Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Safety and efficacy of addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in colorectal cancer with liver metastasis- a single institution experience.

PURPOSE: To evaluate the safety and efficacy of the addition of bevacizumab to oxaliplatin-based preoperative chemotherapy in metastatic colorectal cancer (mCRC) patients. METHODS: Between August 2008 and December 2011, 51 patients with histologically documented CRC and liver metastases were treated with first-line oxaliplatin-based therapy plus bevacizumab: FOLFOX 4 (oxaliplatin, folinic acid and 5-FU) plus bevacizumab or OXFL mod.Mayo (folinic acid, oxaliplatin and 5-FU) plus bevacizumab. RESULTS: The mean patient age was 59.69+ 9.38 years (range 38-78) and 34 (66.67%) were male. Complete response (CR) was achieved in 7 (13.73%) patients, partial response (PR) in 29 (56. 86%) and stable disease (SD) in 6 (11.76%); progressive disease (PD) was registered in 9 (17.65%) patients. Disease control rate was 82.36% (42 patients). Liver resections were performed in 37 (72.55%) patients vs those without resection (p<0.01). The same regimen without bevacizumab was administered postoperatively to 18 (42. 86%) patients. The mean progression free survival (PFS) was 9.90±7.07 months (range 3-26) and was significantly longer in patients with postoperative therapy (p<0.001). Treatment-related toxicity appeared in 28 (54. 90%) patients vs those who did not (p<0.001) Independent of grade, nausea (19.61%), leucopenia (17.65%) and peripheral neuropathy (17.65%) were the most frequent toxicities. Chemotherapy was postponed in 9 (17.65%) patients due to grade 3-4 toxicities. The most frequent grade 3 or 4 toxicities were leucopenia (5.88%) and hypertension (3.92%). CONCLUSION: Bevacizumab plus oxaliplatin-based treatment is safe and efficient as preoperative treatment of mCRC with primarily unresectable liver metastases. Liver resection could offer a possibility for long-term survival in these patients.

Current and future anti-HER2 therapy in breast cancer.

The therapeutic strategy for breast cancer with the use of targeted drugs is, at present, mainly focused on coping with HER2. Currently, lapatinib and trastuzumab are in widespread use. Virtually all completed and in progress clinical trials have demonstrated a significant enhancement in the rate of pathologic complete response (pCR), the primary endpoint in these studies, in cases of patients with HER2-positive breast cancer that received trastuzumab in the neoadjuvant setting. Use of lapatinib in the neoadjuvant setting should be considered experimental. When a 12-month course of trastuzumab was added to adjuvant chemotherapy, the disease-free survival (DFS) was greater and the overall survival (OS) was also greater. Although trastuzumab is approved as single-agent therapy, most patients are treated with trastuzumab plus cytotoxic agents. Trastuzumab, administered as single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Dual targeting approach with a combination of trastuzumab and lapatinib improved progression-free survival (PFS) as compared with lapatinib alone in patients with metastatic breast cancer who have not had a response to trastuzumab. The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged PFS. Novel anti-HER2 targeted therapies are needed to utilise novel approaches to combat trastuzumab resistance.

Case-control design as investigative approach to assessing cancer etiology: development and future perspectives.

The case-control method evolved out of analyses of series of cases. The analytic form of the case-control study can be found in the 19th century medical literature, but did not appear to be viewed as a special or distinct methodology. The first modern case-control study was the Janet Lane-Claypon's study of breast cancer in 1926, but the design was used only sporadically in medicine until 1950, when 4 published casecontrol studies linked smoking and lung cancer. These 1950s studies synthesized the essential elements of the case-control comparison, produced a conceptual shift within epidemiology, and laid the foundation for the rapid development of the case-control design in the subsequent half century. The powerful consistency of these case-control studies, and the replication of their findings in later prospective studies, promoted the general acceptance of the case-control study as a scientific tool in clinical research. Newer case-control studies have benefited from the advances in design, execution and analysis since 1950s. These advances include more rigorous selection and matching of case and control population, improved interviewing techniques, location of the design within a general framework of epidemiologic strategies for relating exposure to disease, understanding of the measures of effect, and application of increasingly sophisticated statistical procedures to findings. This review traces the development and future perspectives of the case-control design to assessing cancer etiology. With illustrations drawn primarily from the literature on its use and the value of its results to unravelling the etiology of malignant diseases, we tried to explore if the case-control approach firmly ensconced in epidemiology as investigational tool and rivals in importance the more straightforward cohort approach.

