Tehran University Medical Journal

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Background: The aim of this study was to assess the role of consolidative intraperito-neal chemotherapy with carboplatin in decreasing relapse and increasing survival in advanced epithelial ovarian cancers, as well as evaluation of its toxicity. Methods: In this clinical trial 30 patients with epithelial ovarian cancer in stages II-IV who had complete surgery (optimal debulking surgery) received six standard cycles of intravenous carboplatin and paclitaxel. They were enrolled through non-random se-quential selection. The control patients were similar to case group in stage (II-IV) and pathology (epithelial ovarian cancer). The control group was evaluated retrospectively through hospital files. This clinical trial performed in Gynecology Oncology department in Tehran Valiasr University Hospital, during 2005-2010. They including 18 cases as the intervention group receiving intraperitoneal chemotherapy and 12 patients as the control group with only retrospective follow-up. The cases received 3 cycles of 400 mg/m2 intraperitoneal carboplatin every 21 days following intravenous chemotherapy. Relapse of disease was diagnosed as increasing or even doubling CA125 serum titer during one month, or any CA125 above 100 IU, or an abdominal or pelvic mass in ul-trasound or physical exam. Mean survival of two and five years, progression-free inter-val (PFI), overall survival (OS), relapse, demographic parameters, drug toxicities, path-ologic types of cancers in two groups were coded and compared using SPSS 14. Any P<0.05 was considered as a significant difference. Results: The mean ages of cases and controls were 52.4±8.6 and 55.1±11.5 years. The mean duration of relapse-free survival was 13±8.6 months for the cases and 9.5±4.3 months for the control patients (not statistically different, P>0.05). The mean overall survival for cases and controls were 39±16.5 and 30.8±16.2 months, respectively (no significant difference, P>0.05). The frequency of drug toxicities in the cases was 5.6%, and consisted of mild-to-moderate abdominal pain, nausea and vomiting. Conclusion: It seems that consolidation therapy with intraperitoneal carboplatin may not increase overall survival, reduce relapse rate or decrease mortality, though it does not induce considerable side effects. Since the mean survival in the intervention group was nine months more than controls, this difference may be clinically significant.

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Background: Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the rearranged during transfection (RET) proto-oncogene in MTC development have been well demonstrated. Several studies have been published that indicate the molecular analysis of RET gene may offer early identification of those patients at high risk to develop MTC and may provide the opportunity for early intervention. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. Methods: From 2004 to 2014, 358 participants were studied, including 213 patients (119 female, 94 male) and 145 their relatives (79 female, 66 male) in cellular and molecular research center of Shahid Beheshti Research Institute for Endocrine Sciences, Tehran, Iran. Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. The RET mutations and SNPs, sequences were analyzed. Results: According to DNA sequencing results, 189 individuals (119 patients, 70 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 35.02% in patients and 29.92% in their relatives. Conclusion: The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. This haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. Further analysis is needed to demonstrate the association between this haplotype and MTC development.

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Cancer/Testis antigens (CTAs) as a group of tumor antigens are the novel subjects for developing cancer vaccine and immunotherapy approaches. They aberrantly express in tumors with highest normal expression in testis, and limited or no expression in normal tissues. There are important similarities between the processes of germ-cell and cancer cell development Spermatogenesis begins at puberty when expression of novel cell-surface antigens occurs when the immune system has been refined the ability to distinguish self from non-self. Whereas macrophage and lymphocytes are commonly found within interstitial spaces of the testis, these antigen-presenting cells are rarely seen within the seminiferous tubules. These observations have led to the concept of the immune privileged site for testis. Localized normal expression of the CT genes in testis that makes them immunogenic for immune system, in one side, and their abnormal expression in different kinds of cancer cells, in the other side, has make them as promising target for developing cancer vaccines and new cancer therapeutics approaches. In malignancies, gene regulation is disrupted which results aberrant expression of CT antigen in a proportion of tumors of various types. For some CTAs, data support their fundamental role in tumorigenesis. Several authors believe it is not clear whether they have an essential role in tumorigenesis or they are by-products of chromatin variations in cancer. There is a growing list of CTAs within them advanced clinical trials are running by using some of them in cancers like lung cancer, malignant melanoma and neuroblastoma. In this review we discuss the gene TSGA10 as an example of CT genes. TSGA10 expresses in its highest levels in elongating spermatids and localized in the fibrous sheath of mature sperm. This gene is proposed as a serological biomarker in cutaneous lymphoma. Its abnormal expression has been reported in different cancers such as acute lymphoblastic leukemia, breast, brain, gastrointestinal and a range of other cancers either in mRNA or protein levels. It has an important role in angiogenesis in cancer tumors because of its effects in the gene hypoxia-inducible factor (HIF1). Absence or lack of TSGA10 expression has been reported in ascosporic infertile men.

