bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular and immunologycal basis of a novel therapeutic formulation: Oligoelements Zn, Se and Mn plus Lachesis Muta venom (O-LM)
Authors: Crescenti E. J. , Croci M. , Cremaschi G. , Genaro A. , Mohamad N. , Sambuco L. , Medina V. , Bergoc R. , Rivera E. S. 
Published: March 2020

13158 Background: We have previously reported that O-LM inhibited malignant cell proliferation in vitro and in vivo, increasing survival in rodent tumor models. We also demonstrated a protective action of O-LM against undesirable effects of chemotherapy and ionizing radiation, enhancing their therapeutic action. Furthermore, O-LM applied to patients with advanced breast, colon and pancreatic cancer resulted in increased survival and better quality of life with no side effects. In this work we further investigated the mechanisms involved in O-LM therapeutic effect. Methods: Two groups of Nude mice, control and O-LM (Zn, Se, Mn 4μ g/ml each; L. Muta 4 ng/ml) treated (0.1 ml/day, sc) were inoculated with PANC-1 cells to evaluate tumor development. PCNA, P53, antioxidant enzymes, apoptosis, microvessels and immune cell markers were studied by immunohistochemistry. In control and O-LM treated BALB/c mice we determined in vitro responses to T and B selective mitogens. Results: O-LM treated tumors showed significant lower growing rate, smaller mass (3,77±0,95 vs 9,75±2,30 cm3) and an important peritumoral lymphoid infiltrate. Apoptotic cells and P53 expression were increased while PCNA was negative and microvessels counts were lower than controls. O-LM produced a 3-fold increase in Superoxide Dismutase activity. The infiltrates showed an important number of CD11 bearing cells and B220 positive but CD3 and CD19 negative cells, suggesting the presence of NK cells. In BALB/c mice T selective mitogen Con A, but not B selective mitogens responses were enhanced, with a maximum after 60 days of O-LM treatment. A 4-fold increase in IFNγ release was observed in cell-free supernatants from lymph node culture stimulated with Con A obtained from 60-days treated mice. Conclusions: Present data demonstrate the capacity of O-LM to modulate free radical production, the expression of tumor markers and suggest an important up-regulation of innate and T-cell mediated immunity induced by in vivo treatment with O-LM. These results reinforce the hypothesis that the effective therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development with the additional advantage of the total absence of adverse effects. No significant financial relationships to disclose.
Activity of trastuzumab-based therapy beyond disease progression in heavily pretreated metastatic breast cancer patients—Single institution experience
Authors: Tokajuk P. , Czartoryska-Arlukowicz B. , Wojtukiewicz M. Z. 
Published: March 2020

13159 Background: Benefits from continuing trastuzumab-based (TZB) therapy beyond disease progression in HER-2-overexpressing metastatic breast cancer (MBC) patients (pts) remain obscure. Methods: A retrospective analysis was undertaken to assess activity of TZB therapy for MBC pts treated in our institution from 2002 to 2005 outside clinical trials. Results: 27 pts were evaluated. Median age: 52 years (range, 33–62). 9 pts (33.3%) were premenopausal. Hormonal receptors status: 9 pts ER(+), 4 pts PgR (+), 2 unknown. HER-2 overexpression was determined by IHC staining (3+ score) in all pts. Metastases location: 18 pts soft tissues/bone, 18 pts visceral disease. Median number of metastatic sites: 2 (range: 1–4). 9 pts (33.3%) had metastases in < 2 locations. 16 pts (59.2%) received neo/adjuvant chemotherapy: 11 pts doxorubicin, 8 pts CMF, 2 pts docetaxel, 4 pts other. Median previous chemotherapy lines for advanced disease: 2 (range: 0–6). 16 pts received doxorubicin/epirubicin, 14 pts docetaxel, 13 pts vinorelbine as a part of advanced disease chemotherapy regimen. Trastuzumab was administered at standard doses and combined with docetaxel, vinorelbine, cisplatin, capecitabine, etoposide, gemcitabine or administered as monotherapy. Response for the first-line TZB therapy was as follows: CR 5/27 pts (18.5%); PR 10/27 pts (37%). Median TTP was 5.8 months (range: 0–22). 14/27 pts (51.8%) received a second-line TZB therapy beyond disease progression. Response for the second-line therapy: CR 2/14 pts (14.3%); PR 5/14 pts (35.7%). Median TTP was 5.1 months (range: 0–24). 6/14 pts received a third-line and subsequent lines (up to five lines) of TZB therapy. PR for subsequent lines of therapy was observed in 4 pts. Median survival has not been reached. Pts who received ≥2 of TZB regimens survived significantly longer than pts who had received only 1 regimen (P = 0,02 logrank). Pts with metastasis in 1 location survived significantly longer than pts with metastasis in ≥2 sites (P = 0,01 logrank). Conclusions: Trastuzumab-based therapy seems to be active in MBC pts beyond disease progression even in heavily pretreated population. Durable responses were observed in some cases. No significant financial relationships to disclose.
Detection of seven polymorphisms associated with colorectal cancer therapeutic response and toxicity
Authors: Qu K. Z. , Ren Y. , Liu J. , Sferrozza A. , Bender R. A. 
Published: March 2020