The application of magnetic resonance imaging in preoperative evaluation of patients with endometrial carcinoma.

PURPOSE: The aim of this paper was to assess the usefulness of the preoperative application of magnetic resonance (MRI) imaging in patients with confirmed endometrial carcinoma. METHODS: This prospective study included 50 patients with endometrial cancer. MRI was used for preoperative disease staging and in planning the operative treatment. The parameters monitored by MRI were compared with the findings of curettage pathological examination. Estimated were the depth of myometrial invasion, the involvement of the cervix by the tumor, the presence of adnexal metastases and regional lymph nodes. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of the MRI in relation to the aforementioned clinicopathological parameters were assessed. RESULTS: The presence of myometrial invasion was estimated with 100% specificity, 86% sensitivity, 100% PPV and 40% NPV. The estimation of the depth of myometrial invasion (>or<50%) was defined with 89% sensitivity, 54% specificity, 83% PPV and 60% NPV. MRI provided valuable data about cervical invasion (100% PPV for the presence of cervical invasion and 55% PPV for the depth of cervical invasion), thereby helping to decide on the kind of surgical intervention, the choice of approach (open or laparoscopic surgery) and the choice of the surgeon. CONCLUSION: MRI is useful and reliable in preoperative evaluation. The information obtained by MRI provides space and time for planning the treatment modality.

Recurrence of cervical intraepithelial neoplasias with negative cone margins: risk factors.

PURPOSE: The percent of young patients treated for cervical intraepithelial neoplasias (CIN) has been increasing, thus it is very important to define patients in high risk for relapse. The aim of this study was to establish any possible association of persistent human papillomavirus (HPV) infection, age, smoking, parity, use of oral contraceptives, and Chlamydia infection, with relapse of CIN. METHODS: Between March 2006 and March 2009 a prospective clinical study was performed at the Clinic of Obstetrics and Gynecology in Nis, with the study group comprising the first 35 patients with disease relapse after conization and the control group consisting of 30 patients with more than one year after treatment without relapse. HPV typization was done at the Laboratory for Molecular Biology and Cytogenetics of the Clinical Centre Nis using polymerase chain reaction (PCR). RESULTS: A statistically significant higher percentage of recurrences with lower pathologic stage (CIN I) was found in younger women (below 29 years) (p<0.01). Women in the control group were more commonly non smokers (56.66 vs. 40%) but without statistical significance (p>0.05). The distribution of smoked cigarettes in the study and control subjects showed no statistically significant difference (p>0.05). Patients with recurrences were more commonly HPV-positive compared to controls (68.57 vs. 6.66%; p <0.05). In the study group, HPV-positive smokers recurred with more advanced grades (CIN III and microinvasive carcinoma/MIC; p<0.01). In non smokers, the severity of recurrence was not statistically correlated with HPV positivity. CONCLUSION: Persistent HPV infection, smoking associated with HPV infection and more advanced age were demonstrated to be of statistical significance for CIN recurrence. Parity, use of oral contraceptives, Chlamydia infection, and smoking as independent etiologic factors were not significantly associated with CIN relapse.

Effects of anthocyanins and anthocyanin-rich extracts on the risk for cancers of the gastrointestinal tract.

