Journal of B.U.ON.: official journal of the Balkan Union of Oncology

Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. This was a retrospective analysis of 78 postmenopausal stage I/II SR(+)BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN(-) status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN(+) BC subgroup and 24/25 (96%) of PTEN(-) subgroup (x(2), p=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN(-) had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN(+) BC patients. Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR(+) BC patients treated with adjuvant tamoxifen.
To prospectively and intraindividually compare breast magnetic resonance imaging (MRI) at 1.5 Tesla (T) and 3.0T. A prospective intraindividual Ethics Committee- approved study was performed in 31 women (average age 58.6±12.3 years), with 114 lesions (9 benign, 105 breast cancers; 24 patients with unilateral and 7 with bilateral cancers). Axial bilateral breast high-spatial resolution contrast-enhanced dynamic MRI was performed at 1.5T using 3 dimensional (3D) dynamic gradient-echo sequences in all patients (spatial resolution 1.1×0.7×2 mm; temporal resolution 41 sec per dynamic acquisition), and after 24-48 h at 3.0T (0.6×0.6×1.7 mm; temporal resolution 65 and 72 sec per dynamic acquisition). Contrast enhancement ratio, number and features of enhancing lesions, image quality and reliability were compared by two radiologists independently. 102 cancer lesions were detected at 1.5T and 105 cancer lesions were detected in 31 patients at 3.0T. One cancer lesion was observed at 1.5T which was missed at 3.0T, and 3 cancer lesions and one high-risk lesion (LCIS) were detected at 3.0T while missed at 1.5T. Enhancement rates were significantly higher at 1.5T (224.5±100.2) compared to 3.0T (133.7±38.3). Better image quality was observed at 3.0T. Interobserver reliability was higher at 3.0T (p= 0.684) compared to 1.5T (p= 0.351). Detection of breast cancer shows a trend of better performance at 3.0T than at 1.5T.
The purpose of this study was to analyse the polypeptide patterns of colorectal adenocarcinomas and mirror biopsies and to investigate the expression of calreticulin and the relationship of this chaperon to colon cancer. The investigation was carried out on 21 adenocarcinomas and 21 mirror biopsies using high-resolution two-dimensional (2D) electrophoresis and immunohistochemical PAP method. 2D electrophoresis revealed several polypeptide patterns that were shown to be upregulated in colorectal adenocarcinomas compared to their mirror biopsies. One polypeptide spot being upregulated in colorectal adenocarcinoma, turned out to be calreticulin. The overexpression of calreticulin was confirmed by further examination in immunohistochemical level. Calreticulin was found overexpressed in colon cancer tissues as compared to the corresponding mirror biopsy tissues. The overexpression was particularly intense to high-malignancy tissues and particularly in the poorly differentiated regions of the tissue. Calreticulin showed a direct relationship to the disease stage, a fact strongly indicating that the functional role of calreticulin is directly associated with tumor growth and metastasis.
Purpose: To explore the feasibility and short-term effect of laparoscopy-assisted D2 radical gastrectomy for advanced gastric cancer. Methods: A total of 239 patients with advanced gastric cancer underwent D2 radical gastrectomy between March 2009 and June 2011, from which 106 patients underwent laparoscopic surgery (laparoscopy group) and 133 patients underwent open surgery (open surgery group). The intraoperative and postoperative condition, number of lymph node removed, complications and mortality rates between the two groups were compared. Results: The operation time (268±51 min) and the number of lymph node removed (29.1+6.1) in the laparoscopy group were comparable with the operation time (268±49 min) and the number of lymph node removed (30.2±7.0) in the open surgery group, while there were significant differences in the intraoperative bleeding (134±66 vs 289±139 ml), intraoperative blood infusion cases (5 vs 19), time to first postoperative flatus (3.4±0.9 vs 5.0±1.4 days), time to first taking liquid food (7.3±1.3 vs 8.1±1.4 days) and postoperative hospital stay (12.8±2.6 vs 14.5±3.1 days) between the two groups (p<0.05). These results favored the laparoscopy group. The incidence of postoperative complications in the laparoscopy and open surgery group were 14.1 and 24.8, respectively (p<0.05). Compared with the open surgery, the laparoscopic surgery significantly reduced the incidence of pulmonary infection (p<0.05). There was no significant difference in the postoperative short-term survival rate between the two groups (p>0.05). Conclusion: Laparoscopy-assisted D2 gastrectomy for advanced gastric cancer is advantageous in terms of safety and feasibility, rapid postoperative recovery and few complications. Both groups gave comparable results in terms of lymph node dissection and short-term survival.
A 71-year-old male was diagnosed with a non-small cell lung cancer (NSCLC) within the radiotherapy field that was used for the treatment of a small cell lung cancer (SCLC) 11 years ago. At the initial diagnosis in 1996 the patient had limited-stage SCLC located in the right upper lobe of the lung with mediastinal involvement. He received 4 cycles of chemotherapy and then mediastinal radiotherapy. With a complete response after chemoradiotherapy he was given prophylactic cranial radiotherapy. After 11 years of disease-free period a new mass in left lower lobe of the lung was detected. Bronchoscopic biopsy showed second lung cancer with epidermoid histology. Although the incidence of a second lung cancer is higher in SCLC survivors, this is a unique case in the literature with second NSCLC developing in the previously irradiated side of limited-stage SCLC.