13160 Background: First-line therapy for metastatic colorectal cancer (CRC) is 5-fluorouracil/leucovorin in combination with oxaliplatin (ie, FOLFOX™) or irinotecan (ie, FOLFIRI). Optimizing this therapy for an individual patient, however, is complicated due to wide variability in drug response and potential for toxicity. Such variability may be due to functional genomic polymorphisms in the drug target gene or in the metabolizing or DNA repair enzyme genes. We report, herein, development and validation of 2 new assays that, together, detect 7 polymorphisms associated with CRC drug response and toxicity. Methods: The first assay (SNaPshot) simultaneously detects 4 polymorphisms by using primers targeting the ERCC1, XPD, GST-P1, and XRCC-1 genes, single nucleotide primer extension of PCR products, electrophoresis and fluorescent detection on an ABI PRISM® 3100 Genetic Analyzer, and data analysis using GeneMapper® software (Applied Biosystems, Inc.). The second assay (F-PCR) simultaneously detects 3 polymorphisms using paired primers targeting the TS and UGT1A1 genes. One primer per pair is labeled with a fluorescent tag, and electrophoresis, detection, and data analysis are performed as described for the SNaPshot assay. Results: Based on fragment size and color, the intra- and interassay precision for SnaPshot ranged from 0.04%-0.51% and 0.14%-0.59%, respectively, and for F-PCR from 0.02%-0.16% and 0.09%-0.29%, respectively. There was 100% concordance in the genotypes determined in 3 separate SNaPshot (n=44 samples) and F-PCR (n=32 samples) assays. Furthermore, there was 100% agreement between genotypes determined by the SNaPshot method and those determined by RFLP (n=10) and between genotypes determined by the F-PCR method and those determined by pyrosequencing (n=17). Conclusions: Our multiplex SNaPshot and F-PCR methods can accurately detect 7 polymorphisms associated with CRC drug response and toxicity. These multiplex PCRs should lead to improved precision and ease of interpretation relative to that of single PCR methods. These methods may help the clinician optimize CRC therapy for individual patients. No significant financial relationships to disclose.
Phase I/II study of capecitabine plus irinotecan (XELIRI) in combination with bevacizumab as first-line therapy in metastatic colorectal cancer
Authors: Kocakova I. , Spelda S. , Kocak I. , Demlova R. , Simickova M. , Vyzula R. 
Published: March 2020