Anthocyanins are the largest group of water-soluble pigments in the plant kingdom. Anthocyanins are responsible for most of the red, blue, and purple colors of fruits, vegetables, flowers, and other plant tissues or products. In recent years, numerous studies have shown that anthocyanins display a wide range of biological activities. This review summarises recent literature evidence on the association of anthocyanins and anthocyanin-rich extracts consumption with the risk for gastrointestinal tract cancer, concentrating on the results from in vivo animal model tumor systems, as well as data from human epidemiological studies. Potential cancer chemopreventive activities of anthocyanins were revealed from in vitro studies. In vivo animal model tumor systems showed that dietary anthocyanins inhibit cancers of the gastrointestinal tract. Some epidemiological studies have revealed protective effects of anthocyanins consumption on gastrointestinal cancer risk in humans. Pharmacokinetic data indicate that absorption of anthocyanins into the bloodstream of rodents and humans is minimal, suggesting that they may have little efficacy in tissues other than the gastrointestinal tract and skin. Future studies should be undertaken to determine if the anticancer effects of anthocyanins are due to the parent compounds and/or to their metabolites.

Breast cancer in women under 40 years of age.

PURPOSE: It is widely believed that breast cancer in young women is characterized by a relatively unfavorable prognosis and unusual pathological features. The aim of this study was to investigate clinicopathological and biological characteristics in young patients with breast cancer. METHODS: The study enrolled 1029 consecutive female breast cancer patients who were admitted to the Clinical Centre Nis between July 2002 and December 2008. RESULTS: 91 (8.8%) patients were under and 938 (91.2%) were over 40 years. The mean age was 35.9 years for those under 40 years and 58.3 for those older than 40 years. In both patient groups, left breast was most commonly involved; the most common primary tumor site was the upper lateral quadrant; the most common histological type was ductal carcinoma; histological and nuclear grade 2 was most common. In the younger group of patients, the proportion of patients with T3 and T4 disease was higher (13.0 vs. 9.3% and 16.5 vs. 12.0%), the number of patients with histological and nuclear grade 3 disease was higher (27.5 vs. 24.7% and 37.4 vs. 33.2%), the proportion of patients with 4-9 and >10 positive lymph nodes was higher (22.6 vs. 18.3% and 7.1 vs. 4.0%), and the percentage of family history of breast cancer was higher (5.5 vs. 3.1%), without statistically significant differences between the two age groups. Patients in the younger age group exhibited higher estrogen (ER)/progesterone (PR) receptor negativity (32.6 vs. 24.4%) (p<0.05). CONCLUSION: Although uncommon, breast cancer in young women is worth special attention. The underlying causes of the disease must be investigated in large population- based studies in the future.

Concurrent chemoimmunotherapy: is it still the best option for the treatment of metastatic melanoma in patients with good performance status?

PURPOSE: To determine the efficacy, toxicity and survival of metastatic melanoma patients with Eastern Cooperative Oncology group good performance status (ECOG PS 0-1) receiving concurrent chemotherapy and immunotherapy. METHODS: From March 2003 to August 2008, 25 patients with metastatic melanoma were enrolled in the study. No patient had previously received chemotherapy or immunotherapy. Patients with ECOG PS 0-1 were treated with cisplatin+vinblastine+DTIC (CVD) and interferon-A2a (IFN-a). RESULTS: Response rate was 11/25 (44%): complete response (CR) 2, partial response (PR) 9, stable disease (SD) 11, progressive disease (PD) 3. Adverse effects were mild. The most common toxicities were nausea, vomiting and fever. Grade 3 and 4 toxicity was more common in hematologic parameters. No treatment-related deaths occurred. The median overall survival (OS) was 14 months and time to progression 8.0 months. CONCLUSION: Concomitant chemoimmunotherapy appeared to be a beneficial option for metastatic melanoma patients with good PS. Therapeutic approaches with less toxicity and regimens that could improve OS are still highly desired in the treatment of advanced malignant melanoma.

