bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of ZEN-008 (AN-152), a targeted cytotoxic LHRH analog, in female patients with cancers expressing LHRH receptors
Authors: Emons G. , Kaufmann M. , Günthert A. R. , Hamid-Werner M. , Gründker C. , Loibl S. , Schally A. V. 
Published: March 2020

13146 Background: Human ovarian, endometrial, and breast cancers commonly express receptors for luteinizing hormone releasing hormone (LHRH-R). LHRH-R can be used for targeted chemotherapy with ZEN-008 (AN-152), in which doxorubicin is linked to [D-Lys(6)]-LHRH. Safety pharmacology and toxicity studies in mice, rats and dogs demonstrated a significantly reduced cardiotoxic potential of ZEN-008 compared with doxorubicin, e.g. no QT prolongation, myocarditis or fibrosis in the appropriate models. The Phase I study assessed dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of ZEN-008 given once every 3 weeks in patients with gynecological and breast cancers. Methods: Patients with tumors proven immunohistochemically to be LHRH-R positive were eligible if prior therapy did not exceed 70% of the recommended maximum lifetime dose for doxorubicin. Starting at 10 mg/m2, doses were doubled between patients until occurrence of side effects of CTCAE grade 2 or higher, thereafter escalation would follow a modified Fibonacci scheme, with 3–6 patients/group. Safety monitoring included repeat assessment of pituitary and cardiac function. Response evaluation followed the RECIST criteria. HPLC with fluorescence detection was used for plasma PK of ZEN-008 and free doxorubicin. Results: Five patients entered the study and received ZEN-008 by intravenous infusion over 2 hours at dosages of 10, 20, 40, 80 and 160 mg/m2. Patients 1 to 4 received 2 treatment courses 21 days apart and went off study with progressive disease. Infusion of ZEN-008 was well tolerated at all dosages, without supportive treatment. PK analyses showed dose-dependent plasma levels of ZEN-008 and only minor (10–20%) release of doxorubicin. Conclusions: Infusion of ZEN-008 is well tolerated in female patients. No dose-limiting toxicities were seen up to 160 mg/m2 which is equimolar to a doxorubicin dose of 46 mg/m2. Dose escalation is ongoing. The cytotoxic LHRH analog is stable in human plasma, a prerequisite for receptor-mediated uptake by tumor tissue. [Table: see text]
PPARr agonist, troglitazone induce growth arrest and apoptosis in MDA-MB-231 human breast cancer cell
Authors: Park J. , Lee Y. , Yu H. , Han M. , Kim B. , Kim J. 
Published: March 2020

13155 Background: Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. It is recently reported that peroxisome proliferator-activated receptor-gamma (PPAR-γ) has become a potential target for the prevention and treatment of human cancer. Therefore, PPAR-γ agonist, troglitazone has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The purpose of this study was to assess whether troglitazone (TRO) would induce cell growth arrest and apoptosis in MDA-MB-231 (ER-negative) human breast cancer cells. Methods: Cytostatic/cytotoxic effects of troglitazone were measured with MTT assay. The cell cycle distribution was evaluated with flow cytometer. The expression of cyclin-dependent kinase inhibitors, p21, p27, and cell cycle dependent kinases was measured with Western blotting. Apoptotic cells were determined by Hoechst staining and TUNEL assay. Results: Troglitazone inhibited cell proliferation by inducing 65% G0/G1 arrest after 48 h. Accumulation of cells in G0/G1 was accompanied by a decrease of Rb protein phosphorylation associated with reduced activities of cell cycle dependent kinases (CDKs) such as cdk2 and cyclin D. Troglitazone increased the expression cyclin kinase inhibitors, p21 and p27 as MDA-MB-231 cell underwent G0/G1 arrest. Apoptotic effect by troglitazone demonstrated that apoptotic cells elevated from 2.5-fold of the control level at 10 uM, to 3.6-fold at 50 uM and to 4.7-fold at 75 uM. Conclusion: These results indicate that activation of PPAR-gamma with troglitazone induces apoptosis through cell cycle inhibition in estrogen receptor-negative breast cancer cell MDA-MB-231. PPAR-gamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of breast cancer growth. No significant financial relationships to disclose.
Anti-cancer activity of NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, against pancreatic carcinoma
Authors: Hatakeyama S. , Tomioka D. , Kawahara E. , Matsuura N. , Masuya K. , Miyake T. , Umemura I. , Kanazawa T. , Honda T. , Ohmori O. 
Published: March 2020