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Background: Medullary thyroid cancer (MTC), includes 5-10% of all the thyroid cancers. RET proto-oncogene mutations have been found in association with MTC development. Therefore, identification of the mutations in RET can allow early diagnosis of the families who are at the risk of the disease. The goal of this study was to investigate existence and association between mutations in exon 19 of the RET proto-oncogene in an Iranian population medullary thyroid cancer patients and their family members. Methods: This study was run in the research laboratory of Research Institute for Endocrine Research Center Shahid Beheshti University of Medical Sciences from May, 2013 to May, 2014. In this study, 110 patients with confirmed medullary thyroid carcinoma were selected and examined. At first, the genomic DNA content of the peripheral white blood cells (WBC) of the samples were extracted using a saturated salting out and proteinase K standard method. Exon 19 of the RET proto-oncogene using polymerase chain reaction (PCR) method was amplified. Then the desired PCR products formation was confirmed by electrophoresis technique for true amplification, and finally the amplified samples were used for direct sequenced for finding and assessing any possible mutations Results: In this study, two nucleotide changes at position rs2075912 (Y: T/C) and position rs2075913 (W: T/A) exon 19 RET proto-oncogene were found in the patients with medullary thyroid cancer. The frequency of both nucleotide changes were higher in men than women with medullary thyroid cancer. The frequency of the rs2075912 and rs2075913 were 11.2 and 6.3% higher in men than women. But in statistical analysis, there was no association between age, sex and the founded two mutations. Conclusion: In addition to mutations in other exons of proto-RET, mutations in exon 19 can also be used for early detection and confirmation of medullary thyroid carcinomas.

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Background: Endometrial carcinoma is considered the most common gynecological cancer in the world. Pelvic and para-aortic lymphadenectomy is widely advised based on FIGO staging system. The purpose of this study was to determine whether the biomarker human epididymis protein 4(HE4) correlates with depth of myometrial invasion, histologic grade and metastases in patients with endometrioid adenocarcinoma of the uterus. Methods: This was a cross-sectional study in women with biopsy-proven endometrioid adenocarcinoma in the gynecological ward of Vali-e-Asr Hospital from October 2012 to October 2014. The concentrations of HE4 and CA125 were assessed before surgery and all surgical specimens were reviewed by dedicated gynecologic pathologists. The results were compared with the final histopathology report. Results: A total of 80 patients were initially entered in this study. Twelve patients were excluded because they didn’t have tumor marker. Most of patients (76%) was in stage I disease. Levels of serum HE4 greater than 140 PM and CA125 greater than 35 kU/L observed in 12(17%) and 26(38.2%) of patients, respectively. Of the 52 patients with satge I, 14(26.9%) had CA125&ge35 KU/L, compared with 6(66.7%) of the 9 patients with stage II and 6(85.7%) of the 7 patients with stage III (P<0.002). A significant increase in serum CA125 level was noted in patients with grade III tumors, deep myometrial invasion, cervical stromal involvement and nodal metastasis (P<0.001, P<0.0001, P<0.006, P<0.002). Among the group of patients with early stage disease a significant increase in serum CA125 was noted in patients with deep myometrial invasion. Five out of 52 patients (9.6%) in stage I had HE4 level&ge140 PM, compared with 3 patients (33.3%) with stage II and 4 patients (57.1%) with stage III disease (P<0.003). A significant increase in serum HE4 level was noted in patients with grade III tumors, deep myometrial invasion, cervical stromal involvement and nodal metastasis (P<0.035, P<0.001, P<0.012, P<0.007). Conclusion: Human epididymis protein 4 (HE4) and CA125 may be a useful markers preoperatively in the clinical decision making for determining the need for lymph node dissection in women with endometrial cancer.