This phase II pilot study was conducted to evaluate the results of a three-modality approach (which included post-chemoradiotherapy surgery) in advanced-stage cervical carcinomas. Thirty-six patients underwent either surgery or were put on follow-up after having received radical cervical radiotherapy (RT) combined with radiosensitizing chemoimmunotherapy with irinotecan (CPT-11), interferon (IFN) A2b, and amifostine. The last selection (surgery or follow-up) was based on clinical evaluation (downstaged or not). Feasibility, morbidity, surgical outcome and survival were evaluated. Twenty-six patients had stage IIb and 10 IIIb disease at diagnosis. Sixteen (44%) were clinically downstaged, thus becoming eligible for surgery. Twelve (33%) were operated and the others were put on follow-up. There was no significant increase in treatment-related morbidity of the group of patients receiving three-modality therapy, since only one intraoperative complication had occurred. In 58% of the operated patients, chemoradiotherapy-resistant tumor was found on pathology of the cervical specimens, while 29% of them had lymph nodes infiltrated by the tumor. After a median follow-up of 42.5 months, overall survival (OS) of operated vs. non-operated patients (88 vs. 56%, respectively) show only a trend toward significance (p=0.10). The overall recurrence/metastasis rate was 36.1% and the disease-free survival (DFS) 56% for operated vs. 76% for non-operated patients, respectively (p=0.63). These results indicate that post-chemoradiotherapy surgery is justified because of the high rate of residual disease found. Morbidity can be effectively limited with proper patient selection. A considerable survival benefit is expected, although this remains to be confirmed with phase III studies.
Detection of CHEK2 1100delC mutation by allele specific PCR DNA ladder (O'GeneRuler TM Fermentas): column 1; heterozygote 1100delC: control sample (columns 2 and 3) -amplification products of both mutated and wild-type alleles. Homozygote wild-type samples: sample 1 (columns 4 and 5), sample 2 (columns 6 and 7), sample 3 (columns 8 and 9) – amplification of product only in tube which contains primers specific for wild-type allele.  
Detection of CHEK2 Del5395 mutation by multiplex allele specific PCR DNA Ladder (O'GeneRuler TM Fermentas): column 1; heterozygote Del5395: control sample (columns 2 and 3) -beside two bands (379bp and 522bp) corresponding to wild-type allele, additional band of 450bp was amplified from mutated allele. Homozygote wild-type samples: sample 1 (columns 4 and 5), sample 2 (columns 6 and 7), sample 3 (columns 8 and 9) -only two amplified bands from wild-type alleles (379bp and 522bp) without 450bp mutation product.  
A 5395bp deletion detected in Serbian population. Sequencing electropherogram of PCR product containing deletion. Dashed line represents site of deletion.  
Purpose: Hereditary breast/ovarian cancer (HBOC) occurs in families with several members affected. Most HBOC is caused by mutations in high penetrance BRCA genes accounting for about 5% of all breast cancers. There is a large number of genes with moderate or low penetrance, contributing to non-BRCA aggregation of breast and ovarian cancers. In the present study, we evaluated the presence and frequency of 1100delC and Del5395 mutations in CHEK2 gene in Serbian BRCA-negative HBOC cases. Methods: We analyzed 57 BRCA-negative subjects from high risk breast/ovarian cancer families from Serbia for CHEK2 1100delC and Del5395 mutations. We used two multiplex allele specific PCR in order to detect them. All suspected positive cases were compared with controls and confirmed by DNA sequencing. Results: 1100delC was not detected in the tested group. However, we detected one Del5395 mutation in a female diagnosed with breast cancer at the age of 32 and with apparent family history of breast cancer (her mother and sister were diagnosed with breast cancer at 42 and 39 years of age, respectively). The frequency of Del5395 mutation in our tested group was 1.7% (1/57). Conclusions: 1100delC variant in CHEK2 gene was not present in the tested subjects from HBOC families in Serbia. However, the finding of Del5395 mutation does not allow us to discard a possible involvement of this gene in breast cancer susceptibility in Serbian population. It would be of great interest to assess the distribution of this large deletion in other countries from the Balkan region in order to assess its geographical distribution and possible founder effect.
Purpose: Considering tumor-induced suppression of natural killer (NK) cell activity the aim of this study was to investigate the in vitro effect of a standard immunotherapeutic cytokine, interferon (IFN)α, and a less investigated agent, 13-cis retinoic acid (RA) on the functional and receptor characteristics of CD16-defined NK cells and their functionally diverse dim and bright subsets in patients with metastatic melanoma (MM). Methods: Peripheral blood lymphocytes (PBL) of patients with clinical stage IV MM were stimulated in vitro for 18 h in RPMI 1640 culture medium (CM) alone, CM supplemented with IFN-α (250 U7sol;ml), RA (10-6M) and their combination. NK cell activity was determined using standard 4 h radioactive cytotoxicity assay, while the expression of activating (NKG2D, CD1617rpar; and inhibitory (CD158a, CD158b) NK cell receptors on CD3-CD16+ NK cells and their functional bright and dim subsets were analyzed by flow cytometry. Results: NK cell cytotoxic activity was increased after in vitro treatment with IFN-α alone and in combination with RA, while only IFN-α induced increase in NKG2D and CD161 activating NK cell receptor expression. Contrary to this, RA treatment increased the expression of inhibitory KIR CD158b. IFN-α-obtained increase in CD161 expression was due to its induction on both NK cell subsets, while for NKG2D only on CD16bright subset. Conclusion: The favorable enhancement of NK cell activity of MM patients obtained with IFN-α is associated with upregulation of activating NKG2D and CD161 receptors, while the lack of RA-associated upregulation is probably due to the shown increased expression of inhibitory KIR receptor CD158b after in vitro treatment with this agent.
The impact of adjuvant chemotherapy (CT) in the management of radically resected stage IB non-small cell lung cancer (NSCLC) is highly debated. The aim of this study was to evaluate the outcome of this category of patients treated at our institution. We retrospectively analysed the survival data of patients with pathologic stage IB NSCLC, who received at least 1 cycle of adjuvant CT. CT was planned to be platinum based and to be delivered for 6 cycles. One hundred and twelve consecutively treated patients were evaluated. Patient characteristics: median age 60 years, median tumor diameter 4 cm, 87% underwent lobectomy and 13% pneumonectomy, 58% had visceral pleural involvement (VPI). After a median follow up of 46 months, the estimated 5-year disease-free (DFS) and overall survival (OS) rates were 68% and 77%, respectively. The mean number of CT cycles was 5.2 (range 3-6), with 82% of patients receiving ≥ 5 cycles. The median cisplatin dose intensity (DI) was 22 mg/m(2)/week, and the relative DI was 85%. Median total cisplatin (CDDP) dose/patient was 416 mg/m(2). A total of 31 (27.6%) relapses were recorded, of which 81% were distant. Multivariate analysis showed no significant interaction between overall survival and the following variables: gender, type of surgery, histology, tumor volume, VPI. Our results compare favorably with the historical data evaluating the outcome of stage IB patients treated by surgery alone in a customary medical setting. Overall, our data support the use of adjuvant CT in stage IB NSCLC patients.
