Faculty of Medicine

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    Small and large cell neuroendocrine carcinomas of the uterine cervix. A report of 10 cases.
    (Springer, 2005-08)
    Kubelka-Sabit, Katerina
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    Plaseska-Karanfilska, Dijana
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    Prodanova, Irina
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    Yashar, Genghis
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    Hadzi-Nicheva, Biljana
    BACKGROUND: Small (SCC) and large cell (LCC) neuroendocrine carcinomas of the uterine cervix are rare and highly aggressive neoplasms. Their association with the integration of human papilloma virus (HPV) DNA of the types 16 or 18 has been documented in many studies. AIMS: The purpose of this study is to present the clinical, histopathological, immunohistochemical characteristics and the presence of HPV DNA in ten cases of SCCs and LCCs of the uterine cervix. METHODS: Seven patients with primary SCCs and three patients with LCCs of the uterine cervix were diagnosed at our department between 1989 and 2004. Clinical data were retrieved from the patients’ files and included age, recurrence and survival. Routinely processed operative and/or biopsy specimens were used for immunohistochemical stains and hybridization procedures. Primary antibodies against several epithelial, neuroendocrine, mesenchimal and proliferative markers were included. The presence of HPV DNA was assessed by conventional in situ hybridization (ISH) using probes for HPV 16/18 and 31/33/51 and polymerase chain reaction (PCR), using three primers (MY09/11, GP5+/GP6+, E6). Six of the patients were surgically treated. Postoperatively, four received chemo and/or radiotherapy, two rejected further treatment and one patient was lost to follow-up. The other four patients underwent conservative treatment due to advanced disease. RESULTS: The patients’ age ranged from 25 to 71 years. Histologically, the tumors showed trabecular, nesting or a sheet-like pattern, with areas of necrosis and frequent mitoses. Their neuroendocrine nature was confirmed by diffuse positive immunostaining for neuron-specific enolase and low-molecular weight cytokeratins. Focal positivity for chromogranin, synaptophysin and S100, together with pancytokeratin and EMA, was evident in the majority of the tumors. Their aggressive potential was confirmed by high Ki-67 proliferative index (50-90%). HPV types 16/18 were found in 4 tumors using ISH, and HPV 16 in additional 3, using PCR (type 16). 3 of the patients developed distant metastases and died 7-48 months after receiving partial or full treatment, while 6 are alive and without evidence of disease after 4-38 months. CONCLUSIONS: SCCs and LCCs are highly aggressive neoplasms. However, early diagnosis and combined therapy may improve survival in some patients. Although mainly a morphologic diagnosis, immunohistochemistry may help in the diagnosis of SCC and LCC.
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    Blood vessel invasion and inflammatory stromal reaction at the invasion front as additional significant prognostic factors in surgically treated patients with cervical carcinoma.
    (Springer, 2001-09)
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    Yashar, Genghis
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    Veljanoska, Slavica
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    Kubelka, Katerina
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    Prodanova, Irina
    Introduction: The objective of this study was to evaluate the prognostic significance of 23 clinical and histopathological variables in relation to disease-free (DFS) and overall survival (OS) in patients with early stage cervical carcinomas. Methods: A retrospective analysis of 237 patients with cervical carcinoma, undergoing radical hysterectomy and postoperative irradiation between 1988 and 1997 was conducted. The operative specimens were subjected to detailed and uniform histopathological work-up. The patients were staged according to the postoperative TNM classification of UICC (1997) guidelines. Mean follow-up time was 57 (18-124) months. Results: The 5 and 10-year OS rate was 80.8%, while DFS rates at 5 and 10 years were 76.8% and 75.5%, respectively. In multivariate analysis, blood vessel invasion, pelvic lymph node metastases, tumor diameter, inflammatory stromal reaction at the invasion front, and minimum thickness of uninvolved cervical stroma/parametrial extension, were independent and significant variables. The prognostic index, as an indicator of the patient's place in the prognostic spectrum, defined by the Cox regression model, was able to categorize the patients into three distinct risk groups. The 5-year DFS and OS rates of the low-, intermediate-, and high-risk groups were 97.5%, 86.3%, and 43.8%, vs. 98.8%, 84.5%, and 45.3%, respectively (P<0.0001). Conclusions: The prognostic index could be a sound basis for an appropriate planning of the following therapeutical strategy for the surgically treated patients with cervical carcinoma. The postoperative TNM classification should be modified, incorporating the blood vessel invasion and the inflammatory stromal reaction at the invasion front, as additional significant prognostic factors.