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Primary ovarian insufficiency (POI), commonly referred to premature ovarian failure, is defined as ovarian failure before the age of 40 years. It is the loss of ovarian function caused by a process directly affecting ovaries. Cancer therapy which includes surgery, radiotherapy, and chemotherapy influence ovarian function, leading to premature menopause and loss of fertility. POI is idiopathic in most cases (74-90%). The known causes, in addition to anticancer treatment, are other processes like chromosomal abnormalities, autoimmunity, and natural aging can result in secondary ovarian failure, which is detected by an increase in serum gonadotropin levels (FSH and LH). There are evident risks of POI in women treated for cancer. Those who receive anticancer treatments have an increased risk of developing POI. There by, anticancer drugs and radiation therapy are considered as the most common toxins of ovaries. Although cancer incidence rates in women less than 50 years old continue to increase during recent years, mortality rates are dramatically decreasing due to modern advances in treatment. Increasing numbers of survivors are now confronted with the long-term consequences of exposure to these treatments. The pool of primordial follicles in the ovary is fixed and any injury to the ovary can potentially reduce this ovarian reserve, effectively advancing the patient’s reproductive age, thus narrowing the window of reproductive opportunity. Ovarian failure occurs in a significant percentage of childhood cancer survivors and many of them will seek care for reproductive dysfunction. Nevertheless, Embryo cryopreservation, oocyte cryopreservation, ovary tissue cryopreservation, ovarian suppression and oophoro-pexy are some options to preserve fertility in these groups. As a result, having foreknowledge of potential treatment related ovarian failure will allow the physician to give a better counsel to patients and their family regarding the importance and timing of fertility preservation by giving an estimated window of fertility. The objectives of the current review are to report on the etiology of POF induced through cancer therapy.

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Background: Metformin has been suggested as anti-cancer in retrospective studies. We design a prospective controlled study about metformin efficacy in the window time between biopsy and definite surgery with changes of Ki-67 as the primary endpoint.

Methods: The primary cohort had composed of 50 pathologically diagnosed invasive breast cancers, accrued in Medical Oncology Department of Iran Cancer Institute from February to November 2014. Patients neither had indication of neoadjuvant chemotherapy, nor involved with diabetes mellitus. They followed during the time period of biopsy and definitive surgery with taking tests on pathology specimens for ER, PgR, HER-2/neu and Ki-67 index. We checked fasting insulin and glucose level as well as quality of life and adverse effects in both times in the intervention group. Metformin (1500 mg/day) was prescribed to intervention group from pathology report to the night before surgery.

Results: From 45 patients, 25 had been received metformin for median time of 2.8 weeks. Controlled group included 20 patients who followed in the window time. There were no statistically significant differences between two groups regarding baseline clinical and tumor characteristics such as age, stage, grade, ER, PgR, HER2 status, time and type of surgery. However, immunohistochemistry study showed decrease of median Ki-67 from 35.14 to 29.6% in the intervention group and increase from 24.5 to 30.6 in the control group. Both of these results were statistically significant. Patients tolerated metformin very well, but mild gastrointestinal symptoms were seen in 30% of cases. There was a correlation between metabolic factor of HOMA score (fasting insulin level fasting blood sugar/405) and changes in Ki-67.

Conclusion: In the present study metformin prescription in the short period of time between Biopsy and definite surgery had shown inhibition of breast cancer cell growth. We found relationship between metformin anti-proliferative effect and glucose and insulin metabolism. To find direct apoptotic stimulation of metformin and long-term results of this drug further studies in the adjuvant settings with cooperation of pharmacokinetic groups are recommended.

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Background: Breast cancer is one of the most prevalent cancers among women and features increasing trends of incidence rates. Worldwide, yearly about 1.67 million of new cases and 522,000 of deaths from breast cancer are registered. The aim of this study was to determine the risk factors of breast cancer in women and to identify high risk groups.

Methods: In a case-control study, 170 women with breast cancer who were registered in cancer registration system from 2011 to 2015 at Dezful City, Iran, were compared with 170 healthy women with confirmation of mammography. After age matching of groups, the needed information about risk factors and demographic information including information, educational level, marital status, family history of breast cancer, age at menarche, parity, oral contraceptive use, age at first pregnancy, menopausal status, and age at menopause, breastfeeding, stress, abortion, alcohol use and smoking, hormone therapy and physical activity was collected by a questionnaire. The analysis of collected data was performed by using odds ratio and logistic regression model and SPSS software, version 16 (SPSS, Inc., Chicago, IL, USA). The statistical significance was set at a two-sided p-value of %5.