13504 Background: First-line treatment of metastatic colorectal cancer (MCRC) is based on regimens combining oxaliplatin or irinotecan with intravenous 5-fluorouracil (5-FU) and leucovorin (FOLFOX or FOLFIRI/IFL). A few phase II studies of capecitabine with irinotecan (XELIRI) proved to be comparable to FOLFIRI. Methods: A phase I/II study was conducted to assess the efficacy and tolerability of XELIRI + bevacizumab in MCRC. Indication for the therapy: histologically confirmed colorectal adenocarcinoma, metastatic inoperable disease, no prior systematic therapy for metastases, performance status 0–1, normal hematological, biochemical parameters, no other malignity. Therapy consisted of capecitabine 1000mg/m2 bid on days 2–15 and intravenous irinotecan 250mg/m2 on day 1, bevacizumab 7.5mg/kg on day 1, q 21 days. The response was evaluated after 2 or 3 cycles by RECIST criteria. Results: From March 2005 to December 2005 14 patients (pts) 9 males, 5 females with median age 53 years (range 39–67) have been included. 9 pts were initially disseminated, 5 pts relapsed after adjuvant therapy. Liver metastases were in 12 pts, number of metastatic sites was from 1 to 4, median 2. The overall number of cycles was 96, range 2–13, median 7 cycles. 13 pts have been evaluable for response. The CR occurred in 1 (7%) patient, PR in 10 (77%) pts, SD in 2 pts. During therapy CEA and Ca19–9 declined in all pts. Pretreatment level of CEA: median 32 μg/l, range: 2.4 - 9 265 μg/l. CEA at the response evaluation: median 5.3 μg/l, range: 1.2 - 573 μg/l. Pretreatment level of Ca19–9: median 119,7 kU/l, range: 0 - 4 692. kU/l. Ca19–9 at the response evaluation: median 17.4 kU/l, range: 0–666 kU/l. The toxicity: epistaxis in 1 patient, proteinuria < 1 gram / day in 2 pts and granulocytopenia G3 in 1 patient. No other hematologic toxicity > G2 has occurred. The therapy has been continued in all pts so far with median time of therapy 6 months. The time to disease progression and overall survival has not been reached yet. Conclusions: Irinotecan / capecitabine + bevacizumab has shown high efficacy with response rate 84% and low toxicity. The regimen seems to be appropriate for using in further phase II studies. No significant financial relationships to disclose.
Concurrent radiotherapy (RT) and chemotherapy (CT) with oxaliplatin as primary treatment of advanced rectal cancer: a phase II study
Authors: Alberti A. , Tomei F. , Miele E. , Pizzardi N. , Ramponi S. , De Paula U. , Gentile P. , Proietti F. , Marmiroli L. , De Quarto A. 
Published: March 2020

13507 Background: Combined pre-operative RT and CT increase the possibility for conservative surgery in locally advanced rectal cancer. Most clinical trials show that responding patients could obtain a reduction of local relapse and an improvement of overall survival, especially when a complete pathological response is obtained (pCR 9–29%). The aim of our study was to determine the activity of RT concomitant to oxaliplatin (OHP) in combination with c.i. 5-fluorouracil (5FU). Methods: Primary endpoint was pCR. Sample size was defined according to Simon Two-Stage phase II design (planned sample size: 29 evaluable patients). From May 2002 to November 2005, 33 patients (15 males, 18 females) were enrolled: median age was 64 years (range 21–74); clinical stage was cT3/cT4 cN0 or cTany cN+ M0. In 24 patients rectal cancer was ≤ 5 cm from anal verge. Weekly OHP 60 mg/m2 was administered in combination with c.i. 5FU 225 mg/ m2 for 5 days per week. Twelve patients received conventional RT (CRT): 25 fractions with 1.8 Gy, total dose 50.4 Gy on the pelvis and a boost on tumor bed with 3 fractions of 1.8 Gy. 21 patients received hyperfractionated RT (HRT): 1.2 Gy b.i.d. for 5 days per week for 4 weeks and a concomitant boost on tumor bed with daily 3 Gy (total dose 54–56 Gy on tumor bed, 48–50 Gy on the pelvis). Patients underwent surgery after 6–8 weeks from the end of treatment. Results: All patients were evaluable for pathological response. Sphincter preservation was obtained in 30 patients (=90.9%), a clinical down-staging in 30 patients (=90.9%). Overall, 12 patients (=36.4%) experienced a pCR: 9 of 21 patients (=42.8%) who received HRT obtained a pCR; 3 of 12 patients (=25%) who received CRT showed a pCR. Treatment was well tolerated. No G3–4 toxicity was observed. Conclusions: The results of our study are promising in terms of sphincter preservation, clinical down-staging and pCR. Moreover in this trial patients who received HRT obtained an encouraging outcome. No significant financial relationships to disclose.
Phase II study of S-1 plus irinotecan (SIR) in patients with advanced colorectal cancer
Authors: Goto A. , Yamada Y. , Shimada Y. , Shirao K. , Hamaguchi T. , Muro K. , Yasui H. , Kato K. 
Published: March 2020

