bluuebunny/crossref_metadata_2025 huggingface dataset:
AG-013736, a novel VEGF receptor and PDGF receptor inhibitor with potent activity against human bladder carcinoma in vitro and in vivo.
Authors: Zhu K. , Pino M. , Siefker-Radtke A. O. , Shalinsky D. , Hu-Lowe D. , McConkey D. J.
Published: March 2020

13109

The receptors for vascular endothelial growth factor and platelet-derived growth factor (VEGFR-2 and PDGFR) play essential and complementary roles in angiogenesis, and combined inhibition of these receptors may therefore result in potent antitumor activity in vivo. Here we characterized the effects of a small molecule tyrosine kinase inhibitor AG-013736 (Pfizer) in HUVEC and human bladder cancer cells. Previously, AG-013736 was reported to inhibit VEGFRs with picomolar potency and PDGFRs with nanomolar activity. All of the cell lines examined displayed cell surface VEGFR-2 and PDGFR α and β expression as measured by flow cytometry. Low nanomolar concentrations of AG-013736 blocked the HUVEC cell proliferation with inhibition of VEGF receptor 2 and PDGF receptor phosphorylation. AG-013736 caused regression of established subcutaneous human bladder cancer xenografts, effects that were associated with inhibition of VEGFR-2 and PDGFR β phosphorylation but not EGFR phosphorylation and reduction in tumor microvessel densities (MVDs). Our results demonstrate that AG-013736 has substantial anti-angiogenesis activity in preclinical models of human bladder cancer, which warrants further exploration either alone or with the combination of other pre-clinical drugs in bladder cancer treatment.

No significant financial relationships to disclose.
Gene expression profile related to oxaliplatin resistance in a panel of sensitive human colorectal cancer cell lines with acquired resistance to the drug
Authors: Martinez-Cardus A. , Martinez-Balibrea E. , Manzano J. L. , Bandres E. , Malumbres R. , Marti C. , Taron M. , Garcia-Foncillas J. , Abad A.
Published: March 2020

13143

Background: Platinum drugs resistance acquisition is a complex process based in the alteration of genes that belong to several pathways related to drug metabolism. To clarify the multifactoriality of these mechanisms, we analyzed gene expression profile in the four CCR cell lines HT29, LoVo, DLD1 and LS513, and their sublines HTOXAR, LOVOXAR, DLDOXAR y LSOXAR that we induced oxaliplatin resistance in our laboratory. The aim of this work consisted on comparing gene expression profile between resistant cells group (cluster R) and sensitive cells group (cluster S) to determine genes and pathways that could play a role in oxaliplatin resistance acquisition process. Methods: Resistance level determination by MTT assay. Gene expression profile analysis through microarray technology (Human 19K oligo): labeled with Genisphere 3DNA Array350 (Dye Swap), and data analysis using Imagene 4.1, ArrayNorm1.7.2 y Genesis 1.5.0 (ANOVA). Results: According to ANOVA analysis of cluster R versus cluster S, we obtained 32 genes that showed significant changes in expression. 15 of these genes were up regulated and 17 were down regulated. We emphasize genes that belong to pathways previously related to oxaliplatin metabolism (AKT1, TRIP and NLK), family of genes that does not expressed in the same chromosome (KIAA0232 and KIAA0256, SLC39A9 and SLC30A9), and family of genes that had previously related to carcinogenesis processes (KRT19, KRT18 and KRT8). Conclusions: It is possible to develop oxaliplatin resistant CCR cell lines. In our oxaliplatin acquired resistance model, 32 genes showed gene expression changes between groups. These genes belong to signal transduction pathways and cellular integrity mechanisms and they could be a future oxaliplatin resistance prediction profile in colorectal cancer patients.