13162 Background: Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that regulates multiple cell functions. Elevated expression levels of FAK have been detected in various tumor samples and are closely correlated with invasive potential. Activation of integrins and the growth factor receptors result in FAK autophosphorylation at Y397 and the presentation of suitable binding sites for proteins containing either SH2 or phosphotyrosine binding domains. Recent evidences suggest that FAK plays important roles in cancer cell proliferation and survival. IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: In this study, anti-cancer activity of NVP-TAE226 that is identified as a potent and selective FAK inhibitor was evaluated in cancer cell lines panel and MIA PaCa-2 pancreatic carcinoma in vivo model. Results: Mean GI50 value of NVP-TAE226 against 37 cancer cell lines was 0.76 μmole/L. Inhibition of cancer cell proliferation was not affected by expression of P-glycoprotein, suggesting that NVP-TAE226 is not served as a substrate of P-glycoprotein. Oral administration of NVP-TAE226 efficiently inhibited MIA PaCa-2 human pancreatic tumor growth at all doses tested. Tumor stasis was observed at a dose of 30 mg/kg, qd for 7×/week and tumor regression was observed at a dose of 100 mg/kg, qd for 5×/week. All animals tolerated NVP-TAE226 treatment up to 100 mg/kg, 5×/wk, qd, po for 2 weeks with no body weight loss. Inhibition of downstream signaling such as phosphorylation of Akt at Serine473 was accompanied by inhibition of FAK phosphorylation in human pancreatic carcinoma cell lines. Conclusions: NVP-TAE226 is a novel class of selective and small molecule kinase inhibitors with a potent in vivo activity and potential therapeutic application. No significant financial relationships to disclose.
A3 adenosine receptor is highly expressed in hepatocellular carcinoma: A new therapeutic target
Authors: Bar Yehuda S. , Stemmer S. , Castel D. , Ohaion A. , Cohn S. , Barer F. , Zabuti A. , Fishman P. 
Published: March 2020

13164 Background: The A3 adenosine receptor (A3AR) belongs to the family of the Gi-protein associated receptors and is highly expressed in various solid tumor tissues. The high receptor expression is reflected also in the peripheral blood mononuclear cells (PBMNC) of the cancer patients. Synthetic agonists to A3AR such as IB-MECA and Cl-IB-MECA (CF101 and CF102, respectively) suppress the development of melanoma, colon and prostate carcinoma in vitro and in vivo. The molecular mechanism involves de-regulation of the Wnt and the NF-kB signal transduction pathways. In this study we looked at A3AR expression in tumor and PBMNC of hepatocellular carcinoma (HCC) patients. In addition, receptor status model and the effect of CF102 on tumor development were examined in an HCC rat. Methods: A3AR mRNA expression level was examined in paraffin embedded slides derived from human HCC samples. A3AR protein expression was evaluated in human PBMNC by Western blot (WB) analysis. Rat HCC was established by inoculating N1S1 cells to the liver. Oral treatment with CF102, administered BID, was initiated 24h after tumor inoculation. A3AR and key growth regulatory proteins expression level in tumor lesions and PBMNC was tested by WB analysis. Results: A3AR was found to be highly expressed in the human HCC tumor tissue and the PBMNC compared to normal adjacent and PBMNC from healthy subjects, respectively. Similar data were found in tumor and PBMNC derived from N1S1 hepatoma bearing rats. In tumor lesions from CF102 treated animals, down-regulation of PKB/Akt, IKK, NF-κB and TNF-α, members of the NF-kB pathway was noted. In addition de-regulation of the Wnt pathway was observed by up-regulation of GSK-3β and down-regulation of β-catenin, Lef/Tcf and c-Myc, resulting in tumor growth inhibition. Conclusion: CF102, a small orally bioavailable molecule, binds to the A3AR which is highly expressed on tumor cells and via the de-regulation of the NF-kB and Wnt pathway induces inhibition of HCC growth. No significant financial relationships to disclose.
Value of postoperative adjuvant chemotherapy (ac) for patients with completely resected hepatic (hm) and/or pulmonary metastases (pm) from colorectal cancer (crc): retrospective analysis of 146 patients
Authors: Muñoz A. , Barceló R. , Gil-Negrete A. , Carrera S. , López-Argumedo G. , Ruiz de Lobera A. , Diaz de Corcuera I. , Rubio I. , Viteri A. , López-Vivanco G. 
Published: March 2020