13508 Background: Infusional fluorouracil and leucovorin (5-FU/LV) plus irinotecan is one of the standard regimens for the treatment of metastatic colorectal cancer (MCRC). S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid, is an oral DPD inhibitory fluoropyrimidine shown to be very effective as first-line treatment for MCRC. The response rate with S-1 was 35–40% in patients with chemo-naïve MCRC. This study evaluated the efficacy and toxicity of S-1 plus irinotecan (SIR). Methods: Eligible patients had untreated MCRC as confirmed histologically, PS 0–1, adequate organ function, and provided written informed consent. First-line SIR was given in 3-week treatment cycles: intravenous irinotecan 150 mg/m2 (day 1) and oral S-1 40 mg/m2 twice daily for 14 days followed by 7 days of rest. Results: Forty-one patients were enrolled; 40 fulfilled all eligibility criteria, and 1 had double cancers. There were 28 men; median age 60 years (range, 23–74); ECOG PS 0/1, 35/6. The overall response rate was 63% (95%CI, 48–78%). Five patients had a CR, 20 a PR, 11 SD, and 2 PD. Median TTP was 8.0 months (range, 1.4–13.8 months); MST was not reached. The most frequent grade 3/4 toxicities included: neutropenia (17%), diarrhea (15%), and anorexia (12%). One patient had Grade 4 constipation. The relative dose intensity of irinotecan was 84%, and that of S-1 was 79%. Dose reduction of irinotecan was required in 41 of 327 administered cycles, and that of S-1 was required in 15 of 327. Conclusions: SIR is a highly active and convenient first-line therapy for MCRC, with an acceptable toxicity profile. S-1 has the potential to replace infusional 5-FU/LV plus irinotecan for MCRC. No significant financial relationships to disclose.
Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer
Authors: Nakajima G. , Uchida K. , Hayashi K. , Xi Y. , Takasaki K. , Ju J. 
Published: March 2020

13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.
Combined modality therapy of locally advanced adenocarcinoma of the rectum: Update of a phase I trial of preoperative radiation (RT) with concurrent capecitabine (Cap) and irinotecan (Ir)
Authors: Mitchell E. P. , Anne P. , Goldstein S. , Isenberg G. , Fitzgerald J. , Palazzo J. , Hauck W. , Lavarino J. , Sanson J. , Curran W. J. 
Published: March 2020

13547 Background: We previously reported the combination of preoperative radiation (RT) with concurrent Irinotecan and 5-FU in locally advanced rectal cancer, was well tolerated and had an excellent pathologic complete response rate (CR) of 25%, but with catheter related infections and thromboses as major toxicities (Proc Am Soc Clin Onc 22: 2003). With the potential benefits of capecitabine (Cap) and no need for an implanted catheter, a phase I study was initiated to determine the toxicity and maximum tolerated dose (MTD) of Cap with concurrent Ir and RT. Methods: Eligible patients (pts) had primary or recurrent Stage II or III rectal adenocarcinoma, without a history of prior RT or chemotherapy. The treatment regimen was as follows: external beam RT at 1.8Gy daily M-F, to a total dose of 50.4 or 54 Gy; Ir 50 mg/m2 IV, d 1, 8, 15, 22; dose escalating Cap starting at 825 mg/m2 PO divided in 2 doses, Q 12h. Surgical resection occurred at 6–10 weeks. Dose limiting toxicity is defined as Gr4 heme or non-heme Gr3. Results: A total of 16 pts have enrolled on the study, 10 male and 6 female;the median age was 57 (range 44–77). All are evaluable for toxicity. The Table reviews the maximum toxicities. Grade three diarrhea is the only dose-limiting toxicity to date. There has also been 3 pts with Gr 3 hematologic toxicity. There has been no Gr 4 toxicity. Patients are currently accruing on the 4th dose level of capecitabine. A total of 13 pts have completed the preoperative phase and three are currently on treatment. Eleven pts have had surgical resection. One pt refused surgery due to a biopsy proven CR to chemoradiation. One pt refused surgery and died of disease. Of the 11 pts undergoing surgical resection, there have been 3 pathologic CR. Conclusions: The preoperative combination of capecitabine, irinotecan and radiation in locally advanced rectal cancer pts is feasible and well tolerated. The study continues to accrue, and the MTD has not been achieved. [Table: see text] [Table: see text]
A study for establishment of individualized chemotherapy for colorectal cancer using the area under the concentration curve (AUC) based on the collagen gel droplet embedded culture-drug sensitivity test (CD-DST)
Authors: Ochiai T. , Nishimura K. , Noguchi H. , Kitajima M. , Tsukada A. , Watanabe M. , Futagawa S. , Nagaoka I. 
Published: March 2020