No significant financial relationships to disclose.
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.
Neoadjuvant treatment for rectal cancer in fit and vulnerable patients older than 70 years
Authors: Friso M. L. , Pasetto L. M. , Basso U. , Pucciarelli S. , Rugge M. , Agostini M. , Serpentini S. , Favaretto A. , Nitti D. , Monfardini S.
Published: March 2020

13586

Background: To evaluate the toxicity and feasibility of neoadjuvant 5FU continuous infusion or bolus in combination with pelvic radiotherapy (RT) in rectal cancer patients older than 70 years. Methods: From June 2000 to June 2005, 36 patients older than 70 years out of a total of 300 consecutive cases with histologically proven locally advanced rectal adenocarcinoma (≤ 12 cm from the anal verge) classified as either T3 or T4, N0 or N1–2 M0 disease, were examined. Comorbidities were evaluated according to Cumulative Illness Rating Scale-Geriatric (CIRS-G) and patients were deemed “fit” if they were otherwise healthy or had one or more comorbidities of only grade 1; “vulnerable” if had one or more comorbidities of grade 2. Results: Median age was 74 years (range, 70–82). 14 patients (5 healthy, 13.8%, and 9 with slight comorbidities, 25%) were fit and 22 (61.2%) were vulnerable. All the patients received the full course of RT, with a total dose of 50.4 Gy. The mean number of chemotherapy weeks was 5.34 (range, 2–6). 4 out 14 (28.6%) fit patients and 9 out 22 (40.9%) vulnerable patients had to interrupt chemotherapy prematurely because of toxicity (p=0.26). Vulnerable patients did not experience superior toxicity compared to fit patients (8/22 vulnerable and 6/14 fit patients developed toxicities of grade ≥ 2, p=0.69). With the exception of 2 fit and 2 vulnerable patients who were lost to follow up before surgery, 32 patients (88.9%) were operated. Thirty cases (12/14 fit patients, 85.7%, and 18/22 vulnerable patients, 81.8%) were radically resected without relevant postoperative complications. 13/20 vulnerable and 10/12 fit patients had a pathological downstaging of disease (p=0.24). Conclusions: Selected vulnerable elderly patients with rectal cancer can receive the same neoadjuvant chemoradiotherapy and undergo surgery as well as fit elderly patients since tolerability and response rate seem to be similar in both categories of patients.

No significant financial relationships to disclose.
Immunological relevance of the tumor associated antigen (TAA) COA-1 in colorectal cancer (CRC)
Authors: Corsi D. C. , Maccalli C. , Ciaparrone M. , Scinto A. F. , Cucchiara G. , Belardelli F. , Zagonel V.
Published: March 2020

13590

Background: Immunotherapy (IT) in CRC has often produced discouraging results. COA-1 is a new TAA recognized by CD4+ T cells from peripheral blood (PB) of a CRC pt; its immunogenic epitope is presented on the surface of tumor cells in association with DRβ1*1301 or *0402 HLA class II molecules. Our aim is verifying whether an immune response directed against COA-1 mediated by CD4+ T cells can be isolated from PB of CRC pts. To achieve a more efficient anti-tumor response a recognition of a specific antigen by both the CD4+ and CD8+ lymphocytes should be performed; so different epitopes deriving from the processing of the same antigen should be presented to the immune system in association with both class I and class II MHC molecules. We identified a list of COA-1 derived peptides with the calculated score for the binding to HLA-A2, the more common HLA class I molecule within the Caucasian population. A failure in generating COA-1 specific T cells was observed in stage I-II CRC pts. Methods: From Jan 04 to day PB samples from 36 CRC pts (14 stage III/ 22 stage IV) have been collected and the HLA typing has been performed. Pts. expressing HLA DRbβ*0402, HLA DRβ1*1301 or HLA-A2 have been selected to collect other blood drawns and verifying whether an immune response directed against COA-1 could be isolated from their PB. Results: 4 pts were positive for the expression of DRβ1*1301 and 2 for the expression of DRβ1*0402. PB lymphocytes have been in vitro stimulated with the COA-1 derived epitopes and tumor reactivity has been verified. An immune response directed to COA-1 was detected in the PB of these 6 pts; anti-COA-1 CD4+ T cells were in vitro isolated and their cytotoxicity measured by granzyme B release. 9 pts were positive for the expression of HLA-A2 and we are stimulating the lymphocytes isolated from these pts with 6 selected COA-1 derived peptides binding the HLA-A2. We observed specific CD8+ T cells for 2 peptides in 1 pt. Conclusions: Our data identify COA-1 like an immunogenic antigen that can evoke an anti-tumor immune response CD4+ mediated in CRC; the response correlates with disease progression. Experiments are ongoing to evaluate an immune response mediated by both CD4+ and CD8+ T cells. These results will determine whether COA-1 could be used for future protocols of IT in CRC.