To present the results from the first 116 patients with localized prostate cancer treated with transperineal ultrasonography-guided permanent brachytherapy, with special emphasis on the complications of this method. During the last 3 years, 116 patients with localized prostate cancer underwent transperineal ultrasonography-guided permanent implantation with I(125) seeds. Permanent implantation consisted of 21-82 I(125) seeds of 0.529 mCi each, for a total implant dose of 145 Gy. The peripheral loading implant was used and a-blockers preimplantation were administered to most of our patients.The follow-up consisted of clinical examination and serum prostate specific antigen (PSA) estimation every 3 months. Three successive rises of PSA with a 3-month interval inbetween constituted a biochemical failure. No patient was incontinent after treatment. Acute urinary retention was developed in 9 (7.7%) patients. During the first 3 months postimplantation approximately 55% of the patients complained of dysuria, urgency, frequency and nocturia, but their urinary complaints disappeared within one year postimplantion. Three (2.5%) patients developed mild proctitis. Sixty-seven percent of the potent patients remained potent at the end of the first year. Biochemical relapse appeared in 5 (4%) of the 116 patients studied. It seems that prostate brachytherapy, a method that is well tolerated and safely administered, can be accomplished with minimal acute and chronic complications. Prostate size is a predictor for acute urinary retention and prophylactic use of a-blockers seems to reduce the incidence of postimplantion acute retention. Also, lower incidence of impotence was found in comparison with the incidence after radical prostatectomy.
Preoperative serum CA 125 levels in relation to disease stage 
Kaplan-Meier curve for disease free survival in relation with preoperative CA 125 levels in endometrial carcinoma. 
Kaplan-Meier curve for overall survival in relation with preoperative CA 125 levels in endometrial carcinoma. 
Purpose: Previous studies have shown that elevated preoperative serum CA 125 levels strongly correlate with various clinical and pathological variables and prognosis of patients with endometrial carcinoma (EC). The aim of the present study was to evaluate the clinical significance of preoperative serum CA 125 levels in patients with EC. Methods: A retrospective study of all EC patients treated at our institution between 1995 and 2010 with available follow-up was conducted. The preoperative serum level of CA 125 was measured in 99 patients and evaluated in relation to various clinical and pathological variables and outcome. We used the cut-off level of 20 U/ml for CA 125 on chi-square test for categorical variables. Survival analysis was performed with the use of Kaplan Meier method, the log rank test and Cox proportional hazards regression analysis. Results: In the early stages of disease the mean values of CA 125 were 35 U/ml (SD±70) for stages IA-IB and 21 U/ml (SD±29) for stage IC (Mann-Whitney test for continuous variables). In advanced stages of disease (III-IV), the values of preoperative serum CA 125 levels were statistically increased, with mean value 54 U/ml (SD±44), in comparison to stages IA-IB (p=0.02) and IC (p=0.007). According to the multivariate analysis, elevated preoperative serum CA 125 level (p=0.043) and histological tumor type (p=0.004) were independent prognostic factors for disease free survival (DFS) and overall survival (OS) of patients with EC. Conclusion: The current study suggests that measurement of preoperative serum CA 125 is a useful clinical tool in the prognosis of patients with EC.
To examine the expression of the membrane markers of estrogen (ER) and progesterone receptors (PR), CA-125, CA 19-9 and HER2/neu in ovarian cancer tissues. Fifty-four samples of ovarian cancer tissues originating from 55 patients were examined by immunohistochemistry. Forty-three had serous papillary ovarian cancer, 9 of which were grade I, 12 grade II and 2 grade III. Twelve patients had a classic mucinous ovarian cancer, 5 of which were grade I, 4 grade II and 0 grade III. Out of 43 patients with serous ovarian cancer, 7 expressed both steroid receptors, 22 had only one (10 ER and 12 PR), while 14 were negative. Only 2/12 patients with classic mucinous ovarian cancer expressed of both receptors. CA-125 was expressed in 37/43 patients with serous ovarian cancer and in 4/12 patients with classic mucinous ovarian cancer. CA 19-9 was expressed in 3/43 patients with serous ovarian cancer, and coexpressed with CA-125 in 2/3 patients. In patients with classic mucinous ovarian cancer, 4/12 had expression of CA 19-9 without coexpression with CA-125. HER2/neu positivity (3+) was proven in only one case with classic mucinous ovarian cancer, and any other expression (1+) in 7 additional patients (1 mucinous and 6 serous ovarian cancers). Positive HER2/neu expression in the cells of ovarian cancer is very rare and HER2/neu overexpression is even rarer. Expression of ER and PR does not depend on tumor grade and/or at least not in grade I and II. Positive CA 19-9 expression may be present not only in cases of classic mucinous ovarian cancer but also in typical serous ovarian cancer. However, in the classic mucinous ovarian cancer, CA-125 may be expressed, though in relatively low percentage.
Meigs' syndrome consists of a benign ovarian tumor accompanied by ascites and hydrothorax. Elevated serum CA 125 in postmenopausal women with a solid adnexal mass, ascites and pleural effusion is highly suggestive of a malignant ovarian tumor. We report on an unusual case of a benign fibrothecoma of the ovary associated with Meigs' syndrome and elevated CA 125 level in an 62-year-old white female. Although rarely, a benign ovarian tumor should be considered in the differential diagnosis of an adnexal mass associated with Meigs' syndrome and elevated serum CA 125 levels.
