the safety and efficacy of this new embolic microspheres IRI loaded and administered as TACE in patients with LM from CRC. Methods: 35 patients with LM from CRC Stage II-III Pettavel Classification pretreated were observed from Nov 2005 to Dec 2006. 25 gave their written consent to be treated with one o more cycles of TACE. Imaging was performed before, immediately and 4 weeks after TACE to determine response and the need for further treatment. Each patient received i.v hydration, antibiotics, analgesics and medications against nausea before TACE. Survival was calculated with Kaplan-Meier method. Results: 60 cycles were administered. We observed a Response Rate of 80% by RECIST criteria. A month after TACE we had a reduction of +50% of CEA in 60% of patients. A reduction of the lesional contrast enhancement of the metastases was observed in 80% of patients. 22 patients are alive, with a median survival of 9.5 months (range 6–13). Median duration response was 16 weeks (range 12–25). 14 cases experienced WHO Grade 2 right upper quadrant pain (RUQP) and 11 cases Grade 3 lasting 12 hours (range 3–30). All patients had 2 days Grade 2 fever (range 1–7), ten had 3 days Grade 3. 20 have had Grade 2 nausea and vomiting for 6 hours (range 4–29). No alopecia or marrow toxicity was reported. Conclusions: DC bead -TACE was feasible and effective in patients with LM from CRC. RUQP seems the most significant toxic event and needs analgesic therapy. No survival data are conclusive because the follow up is short. DC bead of IRI 100 mgr-TACE myght be an appropriate palliative therapy for these patients.

No significant financial relationships to disclose.
Preoperative oxaliplatin (O), capecitabine (X), and external beam radiotherapy (RT) in patients (pts) with newly diagnosed, primary operable, locally advanced rectal cancer (LARC)
Authors: Öfner D. , de Vries A. , Thaler J. , Eisterer W. , Greil R. , Lukas P. , Rabl H. , Samonigg H. , Kapp K. , Gnant M.
Published: March 2020

14527

Background: Local recurrence after surgery is a cause of treatment failure and relapse in pts with LARC. Preoperative RT decreases local recurrence but not distant spread. X and O are both highly active chemotherapies for advanced colorectal cancer, particularly in combination, and both are radiosensitizers. Therefore, the addition of X and O to preoperative RT should improve efficacy in terms of local control and prevention of metastases. Methods: This study investigated the efficacy (rate of downstaging) and safety of preoperative chemoradiation in pts with LARC (of lower and middle rectum), T3NxM0 staged by MRT. RT was administered for 5 weeks, 5 days/week, 1.8 Gy/fraction, total dose 45 Gy, 3D conformation technique, in combination with O 50 mg/m2 intravenously on days 1, 8, 15, and 22, and oral X 825 mg/m2 twice a day on RT-days during weeks 1–4. Surgery was performed 14–28 days after completion of RT. Results: 59 pts were enrolled (19 female, 40 male); median age 61 years (range 34–76), 100% of pts are evaluable for efficacy and toxicity. 41 patients had comorbidities: 16 cardiac, 3 hepatic, 6 diabetes, 1 neurological/psychological, 49 others. Tumor downstaging was observed in 53% of pts (23 T2, 2 T1, 6 T0). 5 pts withdrew because of adverse events. 28 pts (47%) experienced grade 1 neurotoxicity and 5 pts (8%) had grade 2 neurotoxicity. The most frequent grade 3/4 NCI-CTC adverse event was diarrhea: 5/59 pts (8%). Total O and X doses received were 90% and 93% of the planned doses, respectively. The main reason for chemotherapy dose reduction was diarrhea occurring during the 3rd-4th week of treatment. Per-protocol therapy was terminated for 8 pts due to interruption of RT for more than 3 days or adverse events such as diarrhea and nausea (total dose received 25.2–34.2 Gy). Conclusions: These results demonstrate that preoperative O and X in combination with RT is feasible in pts with LARC, and comparable with 5-FU. As expected, the only clinically relevant toxicity was diarrhea, and dose intensity of both chemotherapeutic agents and RT was high.