No significant financial relationships to disclose.
5-fluorouracil (5-FU) plus cisplatin (CDDP) induction chemotherapy followed by combined external bean radiation therapy (XRT) and mitomycin-C (MMC) and 5-FU chemotherapy in locally advanced anal canal cancer (ACC)
Authors: Rodriguez-Riao J. J. , Figueira D. , Zarraga E. , Lion L. , Fuentes M. B. , Fernandez P. , Nasr I. , Gamboa C. , Ochoa J.
Published: March 2020

14016

Background: Definitive chemoradiation therapy is the standard of care for squamous or cloacogenic cell ACC. The chemotherapy regimen comprising 5-FU and MMC is the most commonly used among patients with ACC, nearly 70% of patients can get complete response (CR), with the benefit of sphincter preservation, but patients with a large tumors (T3/T4) or nodal metastases have a response of 50%. Methods: To improve outcome, we conducted a phase II, study of 5-FU and CDDP followed by combined XRT plus 5-FU and MMC. Eligibility included patients withT3/T4 ACC with limited locoregional nodal involvement (N0/N1). Treatment: 5-FU 1000 mg/m2/days 1 to 5 in continuous i.v. infusion plus CDDP 100 mg/m2 i.v. day 1 q21d was administered for 2 cycles (weeks 1 and 4) followed by XRT (4.5 Gy) during 6 weeks (weeks 7 to12) with concurrent 5-FU 1000 mg/m2/days 1 to 4 in continuous i.v. infusion plus MMC 10 mg/m2 i.v. day 1 (weeks 9 and 17). RECIST criteria were used to assess tumor response Results: 59 patients were entered on this study from 8/2000 to 2/2005. Median age: 57 yrs (37–83), 49 F/10 M, median ECOG PS 0 (0–1), T3/T4 44/15, N0/N1 20/39. 54 patients were evaluable for clinical response: Induction chemotherapy led to 13 (24%) CR, 38 (70%) partial responses (PR) and 2 (6%) stable disease. After combined modality treatment, there were a total of 36 (67%) CR, 13 (24%) PR, 5 (9%) SD. Median follow up was 21.6 months (5–52).The median time to progression is 20.5 months (3–52). Toxicity grade 3/4: Neutropenia 20% (10/54), thrombocytopenia 13% (7/54), radiodermatitis 13% (7/54), nausea/vomiting 7% (4/54). Our previous experience with concurrent treatment without induction (n=27) resulted in a CR 59%, PR 37%, and 4% progressive disease Conclusions: We concluded that induction chemotherapy followed by combined XRT and chemotherapy could be an option in treatment of locally advanced ACC.

No significant financial relationships to disclose.
Temozolomide/capecitabine therapy for metastatic neuroendocrine tumors of the pancreas. A retrospective review
Authors: Isacoff W. H. , Moss R. A. , Pecora A. L. , Fine R. L.
Published: March 2020

14023

Background: Our laboratory studies suggest additive to synergistic cytotoxicity when neuroendocrine (NET) cells were given continuous exposure to 5 fluorouracil (5-FU) which preceded exposure to temozolomide (T). Based on this in vitro efficacy, salvage treatment with capecitabine (C), an orally-available fluoropyrimidine that is metabolized to 5-FU, and T was initiated in 17 patients (pts) with advanced NET of the pancreas. Methods: A retrospective review was conducted of the 17 pts who received C 1000mg bid on days # 1–14 and T 150–200mg/m2 on days #10–14 of a 28-day cycle, beginning in October, 2002. Pts had imaging performed after every 2 cycles, and serum tumor markers (TM), when present, were measured at every cycle. Median Age 54 (range 33–70). There were 9 men and 8 women. All of the pts had failed first-line treatment with escalating doses of sandostatin LAR. 11 pts had failed multiagent chemotherapy (range 1–5 regimens). Pathology: 10 pts had NET, 3 had non-secretory carcinoid, 1 had secretory carcinoid, one had a glucagonoma; 2 had non-secretory beta cell tumors and one pt had Multiple Endocrine Neoplasia Type I. Results: 13 of the pts are still alive and 12 remain on therapy with SD or PR. One pt did not complete cycle #1 and is not evaluable for response, but is included in an intent-to-treat (ITT) analysis. Grade 3 toxicity was thrombocytopenia in 2 pts, 1 of whom had splenectomy with resolution, and hand-foot syndrome in 1 pt who resumed therapy at reduced dose of C. Of 17 pts with unidimensionally measurable disease, 1 (6%) achieved a complete pathological response. 9 pts (53%) achieved a partial response by RECIST criteria, with a median duration of PR of 284 days (range 85–364 days). Of the 7 pts with evaluable TM, 6 (86%) had a greater than 50% decline. Median overall survival by ITT analysis in the 4 pts now deceased was 268 days (range 111–613 days). Median time to treatment failure was 340 days (range 111–470 days) in 5 pts. Conclusion: The results of this retrospective review suggest that a combination of T + C is active, well tolerated and may prolong survival and palliate symptoms in pts with NET.