CA 125 remains the only tumour marker to have any significant impact on the clinical management of epithelial ovarian carcinoma. Its role has developed over the past two decades by validating CA 125 criteria in large numbers of patients against established methods of disease assessment. CA125 has a role in the work-up of a patient with a pelvic mass. Its role in prognosis and screening remains uncertain. It is of value in the assessment of response to chemotherapy and to identify disease progression. When compared with previous methods of determining the onset of disease recurrence the use of CA 125 has been shown to be more sensitive and to be able to detect it at an earlier stage. However, it remains unknown as to whether the earlier introduction of chemotherapy actually improves survival. Until the results of an MRC / EORTC trial are available regular CA 125 monitoring during follow-up cannot be recommended. Once recurrence is suspected precise criteria based on CA125 can reliably confirm this. With this developing role it is likely that CA 125 will be of even more importance to the management of epithelial ovarian carcinoma in the future.
Extensive non-melanoma skin cancer (NMSC) constitutes a therapeutic challenge especially in old and debilitated patients. Applied treatments include surgical excision, MOHS micrographic surgery, cryosurgery, electrodesiccation, and radiotherapy. We present 3 elderly patients with extensive basal or squamous cell carcinomas and poor general condition who were treated with a combination of 13-cis-retinoic acid 1 mg/kg daily and radiotherapy 2.5 Gy daily. The treatment resulted in rapid improvement of the tumors with significant reduction of their size.
To investigate the in vitro and in vivo activity of an homo-aza-steroid alkylating ester, namely 13beta-hydroxy- 13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17- lactam-p-bis (2-chloro ethyl) aminophenoxy acetate (HASE), in comparison with dacarbazine (DTIC) in the treatment of malignant melanoma. Cytotoxicity was assessed in vitro by the MTT assay using a panel of 6 malignant melanoma human cell lines, with or without the presence of rat liver microsome assay. B16 melanoma-bearing mice were used to evaluate in vivo the antitumor activity of the tested compounds. In all cases of in vitro screening, HASE displayed significantly higher (p <0.0001) cytostatic and cytotoxic activity than DTIC. Moreover, the antitumor activity of HASE in B16 melanoma-bearing mice was satisfactory, prolonging the mice lifespan at 67%, compared to 43% achieved by DTIC. Furthermore, HASE significantly inhibited the tumor growth (tumor growth rate: <42%) as this was defined by tumor volume and weight differences, presenting higher antitumor effect than DTIC. HASE displayed superior in vitro and in vivo activity than DTIC in the treatment of melanoma. Thus, HASE may be considered as a significant candidate anticancer agent for further development.
Demographic and clinical characteristics of the study cohort 
levels. PICP and ICTP levels in patients with and without bone metastases in comparison to control group: A: PICP levels; B: ICTP
PICP and ICTP levels in breast cancer, lung cancer, urinary levels.  
In this study we evaluated the clinical usefulness of serum pro-I collagen peptide (PICP) and I collagen telopeptide (ICTP) as indicators of early bone metastases in patients with breast (BC), lung (LC), urinary bladder (UBC) and prostate cancer (PC). 305 patients were examined. 145 had histologically confirmed BC (92 with bone metastases), 20 UBC (6 with bone metastases), 11 LC (3 with bone metastases) and 129 PC (68 with bone metastases). In BC patients we compared the PICP and ICTP levels with those of CA 15-3, CEA and bone scintigraphy. Patients with LC and UBC had PICP and ICTP measurements, PC patients had serum PICP, prostate specific antigen (PSA) measurements and bone scans. 104 healthy individuals served as controls. ICTP and CA 15-3 levels were significantly higher in patients with BC and bone metastases in comparison to patients without metastases (p <0.05), while PICP and CEA were only marginally higher. Significant correlation was observed between existence of bone metastases and ICTP levels (p <0.05). The sensitivity of PICP, ICTP, CEA and CA 15-3 was 28.1, 48.6, 42, and 78%, respectively and specificity was 83.9, 94, 65 and 86%, respectively. ICTP and CA 15-3 were the most reliable markers for early diagnosis of bone metastases in BC. PICP alone or with ICTP were not sensitive enough. Only CA 15-3 showed sensitivity 78% and specificity 86%. When combined CA 15-3, ICTP and CEA the sensitivity and specificity increased to 82% and 96%, respectively. Furthermore, PICP and PSA levels were significantly higher in patients with PC and bone metastases in comparison to patients with benign prostate hyperplasia (BPH) (p <0.0001) or in patients with PC without bone metastases (p <0.0005 for PICP and p <0.0001 for PSA). The co-evaluation of PICP and PSA improved the sensitivity (78%), specificity (96%), accuracy (97%) and positive predictive value (97%). In LC patients, ICTP levels differed significantly between patients with and without bone metastases (p=0.025). In UBC patients, PICP levels differed significantly between patients with and without bone metastases (p=0.017). ICTP and CA 15-3 are the most reliable markers for early diagnosis of bone metastases in BC patients. PICP could be useful for diagnosing early bone metastases of PC and combined with PSA and bone scan can be an additional tool in the follow-up of PC patients. For LC patients, ICTP showed a significant difference in the discrimination of patients with and without bone metastases. In UBC patients, PICP showed a significant difference in the discrimination of patients with and without bone metastases.
Purpose: The aim of this study was to identify the predictive factors of a positive sentinel lymph node (SLN) in patients with cutaneous malignant melanomas and tumor progression. Methods: From October of 2000 to January of 2006, 144 patients with cutaneous malignant melanoma underwent SLN biopsy. Patients were divided into two groups according to the SLN status (positive vs negative) which were compared with regards to patient demographics and primary tumor characteristics. Results: In 37 (25.69%) patients SLN biopsy was positive . Nodular melanomas (p=0.047), blood (p=0.010) and lymph (p<0.001) vessel infiltration, mitotic rate (p=0.019) and Breslow thickness (p=0.012) were predictive of a positive SLN biopsy. The overall recurrence, mortality and the overall disease free survival (DFS) rates were 6.25, 1.4 and 93.75, respectively. Conclusion: SLN biopsy is the most important predictor of early disease recurrence and survival in patients with cutaneous malignant melanoma. Considering all the examined factors, a positive SLN biopsy is related with Breslow thickness and lymph vessel infiltration.