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    Capecitabine as Second and Third-line Chemotherapy in the Treatment of Platinum-refractory Epithelial Ovarian Cancer
    (Elsevier, 2011-09)
    Veljanoska, Slavica
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    Arsovski, Oliver
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    Background: The aim of the study was to evaluate the value of Capecitabine (Xelode) in treatment of epithelial ovarian cancer, after failure of initial chemotherapy. Response rates to first-line chemotherapy in women with ovarian cancer are high but most patients relapse and need further treatment. Recurrent disease is incurable, however, many patients can obtain good palliation from further treatment. Material and Method: The study included 20 patients with epithelial ovarian cancer treated initially with cytoreductive surgery and followed by chemotherapy treatment: 14 patients received platinum/paclitaxel therapy and 6 patients received platinum/cyclophosphamide therapy. Progression of disease was manifested with hepatic metastases in 11 patients (55%), lung metastases in 2 (10%) and an increase in serum CA125 in 5 patients (25%). Comparison of the value of serum CA125 before and after treatment was taken as an indicator of response to chemotherapy. The treatment schedule consisted of oral capecitabine 1250mg/m2 administrated twice daily for 14 days, followed by 7-day rest period. Treatment was administrated orally within 30 min of breakfast and dinner, and swallowed with approximately 200ml of water. The cycle was repeated every 21 days. Results: 18 patients (80%) received 6 courses chemotherapy with Capecitabine, 4 (20%) did not achieve the planned 6 courses of chemotherapy due to deterioration of their general condition. In 10 patients (50%) deceased value of CA125 was observed, in 8 (40%) value was unchanged, and in 2 (10%) an increase of serum CA125 was noted. All 20 patients were evaluable for safety. Capecitabine was very well tolerated, with the most common clinical adverse events being nausea and diarrhoea, neither of which occurred with grade 3 or 4 intensity. Conclusions: Capecitabine has demonstrated promising activity and a favorable safety profile in the treatment of platinum-refractory epithelial ovarian cancer. The safety and convenience advantages afforded to patients over current i.v. options make capecitabine an ideal agent for administration in the outpatient setting, potentially freeing them from the burden of i.v. therapy.
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    Incidental gonadal germ cell tumours at the time of prophylactic gonadectomy in patients with Swyer syndrome - a report of 3 cases
    (Springer, 2018-08-24)
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    Ognenoska-Jankovska, Biljana
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    Veljanoska, Slavica
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    Plasheska-Karanfilska, Dijana
    Background & Objective: Swyer syndrome (46,XY pure gonadal dysgenesis) is an uncommonly encountered condition in which gonadectomy is recommended upon diagnosis due to a significant risk of malignant transformation of the dysgenetic gonads. The aim of this study was to present our experience with incidentally found germ cell tumours in patients with Swyer syndrome. Method: We report the clinico-pathological characteristics of 3 cases of female phenotypic patients presenting with primary amenorrhea who underwent prophylactic bilateral laparoscopic gonadectomy with salpingectomy following a diagnosis of Swyer syndrome. At the time of diagnosis, they were 17 to 20 years old. The presenting features were hypogonadotropic hypogonadism and 46, XY karyotype. A hypoplastic uterus with normal looking fallopian tubes and bilateral gonads were detected by ultrasonography and confirmed during laparoscopy. The patients with dysgerminoma underwent postoperative chemotherapy. All three patients are alive and well 70, 115 and 144 months following surgery. Results: The histopathological examination of the streak gonads which were completely sampled and embedded revealed the presence of bilateral predominantly “burnt out” gonadoblastoma in all patients. In addition, in two patients, a coexisting dysgerminoma of 1.5 and 3.8 cm in diameter FIGO stage IC1 in the right gonad was confirmed. The sequencing of the SRY gene of the patient with bilateral gonadoblastoma without dysgerminoma overgrowth revealed a C/G substitution at the first nucleotide of codon 133, leading to Arg/Gly replacement in the SRYprotein. Conclusion: Our data suggest that patients with gonadal dysgenesis and 46, XY karyotype should be referred for bilateral gonadectomy and their operative specimens should undergo meticulous histopathological examination because of the high risk of neoplastic transformation.
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    Adjuvant chemotherapy in patients with stage IIIA endometrial carcinoma with solitary adnexal involvement
    (Macedonian Association of Pathology, 2016-09)
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    Veljanoska, Slavica
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    Objective: The optimal adjuvant therapy in endometrial cancer patients with solitary adnexal involvement is still controversial. The purpose of this study was to evaluate, retrospectively, the outcome and efficacy of adjuvant chemotherapy in these patients. Material and Methods: The medical records of the patients with stage IIIA endometrial cancer with solitary adnexal involvement who were treated with surgical resection and adjuvant chemotherapy between 2005 and 2010, were retrospectively analyzed. A total of 40 patients treated with platinum-based adjuvant chemotherapy were included. Following surgery, all patients received 4 cycles of Carboplatin 300 mg/m2 and Paclitaxel 175 mg/m2 by intravenous injection every 3 weeks. The survival and recurrence rates were evaluated. Results: The median follow-up period was 5 years (60 months). Recurrences occurred in 12.5 % (n=5) of the patients. One local recurrence (1/5, 20%) and 4 distant metastases (4/5, 80%) in liver (n=2, 40%), lung (n=1, 20%) and paraaortal lymph nodes (n=1, 20%) were observed. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 87.5% and 92.3%, respectively. Conclusions: In conclusion, platinum-based adjuvant chemotherapy may improve prognosis and survival in stage IIIA endometrial cancer patients with solitary adnexal involvement and could be considered as a potential adjuvant treatment. Although adjuvant chemotherapy has demonstrated improved both disease-fee and overall survival compared to radiotherapy (DFS 87.5% vs 69%; OS 92.3% vs 78%), further studies are needed to define the optimal treatment strategy.