Results: The results of this study showed that, women with the family history [OR: 6.78 (95% CI: 2.15-21.41)] and women with the stress history [OR: 4.86 (95% CI: 2.46-9.59)] had higher risk of breast canser, while women with the history of having physical activity at least once a week [OR: 0.29 (95% CI: 0.13-0.65)] and women with the history breast feeding for 3 to 4 years [OR: 0.36 (95% CI: 0.16-0.81)] had lower risk of breast cancer.

Conclusion: It is recommended that the mentioned risk factors and protective factors be considered in first and second level (screening) of preventive programs.

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Background: Cervical cancer is known to be preventable because of long period of pre-invasive stage, availability of screening tools, and effective treatments for early invasive cervical lesions. Screening is main measures to prevent the disease and Pap smear is a screening strategy for cervical cancer. Current paper aimed to evaluate levels of awareness and practice regarding Pap smear screening among women aged between 20 to 65 years in Tehran (Iran). Methods: This was a descriptive-analytical study conducted in Tehran City of Iran in 2015 at Firoozgar Hospital. The research population included all married, widowed and divorced women aged 20-65 years. Data analysis was performed using the Pearson correlation and Student’s t-tests in SPSS, ver. 23 (Chicago, IL, USA). Results: Among 90 individuals who have fill questionnaire completely, 66.6% subjects had Pap smear tests. 40% of the individuals aged between 30 to 39 and the education level is distributed equally between Intermediate, Diploma and graduate and only 3 percent of them, continue their education to higher level. There was a significant relationship between the awareness of Pap smear and educational level (of both wives and husbands). The people who have graduate degree, have the best awareness. Working women revealed higher level of awareness about Pap smear. Shame and fear of taking the cancer were the most common reasons which lead to avoidance in doing the test by the women, while the most encouraging factors for performing the test were the information mostly provided by physicians and after that, the information provided by friends. Conclusion: The awareness of Pap smear test which was measured by weighting different questions in the questionnaire by experts, prove that the women aged above 39, have an average level of awareness of Pap smear test. Due to high prevalence of cervical cancer and prolonged pre invasive course, role of Pap smear for early diagnosis necessitate the use of proper and inexpensive instructional methods to increase awareness in women about cervical cancer and preventive strategies.

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Background: Human papilloma virus (HPV) is one of the most important factors in cervical cancer. Viral sequences are integrated into the host cell genome. In mild cases the virus causes skin damages, in severe cases it leads to cancer. Like many other cancers, telomerase gene expression was increased in cervical cancer. This enzyme is a reverse transcriptase that contains two common subunits: i) catalytic protein called human telomerase reverse transcriptase (hTERT) and, ii) RNA sequence called hTR. hTERT expression is hardly found in any somatic tissues. Detection of high telomerase activity in human cells, lead to tumor genesis. So hTERT can be used as a diagnostic tool in cancer detection.

Methods: This experimental study was carried out from May 2013 to April 2014 in Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences in Tehran, Iran. Caski and Hela cancer cell lines were used which contain HPV16 and HPV18 respectively. Cell lines were cultured and total RNA was extracted. Following normalization agent glyceraldehyde-3-phosphate dehydrogenase (GADPH), hTERT expression level was determining by real-time PCR method. For each sample, the expression level of hTERT and GAPDH were quantified as copy numbers (per reaction) using the standard curve. Finally, hTERT levels in Hela and Caski cell lines were compared quantitatively by t-test using GraphPad statistic software version 5 (San Diego, CA, USA).

Results: According to the charts real-time PCR, hTERT gene expression in Hela and Caski cancer cell lines is significantly different (t=0.0319).

Conclusion: All results confirm that hTERT expression levels in Hela and Caski cell lines are significantly different and the level of hTERT expression in the Caski cell line was slightly higher than that of Hela cell line. The significant difference between hTERT mRNA expression levels reported here could be used as a tumor marker for HPV16 and HPV18 in cervical cancer.

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Background: Cancer is the most common cause of death in the world, and it incidence has been increasing for many years in economically developed countries. Early detection of cancers greatly increases the chances for successful treatment. So finding cancers before they start to cause symptoms is a most effective treatment. Recent studies have proposed that blood plasma contains a rich source of disease biomarkers for detecting, diagnosing and monitoring diseases. While some researchers have dismissed the low molecular weight serum peptidome as biological trash, recent work using differential scanning calorimetry has indicated that the peptidome may reflect biological event and contain diagnostic biomarkers.