Prostate cancer (PC) is the most common malignant disease in males and the second leading cause of cancer related deaths in men in developed countries. The purpose of this study was to investigate whether microRNA (miR)-150 is a factor influencing survival in prostate cancer patients. miR-150 mRNA and protein expression levels in prostatic cancer cell lines and healthy tissues were determined by quantitative (q) RT-PCR and Western blotting. Additionally, the protein expression of miR-150 was detected by immunohistochemistry. High miR-150 expression was positively correlated with tumor recurrence or metastasis (p=0.010). In addition, PC patients with high miR-150 expression had significantly poorer overall survival/OR (hazard ratio/HR, 1.87; 95% confidence interval/CI, 1.19-2.94; p=0.006) and poorer disease-free survival/DFS (HR, 1.90; 95% CI, 1.21- 2.98; p=0.005) than those with low miR-150 expression. The cumulative 5-year OS was only 35.19% (95% CI, 26.18- 44.20) in the high miR-150 expression group, whereas it was 55.93% (95% CI, 43.26-68.60) in the low miR-150 expression group (p<0.05). Multivariate Cox regression analysis demonstrated that the expression of miR-150, tumor size, and number of tumor lesions were independent prognostic predictors for OS in PC patients. miR-150 was overexpressed in PC at both the mRNA and protein levels, and high expression of miR-150 could serve as a novel and reliable prognostic biomarker for PC patients.
Ambroise Paré, one of the leading surgeons of the 16th century, is acknowledged as the father of surgery. He exercised vast influence on several fields of medicine and surgery through his writings. This article presents and criticizes Paré's conceptions on oncology.
Summarized results of the study for both Samarium and Drugs groups 
Control of demographic or clinical variables 
Side effects 
Cancer pain is the most serious symptom for patients, especially during their terminal phase, when palliative medicine is needed. Our study tried to verify the usefulness of single-shot intravenous administration of Samarium (Sm)-153EDTMP in patients with bone metastases (group-A, N=53, males=25, females=28, age range: 30-69 years), as well as to compare a series of variables, using as a control group (group-B, N=37, males=17, females=20, age range: 30-69 years) with patients who were under drug treatment given from a physician specialized in palliative medicine. Both groups answered the following questionnaires: Greek Brief Pain Inventory (GBPI), Brief Multidimensional Life Satisfaction Scale (BMLSS), Hospital Anxiety Depression Scale (HADS) and ECOG performance status. Pain severity and pain interference improvement p=0.0005 for both groups. HADS-anxiety: Samarium group, p= 0.397, drugs group p= 0.031. HADS-depression improvement for both groups p=0.031 and p=0.003, respectively. BMLSS improvement p=0.029 and p=0.265, while EGOG PS improvement was p=0.005 and p=0.014, respectively (numeric values). Intravenous administration of Sm-153EDTMP was equivalent to drug treatment against cancer pain for patients with multiple bone metastasis, an option for those patients who are intolerant or resistant to drug treatment. Samarium-treated patients needed less or not at all pain killers, having a better cost-effective result.
Local recurrences at the site of tumor resection or after chemotherapy, as well as distant micrometastases represent major problems in oncology. Therapeutic strategies based on insertion of immunostimulatory genes into the genome of tumor cells followed by vaccination with the resulting genetically modified and irradiated cellular vaccines represent a new potential prospect for the treatment of cancer patients. These strategies are based on the presumption that many, if not all tumors, possess cell surface antigens capable of being recognized by defence effectors of the immune system, as well as on the presumption that local treatment of primary tumors can, due to its immunizing potential, result also in the inhibition of distant metastases. Genetically modified cellular vaccines were found to be efficient against cancer both in experimental models and in tumor-bearing patients. It was also shown in various systems that the efficacy of conventional therapeutic modalities can be supported by adjuvant administration of genetically modified vaccines, as well as by depletion of immunosuppressive immunocyte subsets. The purpose of this review was to summarize and evaluate the results obtained with the administration of genetically modified cellular vaccines as well as with depletion of immunosuppressive immunocytes performed as treatment of minimal residual disease after surgery / chemotherapy in the experimental model of murine tumors mimicking human HPV16-associated neoplasms. The prospects and limitations of these adjuvant immunotherapeutic modalities are discussed.
This phase II study was conducted to evaluate the efficacy and tolerability of vinorelbine (navelbine) and oral VP-16 (etoposide) in pretreated metastatic breast cancer (MBC) patients. Twenty-two female patients with therapy-resistant metastatic breast cancer were treated with vinorelbine 25 mg/m(2) i.v. on days 1 and 8 and oral VP-16 50 mg/m(2)/day for 14 days. Cycles were repeated every 28 days. Treatment was given until clear evidence of disease progression. Complete remission was observed in 3 (14%) patients, and partial remission or stable disease in 10 (45%) patients. Median duration of response was 4 months (range 2-8). Symptomatic improvement, irrespective of imaging methods results, as evaluated through improved performance status (PS), the lack of requirement for urgent palliative radiotherapy, and a decrease in steroids and analgesics doses was demonstrated in 10 (45%) patients through a special questionnaire completed by all patients. Side effects were manageable. Dose modification due to leucopenic fever were necessary in only 3 patients. Previous radiation therapy did not mitigate the application of full doses of chemotherapy. Vinorelbine/VP-16 combination is active and tolerable in relapsed and heavily pretreated MBC patients.
Line 1: molecular weight marker; line 2: PCR positive control (HeLa); lines 3 and 5: HPV-neg- ative sample; line 7: HPV-positive sample; lines 4, 6 and 8: PCR product of β globin gene (268 bp); line 10: control without DNA; lines 9 and 11: empty wells. 