13560 Background: The drug sensitivity of tumor cells is one of the key issues to explore for individualized chemotherapy for cancer patients. We reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact duration. We also reported that growth inhibition rate (IR) and area under the concentration curve (AUC) approximated to logarithmic curve in ASCO 2003 (#1283). The aim of this study was to evaluate the individual 50% inhibitory AUC (AUCIR50) and research the usefulness of individual AUCIR50 for establishment of individualized chemotherapy. Methods: Surgical specimen was obtained from resectable 53 CRC patients without any preoperative chemotherapy during 2002 to 2005. CD-DST was performed under nine different conditions: concentration of 5-FU tested: 0.2, 1 and 10μg/ml; duration of exposure: 3, 24 and 120 hours. After converting drug concentration and contact time to AUC and plotting against growth IR, individual correlation between AUC and growth IR was evaluated. The histogram of individual AUCIR50 was also evaluated. Results: The curve between AUC and growth IR approximated to logarithmic curve in all of the patients (R2=0.69–0.96). We could calculate the individual AUCIR50 in all of the patients (AUCIR50= 23.7–98796298.1μg*hr/ml). The histogram of the individual AUCIR50 (AUCIR50<2500μg*hr/ml) indicated CURT(X) pattern (SK=0.0076). Conclusions: We could obtain a position for each patient on the histogram of AUCIR50. We could also indicate the potential for 5-FU sensitivity to each patient. Some patients demonstrating low 5-FU sensitivity could not be recommended for 5-FU based chemotherapy, and non-5-FU chemotherapy should be explored for them. This study demonstrated that the individual AUCIR50 is useful to distinguish the individualized chemotherapy of colorectal cancer patients. Utilization of CD-DST will facilitate establishment of individualized chemotherapy for colorectal cancer. No significant financial relationships to disclose.
Activity and tolerability of mitomycin-C (MMC) and chronomodulated capecitabine (C) in advanced colorecatal cancer (ACC) patients
Authors: Campanella C. , Vanni B. , Garufi C. , Torsello A. , Di Lauro L. , Pellicciotta M. , Terzoli E. 
Published: March 2020

13563 Background: MMC plus continuous infusion (CI) 5-fluorouracil (5-FU) showed activity with acceptable toxicity profile in ACC patients (pts). Nocturnal infusion of 5-FU was shown to reduce hematological and gastrointestinal toxicity. Capecitabine (C) is an oral pro-drug converted to 5-FU which mimics 5-FU CI activity. C is effective as single drug and in combination, providing equivalent activity and efficacy. Aim of the study was to evaluate activity and tolerability of MMC plus C in ACC patients. Methods: fifty-one pts received MMC 7 mg/mq i.v on day 1 followed by C 2000 mg/mq /die for 14 days out of 21 days; 20% of C dose was given at 8:00 while 80% was given at 20:00; each course (c)was repeated q 6 weeks. Pts data: M/F 33/18; median age: 64 (41–88); WHO PS0: 36, 1: 11, ≥2 :2; metastatic sites: liver (35), lung (17), lymphonodes (9), peritoneum (8), other (14); no measurable disease 1; site: colon/rectum 40/11; previuos lines: 0 (17), 1(18), ≥2(16); 43% and 29% of patients had been previously treated by 5-FU with oxaliplatin or irinotecan. Results: Toxicity was evaluated in 45 out of 51 pts and in 94 courses. Grade 2–3 neutropenia occurred in 5 pts/8 c (10/6%), G2-G3 thrombocitopenia in 4 pts/8 c (8/6%). One pt (2%) experienced G3 anemia. G2–3 nausea and vomiting occurred in 5 pts/5 (10/5%), G2–3 diarrhea in 8 pts/12 c (15/13%) and only 1 pt experienced G4 diarrehea. Mucositis of grade 2 was observed in 3 pts/ (6%). G2–3 hand foot syndrome and G2–3 asthenia both occurred in 5 pts (10%). No differences in toxicity were observed between pre-treated and untreated pts. At this time of the study 45 out of 51 pts were evaluated for response: stable disease was observed in 16 pts (31%), partial response in 5, untreated, patients (10%), progression in 23 (45%). Median time to progression (TTP) was 6,0 months (3,0- 8,5 mo) for both groups. Conclusions: Chronomodulated administration of C plus MMC seems to have an excellent toxicity profile even in pre-treated population, with a TTP similar to more expensive treatments. No significant financial relationships to disclose.