Methods: Differential scanning calorimetry (DSC), a highly sensitive tool for analysis of blood plasma and other biofluids has recently been reported. Louisville Bioscience, Inc. (LBIdx™), The Plasma Thermogram™ (pT™) company has made a significant breakthrough in the analysis of blood plasma using differential scanning calorimetry for clinical monitoring and diagnostic applications.

Results: DSC analysis of plasma from diseased individuals revealed significant changes in the thermogram which are suggested to result not from changes in the concentration of the major plasma proteins but from interactions of small molecules or peptides with these proteins. The difference in plasma thermograms between healthy and disease individuals caused this method was recognized as a novel technique for disease diagnosis and monitoring.

Conclusion: Measurement of plasma proteins is a powerful clinical is standard medical practice which hope revolutionizes strategies for early cancer detection.

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Breast cancer is the most common cancer in women and one of the leading of death among them. The high and increasing incidence of the disease and its difficult treatment specifically in advanced stages, imposes hard situations for different countries’ health systems. Body temperature is a natural criteria for the diagnosis of diseases. In recent decades extensive research has been conducted to increase the use of thermal cameras and obtain a close relationship between heat and temperature of the skin's physiology. Thermal imaging (thermography) applies infrared method which is fast, non-invasive, non-contact and flexibile to monitor the temperature of the human body. This paper investigates highly diversified studies implemented before and after the year 2000. And it emphasizes mostly on the newely published articles including: performance and evaluation of thermal imaging, the various aspects of imaging as well as The available technology in this field and its disadvantages in the diagnosis of breast cancer. Thermal imaging has been adopted by researchers in the fields of medicine and biomedical engineering for the diagnosis of breast cancer. With the advent of modern infrared cameras, data acquisition and processing techniques, it is now possible to have real time high resolution thermographic images, which is likely to surge further research in this field.  Thermography does not provide information on the structures of the breast morphology, but it provides performance information of temperature and breast tissue vessels. It is assumed that the functional changes occured before the start of the structural changes which is the result of disease or cancer. These days, thermal imaging method has not been established as an applicative method for screening or diagnosing purposes in academic centers. But there are different centers that adopt this method for the diognosis and examining purposes. Thermal imaging is an effective method which is highly facilitative for breast cancer screening (due to the low cost and without harms), also, its impact will increase by combining other methods such as a mammogram and sonography. However, it has not been widely recognizesd as an accepted method for determineing the types of tumors (benign and malignant) and diseases of breast tissue.

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Background: Cervical cancer is the third most common gynecologic cancer in women worldwide. Cervical cancer has lower incidence and mortality rates than uterine corpus and ovarian cancer, as well as many other cancer sites. Unfortunately, in countries that do not have access to cervical cancer screening and prevention programs, cervical cancer remains the second most common type of cancer. Staging of the disease is made clinically. The aim of this study was to evaluate the role of magnetic resonance imaging (MRI) for diagnosing the invasion of cancer to organs and staging of cervical cancer and the relationship between clinical and pathological findings and the sensitivity and specificity of the assay in cervical cancer.

Methods: The study included records of 40 patients with cervical cancer that undergo surgery or Chemoradiation in Firoozgar University Hospital. In this study that made retrospectively, non-randomized, the MRI reports and clinical findings records and pathology results was discussed. The sensitivity and specificity of MRI for diagnosing the invasion to parameters, bladder, rectum, vagina, pelvic wall and it’s accuracy to determine tumor stage has been set.

Results: A total of 40 patients with pathology information of cervical cancer was retrospectively reviewed in the study. The patients were 28-83 years old by mean age of 49.3 Pathology of cervical cancer in 80% of cases was SCC, 15% adenocarcinoma and 5% melanoma. The sensitivity and specificity of MRI for diagnosing invasion of parameter was 76% and 88%. The sensitivity of MRI in the detection of bladder invasion was 100% and specificity of 100%. The sensitivity of MRI in the diagnosis of rectal invasion was 50% and specificity of 100%. The sensitivity of MRI in the diagnosis of pelvic wall invasion was 100% and specificity of 86%. Sensitivity in detecting invasion into the upper third of the vagina was 100%.