Primary carcinoma of the vagina.

In this paper we reviewed the risk factors for primary carcinoma of the vagina (PCV), diagnostic and therapeutic modalities, and principles leading to rational decision-making in the individualized management of vaginal carcinoma patients. The review was based on the recent literature and our own years- long experience with the disease. PCV is a rare gynecologic malignancy accounting for about 2% of all neoplasms of the female genitals. Most of the affected women are over 60 years of age, peaking between 70 and 80 years. Only 10-15% of patients are below 50 years. Histopathologically, most common are squamous cell carcinoma (80-90%) and adenocarcinoma (4-10%). The leading risk factor for vaginal intraepithelial neoplasia (VAIN) and subsequent squamous cell vaginal carcinoma is long-lasting infection with human papillomavirus (HPV) type 16. Prognosis of the disease depends on several factors, the most important of which are age, histologic type, and tumor stage. Survival depends on the disease stage. Five -year survival rates are about 95% for stage 0, 75% for stage I, 60% for stage II, 35% for stage III, 20% for stage IVa, and 0% for IVb stage. Due to its being a rare entity, there are still controversies as to the most optimal treatment. Individualized treatment approaches have been increasingly used. In most centres, standard treatment for this cancer is radiotherapy. Some reports have shown that surgery might also be an option, while in some centres radiation is supplemented by cisplatin-based chemotherapy. The supposed advantage of radiotherapy is the preservation of the anatomy and function of the vagina. We believe that there are certain psychologic benefits with the preservation of the vagina, regardless of its function. However, preservation of the vaginal function after treatment of invasive vaginal cancer is a rare phenomenon, both in the literature and from our own experience.

Hormone sensitivity of primary breast carcinoma.

PURPOSE: This study was designed to evaluate hormonal sensitivity of primary breast cancer by way of determination of estrogen receptors (ER) and progesterone receptors (PR) status as an important prognostic and predictive parameter of breast cancer. METHODS: The study enrolled 449 breast cancer patients surgically treated at the Surgical Clinic Nis, in a period covering 3 years, who continued treatment at the Clinic of Oncology, Clinical Centre Nis. All of the patients were divided into 4 groups depending on the positive or negative status of ER and PR, and 2 subgroups, those with positive or negative HER2 status. Standard descriptive statistical parameters were calculated and several types of tests were applied: Student's t-test for paired and unpaired samples, chi-square test, Mantel- Haenszel test, Fisher's test of exact probability and binary logistic regression model. RESULTS: The level of ER and PR status positively correlated with patient age, postmenopausal status, lower clinical stage, lower histologic grade (HG) and nuclear grade (NG) and better prognosis. Amplification/overexpression of HER2 positively correlated with premenopausal status and ER negative breast cancer phenotype. According to the model of binary logistic regression, clinical stage and NG of the breast primary were significantly associated with hormonal sensitivity of the tumor. CONCLUSION: Measurements of receptor macromolecules in clinical oncology is very important, especially in breast cancer patients. ER and PR analysis is an integral part of breast cancer study since it can provide information essential for both treatment and prognosis.

Clinical and biological characteristics of breast cancer.