Line 1, 3: HPV16 negative sample; line 2: HPV16 positive sample; line 4: PCR positive control for HPV16 (285 bp); line 5: control without DNA; line 6, 7: HPV18 negative sample; line 8: HPV18 positive sample; line 9: PCR positive control (HeLa) (187 bp); line 10: control without DNA; line 11: O'GeneRuler™ 100bp DNA Ladder; line 12,13 and 14: PCR product of β globin; line 15: control without DNA; line 16: O'GeneRuler™ 100bp DNA Ladder.
Overall HPV and HPV16/18 prevalence by age group in women with normal cervical cytology. 
Infection with high-risk human papilloma viruses (HR-HPV), especially types 16/18, is the main factor in cervical carcinogenesis. Although the incidence of cervical cancer in Serbia is among the highest ones in Europe, data about HPV infection are insufficient. The aim of this study was to investigate the presence of overall and HPV16/18 infections in women with healthy appearance and cytologically (Pap) normal cervix. The study was performed on women who participated in this cervical cancer screening pilot study. Cervical HPV infection was detected by GP5+/6+ PCR. HPV16/18 were detected by amplification of E7/E1 viral gene, respectively. In 350 women we got the following results: cytological abnormalities (10.3%); visible cervical changes (20.3%); previous precancerous lesion (2.3%); normal Pap and speculum finding without history of precancerous lesion (67.1%). In the last group overall HPV prevalence was 41.3%, with 10.5% HPV16 and 23.7% HPV18. The rate of multiple HPV16 plus HPV18 infections was 2.6%. HR-HPV16/18 comprised 31.6% of the total HPV positive participants. Owing to the high prevalence of overall and HPV16/18 infections in women with healthy appearance and cytologically normal cervix, we postulate that testing/ prophylaxis for these HR-HPV types could be introduced in cervical cancer screening and preventive programmes in Serbia.
The incidence rate (age-standardized) of cervical carcinoma in Serbia is the highest in Europe. p53 is mainly inactivated at protein level in carcinomas associated with human papillomavirus (HPV) infection, such as cervical carcinomas. These tumors show low rate of p53 mutations. It is not clear if p53 mutations confer additional impact on disease prognosis. The role of polymorphic variant at codon 72 of p53 gene on patient's prognosis is controversial. The aim of this study was to determine the frequency of p53 mutations and to assess polymorphic variants of codon 72 among cervical carcinoma patients. 53 patients, mainly FIGO stage I (n=50), with squamous cell carcinoma (n=49) were included. 30/32 (94%) patients who received adjuvant radiotherapy were followed-up (median 15 months, range 4-39). DNA was isolated by the salting out method from tumor tissue (n=53) and blood (42/53). p53 mutations were detected by PCR-SSCP (polymerase chain reaction - single-stranded conformational polymorphism) electrophoresis. Codon 72 polymorphism was assessed by the restriction fragment-length polymorphism method. Six p53 mutations were detected in 5/53 (9%) patients with FIGO stage I squamous cell carcinoma (one patient had double mutations). 25/42 (60%) patients exhibited Arg/Arg genotype. HPV16 type was detected in 29/51 (57%) cervical carcinoma samples. Relapse of disease occurred in only 2 patients- both with Arg/Arg genotype and HPV16 positive. One of them exhibited p53 mutation. Our results showed low incidence of p53 mutations and prevalence of Arg/Arg genotype polymorphic variant of codon 72 of p53 gene in early stages of cervical carcinoma.
During the last 25 years the development of cervical cancer and cancer of the anorectum has been related to human papillomavirus (HPV) infection. HPV infection is found in up to 99.7% of all cervical cancers. Head and neck squamous cell carcinomas (HNSCC) have also been related to HPV infection. In this communication we present a 67-year-old female patient, nonsmoker, diagnosed with 3 synchronous cancers--squamous cell carcinoma of the uterine cervix, vagina and larynx. The patient was found positive for immunoglobulin HPV 16 L1 using ELISA method. We believe that in the presented case, the high risk HPV subtype 16 was implicated in the etiology of laryngeal, cervical and vaginal cancers. We also think that HPV infection and related cancers could be prevented effectively by immunization.
Anne of Austria ("the Spain's infant"), was married to Louis XIII, on October 25th, 1615. She became queen of France and they had two children: Louis (the future Louis XIV) and Philippe, duke of Orleans. Everybody knows that Anne of Austria died of breast cancer. This is a widely known fact, so we are not going to add anything but some details, which are generally ignored.
Purpose: To evaluate the effectiveness of different therapeutic managements in relation to clinical disease stage, the location of the lesion and to register the rate of disease recurrence of patients with glottic and supraglottic laryngeal cancer, and to also study some specific epidemiologic characteristics. Methods: A series of 164 patients with laryngeal glottic and supraglottic squamous cell cancer (SCC) treated surgically, with radiation therapy (RT), chemotherapy or combination of these was analysed. After treatment, all patients were followed up for an average of 58 months. All data concerning the primary lesion, therapeutic management, recurrence, staging, 5-year overall survival and epidemiological characteristics such as smoking and alcohol abuse were recorded and analysed in combination with the follow up data. Results: The therapeutic approach most commonly used was RT for stage I tumors and surgery for stages II, III and IV. Stage I and II patients treated with RT had high recurrence rate (60%). Patients with recurrence had 45.3% 5-year overall survival rate and average survival time 80 months, whereas patients with no recurrence had 77.4% 5-year overall survival rate and average survival time 173 months (p=0.0001). There was significant difference in survival between stage I and III (p=0.035), stage I and IV (p=0.0038) and stage II and IV (0.0156). The average overall survival time for non smokers was 195 months (median 1707rpar;, while for smokers it was 99 months (median 100; p=0.0047). The average overall survival time for alcohol abusers was 79 months (median 54), while for those who did not use alcohol it was 153 months (median 150; p=0.016). Conclusion: The 5-year overall survival rate was 61.3%. RT alone in stages I and II proved inferior in decreasing re-currences compared with surgery. Smokers had significantly shorter overall survival.