Conclusion: Overall, this study showed a good sensitivity and specificity for detecting invasion into the bladder, vagina, pelvic wall and parameters and good specificity for the diagnosis of rectal invasion and acceptable accuracy at 67.5% for detection of tumor stage by MRI show.

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Background: Kirsten rat sarcoma (KRAS) gene is a target of genetic alterations which are diagnostic and prognostic biomarkers in patients with metastatic colorectal cancer who are treated with monoclonal anti-EGFR antibodies such as cetuximab and panitumumab. KRAS mutations are seen in 35-42% of patients with colorectal cancer. The high frequency of these mutations in colorectal cancer represents their high potential as a biomarker in early diagnosis of cancer. This study was done to evaluate the frequency of KRAS gene mutations in a small population of Iranian patients suffering from colorectal cancer.  

Methods: 50 formalin-fixed paraffin-embedded tissue blocks with colorectal cancer (CRC), already confirmed by histopathology and immunohistochemistry testing, were received to Payvand Clinical and Specialty Laboratory, Tehran, from across the country in 2015. DNA was extracted from the tissue blocks and its quality was then evaluated. The reverse dot blotting method was used to evaluate KRAS gene mutations.

Results: KRAS mutations were found in 42% of the study patients. 30% and 12% of the mutations were found in codon 12 and codon 13, respectively. Moreover, no mutation was found in codon 61. Results also showed that the most frequency of samples examined belonged to male with 68% (average age of 56 years old) and then to female with 32% (median age of 54.8 years old).

Conclusion: This study was performed to evaluate the frequency of KRAS gene mutations in Iranian colorectal cancer patients. According to the study results, the frequency of KRAS mutations was consistent with that of other countries, reported in previous studies. The high prevalence of these mutations in patients with colorectal cancer indicates the important role of these genes in this group of patients. Thus, the presence of these mutations can be used as a suitable biomarker for evaluation of response to targeted therapies in patients suffering from colorectal cancer.

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Stable molecular changes during cell division without any change in the sequence of DNA molecules is known as epigenetic. Molecular mechanisms involved in this process, including histone modifications, methylation of DNA, protein complex and RNA antisense. Cancer genome changes happen through a combination of DNA hypermethylation, long-term epigenetic silencing with heterozygosis loss and genomic regions loss. Different combinations of N-terminal’s changes cooperate with histone variants with a specific role in gene regulation. It have led to load a setting histone that determine transcription potential of a particular gene or genomic regions. DNA methylation analysis in genome region using methylation-specific digital karyotyping of normal breast tissue detect gene expression patterns and DNA specific methylation can be found in breast carcinoma too more than 100 genes in breast tumors or cell lines of breast cancer are reported hypermethylated. Important of DNA methylation on cancer has been concentrated CpG islands hypermethylation. Most of the techniques are able to identify hypermethylated areas. Often, methylated genes play important role in cell cycle regulation, apoptosis, metastasis and tissue invasion, angiogenesis and hormonal signaling. Cyclin D2 (CCND2) gene is an important regulator of cell cycle and increased of expression inhibits the transition from G1 to S cell cycle. This gene is frequently methylated in breast cancer and has been proposed as the first event. Other cell cycle regulator is p16ink4A / CDKN2A that methylated in a large number of human cancers, including breast cancer. Another regulator of the proliferation of breast cancer that methylated is tumor suppressor RAR-β cancer that has been found in lobular and ductal carcinoma. Recent studies have showed the role of epigenetic silencing in the pathogenesis of breast cancer in which tumor suppressor genes have been changed by acetylation and DNA deacetylation. Histone deacetylase inhibitors have different roles in cancer cells and could show the ways of new treatment for breast cancer. In this review, various aspects of breast cancer epigenetics and its applications in diagnosis, prediction and treatment are described.