[Table: see text]
Significance of ERCC1 and HER2 expression in human colon carcinomas
Authors: Kaskara A. V. , Antonacopoulou A. G. , Scopa C. D. , Rigopoulos A. G. , Iconomou G. , Georgoulias V. , Kalofonos H.
Published: March 2020

14534

Background: Predictive and prognostic markers need to be established in colon cancer in order to tailor chemotherapy and, therefore, improve efficacy of adjuvant treatment. In this study, expression of the excision repair cross-complementing 1 (ERCC1) and HER2 tyrosine kinase receptor genes was evaluated in human colon carcinomas. Moreover, expression levels were associated with survival, time to disease progression and various clinicopathologic parameters. Methods: Fifty formalin fixed paraffin embedded tissues of primary colon carcinomas, resected from an equal number of patients at the University Hospital of Patras, Greece were studied. Forty four patients were treated with adjuvant chemotherapy and four patients with chemotherapy for advanced disease. Total RNA was extracted from tissues, quantified and reverse transcribed. Levels of ERCC1 and HER2 mRNA were quantified using Taqman probes in real time PCR and expressed relative to a calibrator. Results: ERCC1 and HER2 mRNA were detected in 92% and 82% of cases respectively, although overexpression was observed in 43.5% and 26.8%. Levels of expression were not related to age, stage, grade and overall survival. There was a significant association between overexpression of ERCC1 and time to disease progression (p<0.05) although this was not observed for HER2. There was a trend towards decreased relapse following adjuvant therapy in patients with low expression levels of ERCC1 and HER2 mRNA levels. However this difference failed to reach significance. Expression levels of ERCC1 and HER2 were not correlated with each other. Furthermore, coexpression of the two molecules was not related to time to disease progression. Additionally, 99.5% and 93.7% of patients with low expression of ERCC1 and HER2, respectively, having received adjuvant therapy were alive at the 36 months follow up. Conclusions: These data suggest that overexpression of ERCC1 is significantly associated with time to disease progression in colon cancer. Further studies of ERCC1 as a prognostic or predictive marker are warranted.

No significant financial relationships to disclose.
Appropriate schedule of oral tegafur / uracil (UFT) in combination with irinotecan (CPT-11) and bolus 5-FU / l-leucovorin (LV) in patients (pts) with metastatic colorectal cancer (MCRC): A phase I study
Authors: Chayahara N. , Tamura T. , Miki I. , Okuno T. , Kamigaki T. , Nishisaki H. , Inoue Y. , Maeda T. , Sakaeda T. , Azuma T.
Published: March 2020

14538

Background: FOLFIRI is one of the standard regimens for MCRC. Considering the burden of continuous 5-FU administration, oral fluoropyrimidine-based therapy has been proposed in several clinical trials; however, gastrointestinal toxicity makes it difficult to perform successive oral chemotherapy. Therefore, no previous study could confirm whether to replace FOLFIRI with oral regimen. In order to find an appropriate schedule of oral fluoropyrimidine with safety and efficacy instead of continuous infusion of 5-FU, clinical trial using CPT-11, bolus 5-FU / l-LV and oral UFT / LV was conducted in pts with MCRC. Methods: Pts with MCRC, age > 18 years, ECOG PS 0–2, adequate organ function, and no or 1 prior chemotherapy were eligible. Pts received CPT-11 (100mg/m2) / 5-FU (500mg/m2) / l-LV (15mg/m2) i.v. on day 1 and UFT (300mg/m2) / LV (75mg/body) p.o. on days 1–5 (level 1), days 1–7 (level 2), or days 1–10 (level 3). Each course was repeated every 14 days. After determining feasible UFT / LV schedule, CPT-11 was dose-escalated (level 4: 125 mg/m2; level 5: 150mg/m2). Results: Nineteen pts were enrolled. A dose-limiting toxicity (DLT) of grade 4 neutropenia lasting for > 4 days was observed in 1 pt at level 2. Additional 3 pts at this level showed no toxicity of grade 3 or 4. A DLT of treatment delay (>8 days) was observed in 1 pt at level 3 because of prolonged neutropenia. Other 2 pts at level 3 refused to continue treatment within 4 cycles because of prolonged grade 2 anorexia. Obvious difference in toxicity was observed between level 2 and level 3. Therefore, 7-day-administration of UFT / LV was recommended. No DLT was observed at level 4 and 5, and the recommended dose of CPT-11 was 150mg/m2. The overall response rate was 66.7%. The median time to disease progression was 8.0 months. Conclusions: This oral fluoropyrimidine-based regimen is considered feasible and effective. The treatment schedule of UFT might be a key to prevent an early dropout due to gastrointestinal toxicity. Further study will be needed to confirm toxicity and efficacy of this regimen compared to FOLFIRI profile.