[Table: see text]
Gemcitabine, docetaxel, and capecitabine (GTX) in the treatment of metastatic pancreatic cancer (PC): A prospective phase II study
Authors: Fine R. L. , Fogelman D. R. , Sherman W. , Schreibman S. , Siegel A. , Mauer M. , Chen J. , Chu K.
Published: March 2020

14024

Background: We have found that the combination of gemcitabine, docetaxel, and capecitabine (GTX), when administered in a specific sequence, will induce a p53 independent pathway of cell death through the MAP kinase pathway. The sequence overcomes drug resistance in PC cells in vitro. We have begun a prospective, phase II trial of GTX in patients with metastatic PC as first-line therapy. Methods: 23 patients with metastatic PC, ECOG 0–2 were enrolled at either Columbia or a community practice. Each cycle was administered over a 21 days. Capecitabine was administered at 750 mg/m2 twice daily for 14 days. Gemcitabine (750 mg/m2 over 75 minutes) and docetaxel (30 mg/m2) were administered on days 4 and 11. Responses were measured by CT (RECIST) and PET after every three cycles. A response by PET was defined as a 50% reduction in SUV while a CR was an absence of uptake. Results: Median age was 61, including 8 men and 15 women. Metastatic sites included liver (87%), abdomen (65%), and lung (17%). 70% of liver positive patients had at least five metastases. 22% had malignant ascites. 16 patients remain alive and 7 have progressive disease. Median survival has not yet been reached. Progression occurred at a median of 5.1 months. By CT, the response rate at metastatic sites was 39% (17% CR / 22% PR). Stable disease was observed in 48% at metastatic sites. PET showed a 53% response rate at metastatic sites. At the primary site, CT showed a 30% response rate including 17% complete responses. By PET criteria, there was a 31% response rate and a 26% CR rate at the primary site. In three patients, a PET response heralded a CT response by three cycles. In one patient, progressive disease on PET preceded progression on CT by two months. Toxicity: Grade 3 leukopenia and thrombocytopenia were 13% and 9%, respectively. There was no grade four hematologic toxicity. One patient experienced lung disease related to gemcitabine and withdrew from the study. A second patient experienced grade 4 mucositis, thrush, and sepsis which was presumed due to DPD deficiency. Grade 3–4 toxicities: HFS: 9%. There was no grade 3–4 diarrhea. Conclusions: GTX, elicits a promising response rate when used in metastatic P.C. PET detects a response and failure of chemotherapy earlier than CT scans.

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A phase II study of capecitabine and oxaliplatin (CAPOX) in metastatic adenocarcinoma of the small bowel (SBA) or ampulla of Vater
Authors: Overman M. J. , Chedid S. , Morris J. , Waldrum S. , Wolff R. A.
Published: March 2020

