Prediction of Response to Irinotecan and Drug Toxicity Based on Pharmacogenomics Test: A Prospective Case Study in Advanced Colorectal Cancer

Background: FOLFIRI regimen, which is composed of 5-FU, Leucovorin, and Irinotecan, is used in the first-line chemotherapy of metastatic colorectal cancer. Irinotecan life threatening toxicity is partly related to cytotoxic drug metabolite which is primarily inactivated by the UGT1A1 enzyme. The primary aim of the present research was to find the correlation between UGT1A1-genotype and clinical toxicity of irinotecan. Methods: In a prospective study from March 2011 to December 2013, all patients with metastatic colorectal cancer who had been referred to Medical Oncology Department of Iran Cancer Institute were genotyped for UGT1A1*28 before the first cycle of chemotherapy. All of the patients signed informed consent and trial approved by Ethics Committee of the Tehran University of Medical Sciences. Reduction of the standard dose of Irinotecan (180 mg/m2 body surface area) was measured based on NCI toxicity criteria after the first cycle of chemotherapy. Patients with previous treatment with Oxaliplatin and fluorouracil (5-FU) in the adjuvant setting and adequate liver, kidney, and heart function were included in the trial. Both synchronous and metachronous metastatic disease were noticeable. Results: A total of 50 patients with median age of 52 years were included. Most (70%) of the patients had more than one site of metastases in peritoneum, liver, and/or lung. Thirty-one patients had UGT1A1*1 normal genotype, 13 were in heterozygote and 6 were in homozygote state ofUGT1A1*28/*28. A clinically relevant increase in early toxicity was found in patients carrying the UGT1A1*28/*28 genotype with odds Ratio (OR) of 2.6 (95%CI 2.5-27.28). Similarly, there was a trend of lower overall survival in homozygote group with an HR (Hazardous Ratio) of 2.76 (95%CI .88-.61). No statistically significant relationship was found between UGT1A1genotypes and response to therapy. Conclusions: UGT1A1 28*/28* is strongly associated with drug's life-threatening toxicity even in a moderate dose of Irinotecan. On the other hand, UGT1A1 genotype data was not helpful to differentiate response to treatment.

Antibiotic-coated pins for prevention of pin-tract infection: a rabbit study.

PURPOSE. To evaluate the efficacy of antibiotic-coated pins for prevention of pin tract infection in a rabbit model. METHODS. 10 rabbits were divided into 2 groups. A unilateral external fixator was applied to the tibia with 4 self-taping 1.8-mm pins. In the test group, pins were coated with hydroxyapatite and antibiotic. In the control group, pins were not coated. All pins were then placed in Staphylococcus aureus- containing media. At postoperative day 5, all 40 pin sites were subcutaneously inoculated with S aureus. The sites were clinically examined for signs of pin tract infection. Nine days later, a piece of soft tissue around the pin site was harvested for microbiologic examination. RESULTS. In the test group, all except one pin sites appeared clean and without clinical infection, and the culture media remained clear. In the control group, all pin sites showed evidence of clinical infection and yielded positive cultures, and the culture media became dark indicating growth of S aureus. CONCLUSION. Antibiotic-coated pins were effective in preventing pin tract infection.

Rat xenograft chondrosarcoma development by human tissue fragment.

UNLABELLED: Chondrosarcoma is one of the most difficult types of cancers to diagnose and treatment. Therefore, the development of a reliable animal model for chondrosarcoma would be a helpful tool to study of the tumor's growth and progression. AIM: We conducted this study to develop a chondrosarcoma on rat by graft of human chondrosarcoma tumor tissue. METHODS: Fourteen male Sprague-Dawley rats equally divided in xenograft-implanted and control groups. On the lateral side of the right femur distal 1/3, 5 mm incision was done on the skin after animal anesthesia. Then, was drilled 3 mm on the bone and implanted the xenograft in the bone. Radiography was taken from the operated femur weekly until the fourth week and monthly for 3 months. Four animals of each group were sacrificed after 4 weeks of operation; femur was harvested for histopathological study. RESULTS: Radiological images showed sclerotic area on the implanted bone after 4 weeks of operation. Sections from tumoral areas reveal cartilage forming hypercellular neoplastic tissue with lobular pattern of growth and foci of adjacent tissue invasion such as bone trabeculas and bone marrow. CONCLUSION: the present study showed that rat xenograft chondrosarcoma can develop by human chondrosarcoma fresh tissue fragments.

A descriptive retrospective study of bladder cancer at a hospital in Iran (1973-2003).