No significant financial relationships to disclose.
Prognostic factors in metastatic colorectal carcinoma at initial diagnosis, MCCID
Authors: Vallejo C. T. , Zwenger A. O. , Lacava J. A. , Iturbe J. , Perez J. E. , Machiavelli M. , Romero A. , Dominguez M. E. , Rodriguez R. , Leone B.
Published: March 2020

14548

Background: Despite several studies have evaluated the role of prognostic factors (PF) in metastatic colorectal cancer, results are controversial. The aim of the present study was to assess PF in a homogeneous population with MCCID treated with biochemical modulation of 5- Fluorouracil-based regimens. Methods: Analyses were based on individual data of 318 patients (P) with MCCID treated in different prospective trials at GOCS Institutions since May 1984 to Jun 2001. The following variables (V) were considered: a) Clinical variables (CV): age, sex, family history of CC, hypertension, diabetes, tabaquism, weight loss, and performance status (PS), b) Tumor variables (TV): histologic grade, size and location of primary tumor; number of metastatic sites, number and size of liver metastases, uni- bilateral liver involvement; and c) Laboratory variables (LV): CEA, lactate dehydrogenase (LDH), alkaline phosphatase, ALT, AST, and hemoglobin. Overall survival (OS) was analyzed since date of diagnosis by means of Kaplan-Meier and the Log-rank test was used to assess the differences. A Cox’s proportional hazard modeling was used for multivariate analyses. Results: The OS for the entire group was 18.1 months (IC95, 15.0–22.7). Univariate analysis showed statistical significance in the following; a) CV: family history CC (p=0.001), PS (p=0.04), diabetes (P=0.003); b) TV: histologic grade (p=0.01), uni-bilateral liver involvement (p<0.0001), number of liver metastases (p<0.0001) and size of liver metastases (p<0.0001); and c) LV: hemoglobin (p=0.05), ALT (P=0.0006), AST (p<0.0001), alkaline phosphatase (p<0.0001), LDH (p=0.0004); Cox’s analyses showed statistical significance only for PS and alkaline phosphatase (p= 0.01 and p=0.0001, respectively). Conclusions: In this setting of P with MCCID the PS remains the most important PF for OS. High value of alkaline phosphatase may reflect liver involvement. No others PF considered in the analyses had prognostic influence.

No significant financial relationships to disclose.
Safety of neoadjuvant oxaliplatin-based chemotherapy (N-FOLFOX) in patients undergoing resection of colorectal liver metastases (R-CLM). Interim results
Authors: Verghese M. , Pathak S. , Foster C. , Haqqani M. , Poston G. J.
Published: March 2020

14550

Background: Oxaliplatin-5-fluorouracil-leucovorin (FOLFOX) has significant activity against CRC in both the metastatic and adjuvant settings. Consequently, neoadjuvant FOLFOX (N-FOLFOX) is being investigated in R-CLM. This has raised concerns regarding the safety and rate of post-operative complications (P-OCs) with N-FOLFOX, specifically, development of sinusoidal dilatation (SD), fibrosis and steatosis. This single-center cohort study was conducted to prospectively evaluate safety of N-FOLFOX in R-CLM patients. Methods: Planned total sample size is 40 patients [20 N-FOLFOX; 20 no chemotherapy (N-C)]. The N-C group consists of patients undergoing surgery for other hepatic pathology. Normal liver was examined by light (LM) and electron (EM) microscopy for SD, perisinusoidal fibrosis, and steatosis/necrosis; severity was graded from 0 (absent) to 2. The rate of P-OCs, hospital stays, and liver function tests (LFTs) were assessed. Results: At the time of this analysis, 20 patients (10 N-FOLFOX; 10 N-C) have undergone surgery. In the N- FOLFOX group, median number of cycles of N-FOLFOX was 6, with 2 patients receiving only 4 cycles. The median time between completion of N-FOLFOX and surgery was 6 weeks. There were no statistical differences between N-FOLFOX and N-C groups in potentially confounding factors, including previous chemotherapy, alcohol consumption, medical history, or concomitant medications. Number of patients with SD was 8 in each group (all were grade 1 except for 1 patient in N-C who had grade 2). Steatosis was seen in 7 and 6 patients in N-FOLFOX, and N-C groups, respectively (2 patients in each group were grade 2; remaining were grade 1). Fibrosis was noted in only 1 patient in N-C group. No nodular regeneration was observed in either group. There was a subjective loss on EM of mitochondria and Golgi apparatus/body with N-FOLFOX. Median post-operative hospital stay was 12 days in both groups. Conclusions: N-FOLFOX appears to have no clinically significant deleterious effects on normal liver architecture, function, or recovery post-surgery in R-CLM patients. The study is ongoing to accrue up to 40 patients; updated data will be presented.

No significant financial relationships to disclose.