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Breast cancer that is caused by the accumulation of genetic and epigenetic alterations, is one of the main causes of death resulted from cancer. Various therapeutic approaches have been introduced for this cancer and the traditional diagnosis and treatment is based on the prognosis estimation using cancer anatomic features (TNM system) and clinical results, but studies show different responses of these treatments and recurrence after those in some patients. This diversity is resulted by the differences in biological and molecular characteristics. So genomic and molecular studies became more important and the role of targeted treatment based on an individual's genome was highlighted. Today, the progression in personalized medicine using specific individual genome profile has been possible. The ultimate goal of such studies, in the setting of the personalized medicine, is providing markers which can be used to risk assessment of progressing disease. This new science cause great development in the treatment of breast cancer by recognition of specific markers and application of targeted therapy. Trastuzumab and tamoxifen are the most common monoclonal antibodies applied in these patients depends on their biological and molecular profile. The good response to tamoxifen is seen only in patients with estrogen receptor (ER+) which inhibits the binding of estrogen to its receptor. Defect in the metabolizer enzyme of tamoxifen (CYP2D6), which convert it to the active forms, results in the increased risk of recurrence after treatment. Fulvestrant is another monoclonal antibody which its effect is similar to tamoxifen. Trastuzumab suppresses the cell growth by binding inhibition of epidermal growth factor to HER2 receptors. In the metastatic form of disease, the patients may show resistance to trastuzumab, so lapatinib is suitable alternative in these cases. Pertuzumab combination with trastuzumab and chemotherapy with taxane blocks the dimerization of HER2 with another form of HER receptors. The application of personalized medicine in triple negative phenotype is limited due to the lack of appropriate targets and biomarkers, it makes necessary to do further studies. The aim of this review was to describing the different aspects of personalized medicine and introducing the most important biomarkers and targets in the treatment of breast cancer.

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Background: Breast cancer is a malignant proliferation of epithelial cells that lining the ducts or lobules of the breast. It is the second common cancer, after lung cancer in women. Since growth inhibition is an important strategy in cancer treatment, many attempts are in program to find new apoptotic inducer agents. Today there is some reports about effect of metabolites of Pseudomonas on cancer cells, hence, metabolites of Pseudomonas sp. UW4, were isolated and anti-cancer and anti-microbial activity of these metabolites was studied. Methods: This experimental study was performed in cellular and developmental biology of Shahrekord Islamic Azad University from April 2015 to August 2015. Anti-microbial activity of metabolites of Pseudomonas sp. UW4 was tested against a pathogenic bacteria, including Escherichia coli, Bacillus cereus and Staphylococcus aureus. For anti-cancer activity, in this study SKBR3 cells and normal fibroblast cells (HU-02) were cultured in DMEM medium with 10% fetal bovine serum (FBS). The cells were treated by various concentrations of these metabolites 5, 10, 15 and 20 mg/ml for 24, 48 and 72 h. Cell viability was assessed by MTS assay. Cells were seeded at 5×103 cells/ml in 96 well plates and incubated for 24 hr. Then metabolites of bacteria were added, after indicated times MTS (20 µl) was added and the absorbance was measured at 492 nm using ELISA plate reader. Results: Pseudomonas sp. UW4 was able to produce antimicrobial metabolites against Staphylococcus aureus. Metabolites decreases the viability of SKBR3 cell line in a time and dose dependent manner, so that the most effective concentration of this substance was 20 mg/ml and 72 h after treatment (P< 0.01). While Pseudomonas sp. UW4 in various concentrations had no significant effect on normal fibroblast cells (P= 0.24). Conclusion: Bioactive compounds produced by of Pseudomonas sp. UW4 could be used for elimination of infections and treatment of breast cancer SK-BR3.

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Background: Members of the tumor necrosis factor (TNF) superfamily of ligands and their receptors (TNFR) are critical regulators of the adaptive immune system. A proliferation inducing ligand (APRIL) is a member of tumor necrosis factor superfamily. APRIL was identified via database mining in 1998 by Hahne, et al. APRIL allows tumor cells to proliferate at a reasonable rate even in low serum. APRIL is abundantly expressed in many tumor cells and tumor tissues. Increasing level of APRIL expression related to replacement of -Arg-Lys-Arg-Arg- motif by -Ala-Lys-Arg-Ala- between amino acids 101-104 and thus abrogated APRIL processing. Previous studies have shown a correlation between APRIL expression with some autoimmune disease, breast cancer, stomach cancer, esophagus cancer and colorectal cancer. Herein, we explore correlation between serum APRIL with pancreatic cancer. Methods: Our study is performed in digestive disease research institute (DDRI) of the Shariati Hospital in Tehran City and affiliated Hospital of Tehran University of Medical Sciences. In this study, concentrations of serum APRIL in sera (30 pancreatic cancer patients and 30 healthy controls) from November 2011 to November 2013 collected and level of a proliferation inducing ligand measured by ELISA technique. In this study used from SPSS software, version 22 (IBM SPSS, Armonk, NY, USA) to perform statistical data analysis. Results: The case group measurement results compared with control groups results according to some characteristics such as age, smoking and, diabetes. ELISA analysis of APRIL measurements show that mean serum APRIL level of pancreatic cancer patients (7 ng/ml) was significantly higher than control group (5 ng/ml). The p-value of this study was 0.003. Conclusion: Our results indicate that serum APRIL, as a potential biomarker, has a positive diagnosis and prognosis value for pancreatic cancer.