The great anatomist Giovanni-Battista Morgagni by his major textbook De Sedibus is the creator of pathological anatomy and the one who rendered this new discipline an indispensable specialization of modern medicine.
Although one of the most common genetic polymorphisms that predispose to venous thromboembolism (VTE) is factor V 1691 G-A (Factor V Leiden; FVL), the effect of this polymorphism on the development of VTE in cancer patients is unclear. We have therefore performed a meta-analysis to estimate the risk of VTE associated with FVL among cancer patients. Relevant studies published before May 2006 were retrieved from Pubmed/Medline. We selected studies comparing the prevalence of FVL in cancer patients with VTE with cancer patients without VTE. Both fixed and random effect models were used. P-values and odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated by Fisher's exact test. Pooled results from 9 studies, comprising 397 cancer patients with VTE and 678 cancer patients without VTE revealed that the prevalence of FVL was higher among cancer patients with VTE (7.3%) than those without VTE (4.6%) (chi(2) = 34.633 > chi(2) (18; 0.05) =28.869) (p=0.013). It was also found that mean effect size of FVL was 0.22 (95% CI 0.051-0.4892). Using the homogeneity test, there was evidence of statistical heterogeneity (Q(hom)= 46.334> chi(2) (8; 0.05) =15.507) (p=0.0000). Although the published studies were small and the meta-analysis demonstrated an association of FVL with cancer-related thrombosis, testing for FVL can be routinely used as part of clinical thrombophilia assessment in cancer patients from the regions with high incidence of FVL.
To evaluate the proinflammatory effect and molecular mechanism of IL-17 in the intestinal epithelial cell line HT-29. After culture of HT-29 cells with IL-17 and/or TNF-(α), real-time (RT) PCR and Western blot were used to measure the gene expression level of the neutrophil chemokines CXCL1, CXCL2, CXCL5, CXCL6, IL-8 and the Th-17 chemokine CCL20, the phosphorylation level of P38 and TNF-α, and the expression level of IL-8 after treatment with P38 inhibitor. Act1 stable knockdown HT-29 cell line was established to further test the change of P38 phosphorylation after treatment with IL-17 and TNF-α. When HT-29 cells were cultured with IL-17 and TNF-α, the expression level of neutrophil chemokines (CXCL1, CXCL2, CXCL5, CXCL6, IL-8) and Th17 chemokine (CCL20) was significantly improved (24.96±2.53, 28.47±2.87, 38.08±2.72, 33.47±2.41, 31.7±2.38, 44.37±2.73, respectively) (p<0.01). The results of Western blot showed that IL-17 obviously enhanced the phosphorylation of P38 induced by TNF-α. Compared with the control group, the expression level of IL-8 declined significantly (9.47±1.36 vs 3.06±0.67) when HT-29 was cultured together with IL-17 and TNF-α (p<0.01). P38 inhibition assay showed that P38 pathway played an essential role in IL-17 induced inflammatory response. The level of P38 phosphorylation could not be changed after treatment with IL-17 and TNF-α in Act1 stable knockdown HT-29 cell line. IL-17 significantly promoted the gene expression level of TNF-α-induced neutrophil chemokines and Th17 cells chemokine. IL-17 and TNF-α have an obvious synergistic effect on P38.
Changes in Ct values in PBMC, K562 and K562/IMA-3 cells. 
Fold changes in expression levels of miR-17 in PBMC, K562, 3 μM imatinib treated K562, K562/IMA- 3, and 5μM imatinib treated K562/IMA-3 cells. 
Changes in Ct values in K562/IMA-3 cells treated with imatinib, dasatinib and nilotinib. 
Percent changes in expression levels of miR- 17 in K562/IMA-3 cells treated with imatinib, dasatinib and nilotinib. 
Purpose: In this study we examined the expression levels of miR-17 which possesses oncogenic activities through downregulation of CDKN1A, p21 and E2F1 tumor suppressor genes, in imatinib sensitive and resistant chronic myeloid leukemia (CML) cells. On the other hand, we also determined the expression levels of miR-17 in response to tyrosine kinase inhibitors imatinib, nilotinib and dasatinib used for the treatment of CML. Methods: The expression profiles of miR-17 were analysed by Stem-Loop reverse transcription (RT) polymerase chain reaction (PCR). Results: The results revealed significant increase in the expression levels of miR-17 in imatinib sensitive and resistant cells compared to peripheral blood mononuclear cells (PBMCs). On the other hand, significant decrease was observed in miR-17 levels in response to imatinib, nilotinib and dasatinib. Conclusion: These results may imply that miR-17 can be used for diagnosis and treatment of CML.
Purpose: HER2-dependent signalling pathway is deregulated in a subset of colon adenocarcinomas. Although HER2 protein expression patterns demonstrate a broad diversity in these tumors, the critical parameter for targeting the gene is the detection of gene amplification. Our aim was to investigate the correlation between HER2 protein levels and chromosome 17 (chr 17) copies. Methods: Sixty paraffin-embedded samples of primary colon adenocarcinomas were cored at 1 mm diameter and transferred to the microarray block. Immunohistochemistry (IHC) was performed using anti-HER2 monoclonal antibody. Chromogenic in situ hybridization (CISH) was performed using HER2 gene/chromosome 17 centromeric probes. Results: HER2 protein overexpression (score: 2+/3+) was observed in 20/60 (33.3%) samples. CISH analysis detected 11/60 (18.33%) amplified cases, whereas chromosome 17 aneuploidy (polysomy) was identified in 13/60 (21.66%) cases. Significant associations were detected correlating HER2 expression with grade of the tumors (p=0.03), Chr 17 with stage (p=0.01), gene copies with protein expression (p=0.008), and also Chr 17 centromere signals with overall gene signals (p=0.001). Conclusion: Multiple HER2 gene copies lead to different protein expression patterns (score 1+ to 3+) but pure gene amplification is only a subset of them. Identification of chromosome polysomy is a critical parameter in detecting original gene amplification in conventional one-color CISH methods.