13509 Background: AC is indicated for stage III and high risk stage II colon cancer, as well as for stages II-III rectal cancers combined with RT. Moreover, chemotherapy improves survival in metastatic disease. There are no randomised trials evaluating the role of systemic AC after resection of metastases from CRC. Methods: We retrospectively reviewed patients with completely (R0) removed HM and/or PM from CRC, analysing prognostic factors for overall survival, including AC. Kaplan-Meier method with log rank test was used to assess and compare survival curves. Cox regression model was applied for multivariate analysis. Results: From Jan 1993 to Jun 2004, 146 patients were identified: 98 (67%) with HM, 39 with PM (27%) and 9 (6%) with both HM and PM. Gender (M/F): 102/44. Median age: 65.5 y-o (39.3–82.6). Primary CRC: rectum 62 (42.5%), pN+ 87 (60%), stage IV at diagnosis 57 (39%). Number of metastatic nodules resected: mean 2.25 (1–10). Size of the largest metastasis: mean 4 cm (0.5–18). Mean serum CEA value before surgery 20.6 (0–332): normal 73 (50%), increased 45 (31%), missing data 28 (19%). Ninety seven patients (66.5%) received postoperative AC (5FU/LV: 81, CPT11: 15, FOLFOX 1), 10 patients were not treated because of postoperative death (1) or early progression (9), and 39 due to several causes: not referred, medical contraindication or patient refusal. Median overall survival was 46.4 m, with a 3, 5 and 7-year survival probability of 59%, 35% and 22%. At univariate analysis, number (2 vs >2) of metastases resected (60.1 vs 38.3m, p=0.0004) and AC (54.3 vs 31.2m, p=0.0001) were significant prognostic factors. Increased CEA (p=0.088), involved nodes in the primary (p=0.0618) and PM+HM (p=0.0538) showed a trend towards worse survival. In multivariate analysis (excluding patients with early death/progression) AC was associated with longer survival probability (HR 2.049, 95%CI 1.149–3.656, p=0.015). Conclusions: In our retrospective series AC seems to improve survival after resection of liver and/or lung metastases from CRC. The best use of chemotherapy (adjuvant, neoadjuvant or both) in patients with resectable metastatic CRC should be evaluated in a randomised fashion. No significant financial relationships to disclose.
Prevalence, severity, and evolution of anemia in colorectal cancer patients receiving radiation therapy with/without chemotherapy: a retrospective analysis
Authors: Hu K. , Shasha D. , Homel P. , Harrison L. B. 
Published: March 2020

13510 Background: Colorectal cancer (CRC) patients frequently present with anemia. Anemia may also develop or be exacerbated in CRC patients as a consequence of treatment with radiation therapy (RT) with or without (±) chemotherapy (CT). A better understanding of the relationship between anemia and RT ± CT is important as several studies have found that hemoglobin (Hb) levels are predictive of RT outcomes and that low Hb levels can diminish patient quality of life (QOL). However, the prevalence and evolution of anemia before and during RT ± CT are poorly characterized in CRC patients. Methods: Prospectively collected data from 81 CRC patients who received 10 weeks of curative-intent RT alone (26%) or in combination with CT (74%) were analyzed retrospectively to determine prevalence, severity, patterns and contributing factors of anemia. Results: Prior to RT ± CT, 38% of patients (n = 71, evaluable population) were anemic (defined as Hb ≤12 g/dL) and by the end of treatment, 61% were anemic (including 41% of patients not anemic and 93% anemic pre-treatment). A significant (P <.001) decrease in mean Hb for all patients was already apparent after <5 weeks RT ± CT, ie, from 12.6±2.0 g/dL to 11.5±1.8 g/dL, and the decrease in Hb remained consistent over time (see Table). The greatest Hb decrease was noted in patients not anemic pre-treatment, although not all became anemic. Multivariate analysis using logistic regression identified pre-treatment anemia (P = .0006) and age (P = .02) as the factors most strongly associated with intra-treatment anemia. Conclusions: Because anemia can adversely affect QOL and possibly also treatment outcomes in cancer patients, this condition needs to be addressed as part of the overall management of anemic colorectal cancer patients. [Table: see text] [Table: see text]
Outcomes of patients with metastatic colorectal carcinoma (MCRC) treated with first and second line chemotherapy at a multicenter cancer clinic
Authors: Lim H. J. , Lohrisch C. , Kollmannsberger C. , Gill S. , Kennecke H. , Shah A. , Phillips N. , Coldman A. , Melosky B. 
Published: March 2020