14025

Background: Metastatic SBA and ampullary adenocarcinoma (AAC) are incurable, aggressive malignancies. Limited data exists regarding the role of systemic chemotherapy in these diseases. Given the marked activity of CAPOX in other cancers of the gastrointestinal tract, we have investigated the activity of this combination in these two tumor types. Methods: Patients (pts) with either metastatic or unresectable SBA and AAC who had adequate organ function, ECOG performance status (PS) ≤2 and measurable disease per modified RECIST criteria were enrolled. Prior use of 5-FU or capecitabine as adjuvant therapy, neoadjuvant therapy, or with radiation was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130mg/m2 IV on day 1 and capecitabine 750mg/m2 PO BID days 1–14. Up to 30 pts will be enrolled. The primary endpoint is overall response rate (ORR). Results: Eleven pts have been enrolled from 11/04 to 12/05 (6 with AAC and 5 with SBA). Ten pts have received ≥2 cycles and are evaluable for response. All pts had metastatic disease and none had received prior chemotherapy. Patient (pt) characteristics: median age 59 (49–76); M/F (4/7); 91% PS 0–1. Grade 3/4 toxicities included fatigue (5), neuropathy (1), anorexia (1), thrombocytopenia (1), hypokalemia (1), hyponatremia (1), and musculoskeletal (1). Common grade 1/2 toxicities included neuropathy (8), nausea (8), diarrhea (6), and fatigue (5). Four pts required dose reduction and 1 pt discontinued due to toxicity (grade 3 fatigue). Six pts, 3 AAC and 3 SBA, responded with an ORR of 60% (95% CI 31 to 83%). Five responses have been confirmed and 1 AAC pt obtained a complete response after 5 cycles of treatment. Median time to progression was 6.8m (95% CI 4.4 to 9.3+m). Conclusions: The combination of CAPOX is both well-tolerated and highly active. The ORR of 60% is one of the highest yet reported in the literature for the treatment of adenocarcinoma of the small bowel and ampulla of Vater. Enrollment continues on this trial. (Supported by a research grant from Sanofi-Aventis).

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Patient tolerance of palliative chemotherapy for recurrent hepatocellular carcinoma following orthotopic liver transplant
Authors: Sobol A. L. , Kuriakose P. , Colon-Otero G.
Published: March 2020

14034

Background: While orthostatic liver transplant (OLT) is an accepted treatment for localized hepatocellular carcinoma (HCC), little data exists as to the appropriate treatment of recurrent disease. Consensus opinion favors avoiding systemic chemotherapy on the grounds that toxicity would be poorly tolerated by patients medically immunosuppressed to prevent allograft rejection. Methods: Study design: retrospective chart review. The medical records of all patients who underwent OLT at the Mayo Clinic in Jacksonville, Florida, from February 1998 to April 2005 were reviewed. Those patients who developed recurrent HCC treated with systemic chemotherapy and were followed for at least 5 weeks with documented side effects were identified as the study population. Tolerance of treatment was assessed through review of side effects and Eastern Co-operative Oncology Group (ECOG) performance status scores. Disease progression was identified as increasing size of lesions on computed tomography (CT) scans and increasing serum alpha fetoprotein (AFP) levels. The primary endpoint was defined as discontinuation of chemotherapy due to severe side effects. Results: Of 1133 patients undergoing OLT, 179 were diagnosed with HCC. Thirty developed recurrent disease. Of these, 8 did not receive chemotherapy (2 observation only, 2 Hospice care, 2 radiation therapy, 1 surgical resection, 1 chemoembolization), 10 were lost to follow-up, and 2 died of rapidly progressive disease. The remaining 10 patients underwent systemic chemotherapy with six patients receiving multiple regimens. Seven patients received from 2 to 15 cycles of gemcitabine and cisplatin. Cytopenias were the most common side effect. One patient discontinued the regimen after developing neutropenic fever following 2 cycles of treatment. Five patients received from 1 to 12 cycles of capecitabine. Diarrhea was the most common side effect. Three patients received from 3 to 6 cycles of doxorubicin. Stomatitis and cytopenias were the most common side effects. No treatment related mortalities were observed. Conclusions: Palliative systemic chemotherapy is not usually associated with life threatening side effects and therefore is a viable option for patients with recurrent HCC following OLT.