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Background: Surgical staging is the standard treatment of ovarian cancer. Pelvic and para-aortic lymphadenectomy is the important part of the surgery. The aim of this study was to evaluate the effect of para aortic lymph node dissection in early stage of patients with ovarian cancer. Methods: This descriptive cross-sectional cohort study was performed on all stage I of ovarian cancer patients admitted in department of gynecology oncology of Ghaem Hospital, Mashhad University of Medical Sciences in November 2012 to March 2014. Every patient with clinical early stage of ovarian cancer candidate to surgical treatment selected. All cases underwent surgical staging surgery with concurrent systematic pelvic and para-aortic lymphadenectomy. In laparotomy after identification of left and right iliac artery, all lymph nodes have been properly exposed and dissected as a part of a staging laparotomy. The dissection was continued up to the nodal tissues surrounding the aorta, and inferior vena cava, until inferior mesenteric artery lymphadenectomy level. The procedure performed only by gynecologist oncologist. In addition, we assessed other parameters such as operation time, estimated blood loss, associated mortality and morbidity and vascular injuries. Finally, the effect of para aortic lymph node dissection in early stage of ovarian cancer evaluated. Results: Among a total of 57 ovarian cancer patients, 27 of them apparent stage I disease cases were selected. Surgical staging surgery with concurrent systematic pelvic and para-aortic lymphadenectomy was carried for all of them. Positive para-aortic lymph node was found only in one case. The average number removed para-aortic lymph nodes in the pelvis was 9 and in para aortic was 7, respectively. In addition, 20 minutes increase in total length of operation time was observed duo to para-aortic lymphadenectomy. Also the rate increase in intra-abdominal hemorrhage rate was estimated 60 ml. Conclusion: Lymph node dissection will produce a significant benefit in accurate and complete surgical staging. Staging surgery in addition to systematic pelvic and para aortic lymph adenoctomy in early stage ovarian cancer is preferred in gynecologic oncology centers.

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Background: Researchers are always trying to find specific markers which express specifically in cancer. These specific markers help to diagnose and treat cancer without affecting normal tissues. Cancer-testis antigens are among the new promising biomarkers, especially for targeted therapy. These markers are specially expressed in testis. Various studies have been reported individual expression of these proteins in some tumor tissues. Since testis is an immune privilege organ, abnormal expression of the above mentioned genes raises immune response and the serum antibody against them (CT antigene) can be detected as a marker of cancer. However, understanding their differential role in normal and cancer tissues may introduce them as new candidates of cancer biomarkers. The aim of this study was to evaluate AKAP3 gene expression in breast cancer and its correlation with clinicopathologic features of the disease.

Methods: This study is a case-control study conducted at the Brest Cancer Research Center (BCRC)- Iran, between October 2014 to May 2016. AKAP3 gene expression was investigated with real-time PCR in breast samples including: 74 tumors, 73 normal adjacents and 15 normal tissues. On the other hand the correlation between gene expression, clinicopathologic features of the tumors and treatment regimen were evaluated.

Results: Statistical analysis showed a significant correlation between lack of AKAP3 expression, tumor size (P=0.01) and stage (P=0.04). The association between poor prognosis and the absence of AKAP3 expression in normal adjacent tissues were observed. Kaplan Meier plot showed a significant better disease free survival in the normal adjacent patients group that are expressed AKAP3.

Conclusion: It was observed that the better free survival in the normal adjacent group is because of the different AKAP3 expression, not treatment variations between two patient groups. As a result, AKAP3 can be a suitable candidate biomarker for breast cancer patients. Also, the study of gene expression in normal tissue of patients may be used to predict response to therapy.