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    Multimodality treatment of brain metastases from ovarian cancer
    (Macedonian Association of Pathology, 2016-09)
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    Veljanoska, Slavica
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    Objective: Brain metastases from ovarian cancer are uncommon and usually associated with mean survival less than 12 months. In some cases, multimodality treatment may achieve an improved outcome in these patients. Material and Methods: Two cases of multiple brain metastases from ovarian cancer are presented. A combination of whole-brainradiotherapy (WBRT) and chemotherapy (Topotecan) was used. Results: Case 1: A 62-year-old patient was diagnosed and treated for primary ovarian cancer in 2012. She underwent optimal surgical resection and adjuvant platinum-based chemotherapy (Carboplatin/Paclitaxel, 6 cycles). Eleven months after the initial treatment the patient developed right hemiparesis. Brain CT documented multiple brain metastases in the left frontal and parietal lobe. She proceeded to WBRT and subsequent 4 cycles of Topotecan. At a follow-up of 24 months, there is no evidence of recurrent disease. Case 2: A 63-year-old patient was diagnosed with primary ovarian cancer in 2012. Initially, she received neoadjuvant chemotherapy (Carboplatin/Paclitaxel, 6 cycles and Doxorubicin/Carboplatin, 3 cycles) followed by surgical treatment. After 1-year follow-up, multiple brain metastases in the right temporoparietal and occipital lobe were detected by brain MRI. She underwent WBRT followed by 4 cycles of Topotecan. Better motor performance was achieved and the MRI scan evaluation showed volume reductions of brain metastases. Nine months later, CT scan revealed a progression of the metastatic disease and re-WBRT was performed. At a follow-up of 18 months, she is in good clinical condition. Conclusions: In ovarian cancer patients with multiple brain metastases, multimodal therapeutic approach including radiotherapy followed by chemotherapy may lead to prolonged survival.
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    Adjuvant chemotherapy and radiotherapy for Stage III endometrial cancer: Impact on Survival
    (RAD Association, 2018-06)
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    Veljanoska, Slavica
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    Introduction. Adjuvant treatment options for advanced-stage endometrial cancer include chemotherapy (CT) and radiation therapy (RT), but the optimal treatment strategy is currently under debate. The aim of this study is to investigate the utilization of adjuvant RT and CT in patients with stage III endometrial cancer and their impact on overall survival (OS) and disease-free survival (DFS). Materials and Methods. A retrospective review was performed of 40 patients with Stage III endometrial cancer who received adjuvant treatment at University Clinic of Radiotherapy and Oncology (UCRO) in Skopje between 2012 and 2015. Postoperative treatment was administered based on performance status and medical comorbidities. Chemotherapy regimens comprised of Carboplatin (AUC 5) and Paclitaxel (175 mg/m2), a 3-week interval for 6 cycles (chemotherapy alone) and 4 cycles (sequential arm). RT was delivered using 3-D CRT with a total dose of 50 Gy in 25 fractions prescribed in PTV for 5 weeks with/without an additional 7 Gy prescribed at a depth of 0.5 cm from the vaginal surface. The primary endpoints were overall survival (OS) and disease-free survival (DFS). Combined radiotherapy and chemotherapy were compared with radiotherapy alone and chemotherapy alone. Results. The distribution of surgical stages is as follows: IIIA accounted for 60% (n=24), stage IIIB accounted for 9.8% (n=4) and stage IIIC accounted for 30% (n=12). The median age was 65 years and median follow-up was 35.5 months. There were 40 patients who received adjuvant treatment, 10% (n=4) received CT alone, 27.5% (n=11) received RT alone, and 62.5% (n=25) received sequential combined CT followed by 3D CRT with/without vaginal vault brachytherapy. Relapse occurred in 55% (n=22) of the patients. High grade and lymphovascular space invasion (LVSI) are risk factors for recurrence and poor prognosis. Overall survival (OS) and Disease-free survival (DFS) at 3 years for patients receiving combined CT and RT, adjuvant RT alone and adjuvant CT alone were 68.8%, 41.26%, and 37.57% for OS and 58.03%, 33.08%, and 24.96% for DFS, respectively. DFS and OS were significantly longer in patients treated with combined RT and CT than in those treated with CT alone (DFS: p= 0.0005; hazard ratio [HR], 5.677; OS: p= 0.0143; HR, 4.289) or RT alone (DFS: p = 0.0137; HR, 2.482; OS: p = 0.0151; HR, 3.036). Conclusion. Combined modality treatment with chemotherapy and radiotherapy can improve both overall and disease-free survival in patients with Stage III endometrial cancer compared with single modality alone.