BACKGROUND: Bladder cancer is the ninth most common cancer worldwide, and it is the fourth most common cancer in males in Iran. The objective of this study was to collect, analyze, and discuss epidemiologic features of bladder cancer using data from our University hospital. METHODS: A review of medical records of 603 patients with histologically confirmed primary malignant bladder tumors who were then referred and treated at the Radiation-Oncology Department during a time period 1973-2003 was performed. The topography and the histology of cases were coded and classified according to the International Classification of Diseases for Oncology (ICD -O) and a frequency distribution of bladder tumors by age at diagnosis, gender, histology types, was calculated. For age and cancer, mean, standard deviation, and 95% confidence intervals were presented. T test and Chi-squared test with p<0.05 were used depending on the variable analyzed, using the SPSS statistical package. RESULTS: Of the total, 85.2% were males and 15.0% were females (P<0.0001). The mean age of diagnosis was not significantly different between the sexes and the frequency of bladder cancer increased with age in both cases. Overall, two thirds of cases were between 50-74 years of age. For those aged 49 years and below the male to female ratio were 3.6 while after this age the ratio rose to 6.1. The most common histological diagnosis in both sexes among patients was transitional cell carcinoma. CONCLUSION: The frequency distribution and histologic types of tumors were comparable with reported from other studies.

MR relaxivity measurement of iron oxide nano-particles for MR lymphography applications.

The aim of this study was to assess the T1, T2 and T2* relaxivity of Ultrasmall Super Paramagnetic Iron Oxide (USPIO) nano-particles in vitro and in vivo in rat models with magnetic resonance imaging at 1.5T. First, relaxation properties of USPIO nano-particles at different doses were measured using related SE and GRE MR imaging protocols. The relation between dose and relaxation were observed which is linear; Higher dose of the nano-particles means higher relaxivity. Based on this relation, an optimum protocol can be proposed for obtaining the best image contrast at each situation. Then detection ability of MRI protocols was studied for USPIO nano-particles with injection of the particles in the rat. The optimum MR protocols were used to observe the signal change of lymph nodes in rat.

An epidemiological analysis of cancer data in an Iranian hospital during the last three decades.

Cancer is the third leading cause of death in Iranian population. Descriptive epidemiology provides a better understanding of the etiology of cancer and the development strategies. The objective of this study was to collect analysis of data and discuss certain epidemiologic features of neoplasm using data from hospital. Records of 14,540 patients diagnosed for cancer during the time period 1973-2003, who were referred to the department of radiation oncology were studied. The tumors were coded and classified according to the International Classification of Diseases 10th revision and ICD-O. SPSS version 10 was used for statistical analysis. In this study the frequency distribution of cancer patients were computed by age of diagnosis, gender, and anatomical sites. There were 8,178 male patients (56%) and 6,365 females (44%) with a male female ratio of 1.29. Mean age was 44.5?21.6 with a median of 47 years. The mean age of diagnosis for females (43.8.?.19.7) was significantly lower than that of males (45.0?23.1) (P<0.05). The ten most frequent cancer sites among patients were breast (13.6%), brain &CNS (13.6%), skin(13.5%), haemapoitic system(9.7%), lymphoid (7.1%), esophagus (7.1%), colon & rectum (4%), male genital organs (1.3%), bladder (1.3%), lung (1.2%), and stomach (1%). These accounted for 81% of all cases. It was found that 41% of women's cancers were in the breast, female genital organs compared to 7.3%in male genital organs and breast. All tumors except the breast, female genital organs, thyroid, gallbladder and kidney cancers, were more frequent in males compared to women. The frequency of patients with cancers increased with age in both sexes. Overall 53% of cases were between 40-63 years of age. For those aged 54 and below the male to female ratio was 0.99, while after this age the ratio rose to 1.61. About 16.6% of tumors occurred in children aged 15 years or younger. More than four fifths (81%) of patients with cancer of haematopoeitic system were under age of 15 years. In conclusion, the results of this study present an important epidemiological understanding of patients with tumors. It emphasizes that gender plays an important role in the frequency of primary tumors, and how much the sex ratio varies with some types of tumors. We also noted that certain tumor types show a prediction for certain decades of life in our series.

Preconditioning of the rat random-pattern skin flap: modulation by opioids.

Opioid receptors have been implicated in protecting several organ systems from ischaemic events. The authors have studied the effects of opioid receptors on random-pattern skin flap survival. Sixty-nine male Sprague-Dawley rats were used. Bipedicled dorsal skin flaps (2 x 8 cm) were elevated at the midline. Different doses of morphine (0.01, 0.1, 1 and 5 mg/flap) were administered locally in the cranial half of the flap and systemically through intraperitoneal injections (5 and 10 mg/kg). In another experiment, 0.4 mg/flap of naloxone was injected followed by 5 mg/flap injection of morphine to determine whether the effect of morphine is receptor mediated. The role of the opioid receptors in the ischaemic preconditioning (IPC) phenomenon was investigated by administration of naloxone (0.4 mg/flap) 1 h before clamping the cranial pedicle for 20 min followed by 40 min of reperfusion. Appropriate control groups were included. The cranial pedicle was cut 2 h after saline or drug administration in all groups and flap survival area was evaluated on the seventh postoperative day. Local administration of morphine in higher doses (1 and 5 mg/flap) significantly reduced the amount of flap necrosis when compared to that of the control cohort (P < 0.05). Naloxone abolished this protective effect of morphine. Furthermore naloxone significantly decreased the anti-ischaemic effect of the IPC. Systemic administrations of morphine had no significant effect on flap survival area in compare with the control group.