13529 Background: In British Columbia (BC), FOLFIRI and FOLFOX were approved for the treatment of MCRC in 2002. The effect on survival of various treatment and patient related factors was determined for patients with MCRC treated with sequential doublet chemotherapy. Methods: Eligible patients received either FOLFOX or FOLFIRI first-line with a cross over to the alternative regimen for second-line therapy. Patient records were retrospectively reviewed for patient and disease characteristics, treatment, toxicity and survival. Analysis of survival was performed by the Kaplan-Meier method. Results: Between March 2002 and June 2004, 106 new patients met the criteria above. Sixty five patients were treated with a sequence of FOLFOX-FOLFIRI (Group A): 67% M, median age 57y, rectal 20%. Forty-one were treated with the sequence FOLFIRI-FOLFOX (Group B): 64% M, median age 58y, 27% rectal. Survival was statistically similar in both groups. Progression requiring second line chemotherapy within 4 weeks of a first line treatment was associated with inferior survival (13 months vs. 21 months (p<0.018). Grade 3 or 4 toxicity was experienced in 27.5% of the patients treated with FOLFOX and 22% of the patients treated with FOLFIRI. Conclusions: In the general population with MCRC, the median survival achieved with sequential doublet therapy is consistent with that reported in clinical trials. A superior sequence was not identified. The median number of first line chemotherapy cycles with FOLFOX and FOLFIRI was similar, reflecting the general clinical practice in BC to give 10 - 12 cycles of therapy followed by a planned break. Patients who required initiation of second line chemotherapy within 4 weeks of stopping the first line therapy experienced an inferior prognosis. Univariate and multivariate analysis showed no significance of sex, age, site (colon versus rectal), and ECOG status as predictive factors. [Table: see text] No significant financial relationships to disclose.
18F-FDG PET (PET) does not improve CT scan (CT) accuracy in the evaluation of colorectal cancer liver metastases after chemotherapy
Authors: Rimassa L. , Chiti A. , Carnaghi C. , Doci R. , Zuradelli M. , Abbadessa G. , Lutman F. R. , Tronconi M. C. , Pressiani T. , Santoro A. 
Published: March 2020

13530 Background: Neoadjuvant chemotherapy has been successfully used in the treatment of patients (pts) affected by liver metastases from colorectal cancer unsuitable for surgery. We evaluated separately the diagnostic accuracy of PET and CT in this setting in a small series of pts. Methods: We retrospectively reviewed the data from 19 consecutive pts (12 males, 7 females; median age 62 years; range 41–79) affected by liver metastases from colorectal cancer. All of the pts underwent systemic chemotherapy and were evaluated with PET and CT at the end of the treatment. Whole-body PET scan was performed in 3D mode on a Siemens Ecat Accel LSO full-ring scanner, 60 minutes after the injection of 310–450 MBq of 18F-FDG. Contrast enhanced, 3 phases, liver CT was performed on a Philips Aura single slice system. Chemotherapy regimens were: FOLFOX (13 pts), FOLFIRI (2 pts), 5-FU-FA (2 pts), UFT-CPT-OXA (2 pts). Overall response rate was 68%. Median time interval between end of chemotherapy and CT was 6 wks (range 3–8), between end of chemotherapy and PET was 8 wks (range 5–13) and between end of chemotherapy and surgery was 10 wks (range 6–18). All pts underwent surgery to remove liver metastases and had histological confirmation of the lesions. Results: In 16 evaluable pts, 53 liver lesions were confirmed by histology. The table shows the results on a per-lesion basis. A complete agreement between PET or CT and histology was documented in 3 and 4 pts respectively. Conclusions: These results suggest that PET and CT had sub-optimal diagnostic accuracy in the post-chemotherapy evaluation of liver lesions from colorectal cancer. Moreover, the combined use of the two imaging techniques does not significantly increase the sensitivity of CT. Further data are needed to evaluate the metabolic changes induced by chemotherapy which may be the cause for inaccurate PET findings. [Table: see text] No significant financial relationships to disclose.
Phase I trial of thalidomide and capecitabine for treatment of metastatic colorectal cancer
Authors: Goldstein M. J. , Leighton J. C. , Chapman A. , Muskett A. , Sharan K. , Sansom J. , Mitchell E. P. 
Published: March 2020