p53 (gene location: 17p13.1) overexpression is a common event in pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignant neoplasm. Although specific mechanisms of p53 gene deregulation have been identified, correlation between p53 expression and chromosome 17 gross numerical imbalances (aneuploidy) are under investigation. Using tissue microarray technology, 60 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored and re-embedded to the final recipient block. Immunohistochemistry (IHC) for p53 expression and chromogenic in situ hybridization (CISH) for chromosome 17 numerical alterations were performed. Digital image analysis was applied for p53 expression levels evaluation (Nuclear Labelling Index-NLIs). p53 overexpression was detected in 38/60 (63.3%), whereas chromosome 17 aneuploidy was observed in 21/60 (35%) cases, respectively. Polysomy was identified in 19 cases, whereas monosomy in 2 of them. p53 overall expression was strongly correlated to the stage of the examined tumors (p=0.02). Chromosome aneuploidy was not associated to tumors' stage and grade (p=0.42, p=0.71, respectively). Although overall chromosome 17 centromeric imbalances were not correlated with p53 overexpression (p=0.32), both cases with monosomy demonstrated high expression levels. p53 overexpression combined with chromosome 17 numerical imbalances characterizes a significant proportion of PDACs. Because commercially available antip53 antibodies detect mutant and also wild-type protein expression levels, chromosome 17 monosomy maybe is a gross genetic criterion for discriminating them due to point mutation that frequently affects the remaining allele.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm. Many different chromosomal alterations have been identified including structural or numerical changes. In this study we performed a molecular analysis of chromosomes 7,9, and 17 based on tissue microarrays (TMA). Using TMA technology, 50 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored twice and re-embedded to the final recipient block. Chromogenic in situ hybridization (CISH) was performed using centromeric probes of the corresponding chromosomes. SPSS(chi square test and interrater kappa) was performed for statistical analysis. Chromosome 17 analysis detected aneuploidy in 19 (38%) cases. Similarly, aneuploidy regarding chromosome 9 was identified in 9 (18%) cases, whereas 14 (28%) cases were aneuploid, concerning chromosome 7. Statistical significance was assessed, correlating chromosome 7 with grade and stage (p=0.016 and p=0.027, respectively) and chromosome 9 to grade (p=0.023). Similarly, analyzing normal-appearing ductal epithelia adjacent to cancer cell populations, 2 cases were found with alterations regarding chromosome 9 and 17. Molecular analysis for chromosomes 7, 9 and 17 in PDAC confirmed that there is a variety of numerical alterations, and some of them represent very early genetic events in the progression of carcinogenetic process. Performance of CISH, also, provides an easy, accurate approach for their detection, even in a small tissue sample, such as TMA cylindrical cores.
The outstanding London surgeon Percivall Pott made numerous original observations. In 1775 he pointed out that many males who had been chimney sweepers while boys later suffered from scrotal cancer and linked this with irritation caused by soot, and thus identified the first cancer-causing occupation. Thus, he first described "chimney sweeper's cancer" and can therefore be regarded as a pioneer of occupational diseases.
Bertrand Bécane, Professor of surgery in Toulouse Medical School, is considered an eminent precursor of oncology, influencing the 18th century medicine with his syphilitic theory of cancer.
In the following article we briefly present the life and scientific work of John Hunter, founder of the experimental surgery, who by means of his researches and writings in the field of Oncology, contributed enormously to the development of this discipline. In reference to this matter, we quote some examples indicative of his work on Oncology.
Professor Bernard Peyrilhe occupied the chairs of surgical chemistry and medica materia at the Faculty of Medicine of Paris. He was a great surgeon, cancer specialist and historian of medicine. He led in depth studies on cancer and realized the first experimental transmission of cancer by injecting extracts of breast cancer into an animal.
Alexis Boyer, professor of clinical surgery at "La Charité", first surgeon of Napoleon 1st, baron of the empire, left a considerable number of written works covering the whole of external pathology. A large portion of his work deals with cancerous diseases. By studying the chapter of penis carcinoma one can appreciate the astonishing depth of Boyer's knowledge on this matter, a knowledge which constitutes the seed of oncology.
The French doctor Bichat had a brief but outstanding career. Although the training of Bichat was exclusively that of a surgeon, his scientific interests embraced all of medicine, especially descriptive anatomy, histology, pathological anatomy and histopathology. His important contribution was to point out that organs were not homogeneous structures but were composed of different tissues.
Photo 2. The vaginal speculum and several surgical instruments invented by Récamier.
Professor J.C.A. Récamier (1774-1852), the undisputed founder of modern gynecologic surgery, had also excelled in the field of oncology. In particular, he performed the first successful vaginal hysterectomy for cancer; he conducted extensive research on cancer metastatic process and he was the proponent of a cancer treatment method by compression.
Gaspard-Laurent Bayle was a 19th century eminent clinician, pathologist, phthisiologist and statistician that deserves our attention. His very advanced oncologic conceptions rank him among the all-time great pioneers of oncology.
In 19th century, the anatomo-clinical school of Paris linked clinical signs with anatomical lesions establishing clinical medicine. One of the most enlightened promoters of this method was the French physician René-Théophile-Hyacinthe Laennec, known as the inventor of stethoscope. In our article, we reveal his work on pulmonary melanoma.
Before the official foundation of the specialty of urology in 1870 from Félix Guyon, its exercise was in the hands of general surgeons. One of the most distinguished surgeons interested in urology was Claude-François Lallemand, Professor of Surgery in Montpellier. Despite his enormous experience in the diagnosis and treatment of urinary tract diseases as well as the invention of various surgical instruments for the lower urinary system, Lallemand, however, did not avoid serious diagnostic errors because of the lack of diagnostic tools. Characteristically in the present article we present a serious diagnostic mistake in a patient with bladder cancer with fatal outcome.
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Kadri Altundag
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Sercan Aksoy
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Taner Babacan
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Zervoudis Stefanos
  • Rea Maternity Hospital
Evangelos Tsiambas
  • National and Kapodistrian University of Athens