Community-based outpatient practice of antibiotics use in Tehran.

OBJECTIVES: To study patterns of outpatient antibiotic use in the Great Tehran, in order to develop interventional strategies in rationalizing drug and especially antibiotic use. MATERIALS AND METHODS: Ten-percent random sample of all prescription belonging to practitioners in south of Tehran and kept in a data bank was sampled. Drug use indicators were determined in order to develop intervention program to promote rational drug use among practitioners in Tehran. Based on the values of drug use indicators, an interventional program, a program of continuing medical education (CME) targeting rational use of drugs, was designed. Eighty general practitioners (GPs) who contributed to the data bank were selected and allocated to two groups, intervention group and control group. Each group contained 40 GPs. Drug use indicators were measured in each group three times; before and in two intervals after the intervention. The indicators were compared before and after as well as between groups. RESULTS: The drug use indicators determined through the data bank showed that 19% of all prescribed drugs in data bank were antibiotics, which ranked second only after 'analgesics and CNS drugs' with 24%. The drug use indicators were improved in the intervention group (the average number of drugs per encounter lowered from 4.3 +/- 0.5 pre-intervention to 3.6 +/- 0.1 six months thereafter, p value = 0.001). The percentage of encounters with an antibiotic prescribed were lowered in intervention group compared with control group but the difference was not statistically significant. The intervention made a change to all other measured indicators but not all of them were statistically significant. CONCLUSIONS: Irrational use of antibiotics can improve by appropriate educational intervention, using CME programs.

Epidemiologic analysis of the Tehran Cancer Institute Data System Registry (TCIDSR).

OBJECTIVE: To review epidemiological data on thyroid cancer in Iran. METHODS: The Tehran Cancer Institute Data System Registry (TCIDSR) was used to identify patients with different histological types of thyroid cancer (TC) in Iran. Data were analysed from 438 thyroid cancer cases identified by the TCIDSR in 1998-99. Disease prevalence was calculated with reference to age, time and place. RESULTS: The TCIDSR recorded 438 primary malignancies of the thyroid gland: papillary, follicular, medullary, and anaplastic carcinomas accounted for 67.1%, 10.7%, 5.3% and 4.3% of cases, respectively. The remaining 12.6% were classified as OD (other diagnoses). The prevalence of TC was highest in ethnic Farsis. The age range of patients was 8-85 years. Mean patient age was 44.52+17.03 years (mean + SD) overall, 47.74+18.10 years in female patients and 43.04+16.34 years in male patients. Anaplastic (6.5% vs. 3.3%) and medullary (10.0% vs. 3.0%) cancers were more common in men than women. CONCLUSION: This study was undertaken to define the epidemiological aspects of thyroid carcinoma in Iran, an area of endemic iodine deficiency until fairly recently. Against expectation for an iodine-deficient area, the frequency distribution of tumours in our study was closer to that seen in iodine-rich areas. Additional research on the risk factors for thyroid cancer--genetic, ethnic, geographic and environmental--is needed to explain the high incidence of PTC overall, and among ethnic Farsis in particular, in Iran.

Production of monoclonal antibody, PR81, recognizing the tandem repeat region of MUC1 mucin.

A monoclonal antibody (MAb) was generated by immunizing BALB/c mice with homogenized breast cancerous tissues. This antibody (PR81) was found to be of IgG(1) class and subclass, containing kappa light chain. PR81 reacted with either the membrane extracts of several breast cancerous tissues or the cell surface of some MUC1 positive cell lines (MCF-7, BT-20 and T-47D) tested by enzyme immunoassay and for MCF-7 by immunofluorescence method. PR81 also reacted with two synthetic 27 and 16-amino acid peptides, TSA-P1-24 and A-P1-15, respectively, which included the core tandem repeat sequence of MUC1. However, this antibody did not react with a synthetic 14 amino acid peptide that has no similarity with tandem repeat found in MUC1. The generated antibody had good and similar affinities (2.19 x 10(8) M(-1)) toward TSA-P1-24 and A-P1-15, which are mainly shared in the hydrophilic sequence of PDTRPAP. Through Western blot analysis of homogenized breast tissues, PR81 recognized only a major band of 250 kDa. This band is stronger in malignant tissue than benign and normal tissues.