13552 Background: Survival of patients with metastatic colorectal cancer (CRC) has increased with the advent of new chemotherapeutic and biologic agents. Yet, there remains a need for more effective third- and fourth-line chemotherapy. Thalidomide (Thal) has angiogenic and immunomodulatory properties and antitumor effects have been consistently demonstrated in pts with multiple myeloma and occasionally in pts with advance solid tumors. Capecitabine (Cape) has demonstrated efficacy as a single agent and in combination therapy in pts with metastatic CRC. We conducted a phase I study of Thal/Cape in pts with refractory metastatic CRC previously treated with irinotecan, oxaliplatin and fluoropyrimidines. Methods: Pts with metastatic CRC who had received two or more prior chemotherapy regimens were eligible. Treatment consisted of Cape at 1500 mg/m2 po daily for 14 days every three weeks with dose levels increasing to 2500mg/m2; Thal dosing was initially 100 mg with escalations individually to 400 mg per day. Toxicity rates, response and overall survival were analyzed. Results: Twenty-five eligible pts were enrolled; median age= 58 (20–79); M/F=13/12; ECOG PS 0/1/2=11/12/2. The median number of Thal/Cape cycles administered was 3 (range 1–9). Treatment was well tolerated; grade 3–4 non-hematologic toxicities included somnolence/syncope (20%), fatigue (20%), constipation (10%), diarrhea (10%), infections (10%) and neuropathy, thrombosis, hypoglycemia, nausea/vomiting each occurred in 5% of pts; grade 3–4 hematological toxicities anemia (15%), neutropenia (5%), prolonged prothrombin time (15%), increased LFTs (10%). Grade 3–4 hand-foot syndrome occurred in 2 pt (8%). There were no radiographic responses, but 6 pts achieved a decline in CEA of 50% or greater and 6 pts achieved stable disease. Conclusion: The MTD is Cape 2500mg/m2 per day. The combination of Thal/Cape was well tolerated; the recommended dose is thal 200mg and cape 2000mg/m2. Despite the lack of radiographic responses, the rate and duration of disease stabilization observed in this heavily pretreated pt population suggest that this regimen may offer some benefit. [Table: see text]
Preventive approach of allergic reaction to oxaliplatin
Authors: Suenaga M. , Mizunuma N. , Watanabe T. , Hatake K. , Muto T. 
Published: March 2020

13574 Background: Oxaliplatin is a well-known platinum compound as a key agent of FOLFOX regimen, the world standard chemotherapy in colorectal cancer. Allergic reaction due to oxaliplatin is a chronic adverse event regarded as almost type I allergy. In our institute, we have also experienced allergic reaction including severe cases and started to apply practical preventive approach to the patients treated with FOLFOX regimens. Methods: Preventive approach was as follows: 40mg of famotidine and 8mg of dexamethasone before oxaliplatin infusion were given to all patients from the initial cycle and 50mg of diphenhydramine after cycle 4. Further intensive anti-allergic procedure was performed for the patients who showed any allergic reactions against initial preventive approach. Increased dose of dexamethasone to 20mg and diphenhydramine were administered before oxaliplatin infusion and oxaliplatin was prolonged from 2 up to 4 hours for patients with grade 1, 2 allergic reactions (CTCAE v3.0). Treatment was discontinued in patients with severe grade 3 adverse events. Results: 139 patients received FOLFOX regimens during 6 months. 15 patients (10.8%) presented with allergic reaction, 11 (73.3%) of those were grade 1, 2 and the other 4 (26.7%) were grade 3. Immediate discontinuation of oxaliplatin infusion and administration of antihistaminic drugs, steroid or rapid infusion were routine proceeding, and almost of the patients entirely recovered within 2 hours. 9 patients were re-exposed to oxaliplatin using the preventive approach and grade1 reaction appeared in 3 patients (33.3%) again. Conclusions: Our initial preventive approach was effective to reduce the incidence of allergy, severe adverse events. And further intensive anti-allergic procedure contributed to re-expose to oxaliplatin. No significant financial relationships to disclose.