No significant financial relationships to disclose.
A phase I clinical and pharmacokinetic study of escalating doses of fixed rate and escalating infusion duration of gemcitabine given via an intrahepatic pump for patients with hepatic metastases
Authors: Tse A. N. , Raggio G. , Morse M. , Kemeny N. E.
Published: March 2020

14035

Background: Gemcitabine (Gem) is an attractive chemotherapeutic agent for hepatic arterial infusion (HAI) because of its broad-spectrum anti-tumor activity, high systemic clearance, and possibly high hepatic extraction. Pre-clinical models indicate that cytotoxicity of gemcitabine increases with duration of drug exposure. Methods: In this phase I trial, successive cohorts of patients (Pts) with hepatic metastases of colorectal or bile duct cancer were given HAI Gem 3 out of 4 weeks. During the dose escalation phase, increasing doses of HAI Gem (800, 1000, 1200 and 1500 mg/m2) were given at 10 mg/m2/min. During the infusion duration escalation phase, 1000 mg/m2 of HAI Gem was given over increasing duration of infusion (200, 300, and 400 min.). To compare the pharmacokinetics of HAI Gem with that of intravenous (iv) Gem, Pts enrolled to the infusion duration escalation phase received a 60-min. infusion of iv Gem during the first treatment week at the same dose-rate as with subsequent HAI Gem. Results: To date, 23 Pts have been enrolled and 22 were evaluable for toxicity (median age 64; median KPS 90%; 13 males/9 females). All Pts had prior HAI FUDR treatment. HAI Gem is well tolerated up to 1500 mg/m2 given at 10 mg/m2/min and up to 1000 mg/m2 infused over 300 min. Only one Pt had to discontinue therapy due to toxicity (grade 4 alkaline phosphatase) and one DLT was observed (grade 3 rash). Most common grade 2+ toxicities include neutropenia (40%), thrombocytopenia (23%), bilirubin (14%), and alkaline phosphatase (23%). The steady-state level of Gem when given by HAI was lower than that obtained when the drug was given by iv in 3 out of 4 Pts (0.62 vs 1.8; 0.38 vs 2.9; 0.36 vs 0.63 mcg/ml). One Pt with cholangiocarcinoma had a partial response and one Pt had stable disease for 5 months. Conclusions: HAI Gem is safe and can be given as prolonged infusion not achievable with systemic administration. Pharmacokinetic studies indicate good hepatic extraction of the drug. The MTD has not been reached.

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Expression of epidermal growth factor receptor (EGFR) associates with proliferation, apoptosis, and histologically aggressive features in hepatocellular carcinoma
Authors: Morinaga S. , Nakamura Y. , Sugano N. , Tsuchida K. , Shiozawa M. , Miyagi Y. , Akaike M. , Sugimasa Y. , Takemiya S.
Published: March 2020

14039

Background: Epidermal growth factor receptor (EGFR) is over-expressed in many types of cancers, plays an important role in the tumorigenesis, and is indicated to be a promising target for cancer therapy. Hepatocellular carcinoma (HCC) is a cancer with one of the worst prognosis, and new therapeutic approaches are required. The aim of this study was to clarify a possible role of EGFR expression on clinico-pathology of HCC. Methods: HCC tissues were obtained from 36 HCC patients (23 men and 13 women, range 45–80 years old) who underwent curative surgery. EGFR status of the tumors was assessed by immunohistochemical (IHC) analysis on formalin-fixed paraffin-embedded tissue. The percentage of positive tumor cells was scored as follows: 0+, no positive tumor cells; 1+, 1–10% positive cells; 2+, 10–50% positive cells; 3+, >50% positive cells. The staining intensity of membrane was evaluated as follows: 0+, negative; 1+, weak; 2+, moderate; 3+, strong. A composite score (EGFR score) was obtained by calculating the sum of these two scores. The tumor cell proliferation and apoptosis were assessed with Ki-67 labeling and ssDNA labeling, respectively. Results: EGFR expression was detected in 33 (91.7%) of 36 tumors. EGFR score ranged from 0 to 6. Higher EGFR score was related with poorer histologic grade (P = 0.005 by Kruskal-Wallis) and advanced pathologic stage (P = 0.038 by Kruskal-Wallis). EGFR score correlated positively with Ki-67 labeling indices (r = 0.358 and P = 0.032 by Spearman), and correlated negatively with apoptosis indices (r = −0.388 and P = 0.019 by Spearman). EGFR score did not affect disease free survival (DFS) or over all survival (OS), after curative surgery. Conclusions: Higher expression of EGFR, assessed with IHC, associates with more aggressive pathologic features, increased tumor cell proliferation, and reduced tumor cell apoptosis. However, further examination is needed to clarify its predictive significance.

No significant financial relationships to disclose.