PURPOSE: in view of the crucial importance of early detection and diagnosis of breast cancer for subsequent treatment and prognosis, the aim of this study was to identify clinical and biological characteristics of breast cancer at the time of diagnosis. METHODS: the study enrolled 449 breast cancer patients in Clinical Centre Nis. Results were analyzed using Student's t-test for paired and unpaired samples, chi-square test, Mantel- Haenszel test and Fisher's test of exact probability. RESULTS: The average patient age was 56.2 ± 12 years (range 23-85). Seventyhorbar;three percent of the affected women were postmenopausal and 8.3% below 40 years of age. Operable disease was identified in 78% of the cases, and metastatic in 3.6%. TNM clinical stage IIA was identified in 27.6% of the patients, T2 in 49.2% and Tis in 0.9%. Almost 44% had negative axillary lymph nodes. Most common monolocalization of metastatic disease was the liver and the supraclavicular lymph nodes, and combined localization was the liver and bones. Histologic and nuclear grades 2 and ductal carcinoma were most common. Estrogen receptor positive (ER+) status was 3-fold higher than ER negative (ER-) status. Human epidermal growth factor receptor 2 (HER2) positive patients were most commonly ER-. The most common primary tumor site was the upper lateral quadrant. Left breast was more commonly involved. Radical surgery was the most common type of operation. CONCLUSION: in view of the unfavorable age of patients at the time of diagnosis and clinical and biological tumor characteristics, the results confirmed that it is of vital importance to provide breast cancer prevention, screening, and to organize breast cancer units according EUSOMA guidelines.

Therapy of stage IV B anaplastic thyroid carcinoma: single institution experience.

PURPOSE: To evaluate the efficacy of radiotherapy and chemotherapy in stage IV B anaplastic thyroid carcinoma (ATC). PATIENTS AND METHODS: From 1997 to 2007, 16 inoperable patients (12 females, 4 males, median age 60 years, range 27-71) with pathologically confirmed ATC without distant metastases (UICC stage IV B) were treated with radiotherapy and chemotherapy at our Institution. Five patients had Eastern Cooperative Oncology Group (ECOG) performance status 1, and 11 ECOG 2. All patients received the planned radiotherapy tumor dose of 60 Gy. Radiotherapy was followed by chemotherapy with doxorubicin 60 mg/m(2) and cisplatin 40 mg/m(2) every 3 weeks. The primary study endpoint was response rate (RR) and secondary endpoints were toxicity and overall survival (OS). RESULTS: Only one patient achieved complete response (CR: 6.25%, 95% CI: 0-35) and 3 patients (18.75%, 95% CI: 4-46) partial response (PR), for an overall response rate (ORR) of 25% (95% CI: 7-55). No toxic deaths occurred and no grade 4 adverse events were registered after radiotherapy. Grade 4 toxicity was seen in 3 patients (18.75%, 95% CI: 4- 46) after chemotherapy. Mean patient OS was 12.33 months (95% CI: 9.09-15.56) and median OS 11.0 months (95% CI: 8.56-13.44). CONCLUSION: Radiotherapy and chemotherapy of stage IV B anaplastic thyroid carcinoma are well tolerated. Although the clinical benefit was 50%, survival rates remain low with OS of no more than 2 years.

Modern treatment of invasive carcinoma of the uterine cervix.

Treatment of invasive cervical carcinoma is determined by the clinical disease stage. Microinvasive carcinoma of the uterine cervix, due to its limited metastatic potential, is usually curable with non-radical treatment. There are no standard approaches to the treatment of stage Ib-IIa carcinoma of the uterine cervix. Both radical surgery and radical radiotherapy are utilized with similar efficacy but with different associated morbidity and complications. Stage Ib1 was commonly treated with radical hysterectomy plus pelvic lymphadenectomy. Laparoscopically-assisted radical vaginal hysterectomy demonstrated similar efficacy and recurrence rates for this disease stage. In cases where fertility is to be preserved, radical vaginal trachelectomy is a valid option for small cervical cancers. Among the papers dealing with bulky cervical disease (stages Ib-IIa) a great deal of disagreement is evident. Some oncologic centres prefer primary surgery with postoperative radiotherapy, with or without chemotherapy, while others prefer primary chemoradiotherapy. Moreover, as a possible alternative, neoadjuvant chemotherapy followed by radical surgery is recommended for stage Ib2 disease. Simultaneous chemoradiation is being introduced as a new standard for advanced cancer, since it has been clearly demonstrated that it can prolong disease-free and overall survival. The treatment of recurrent carcinoma depends on the type of previous treatment, site and extent of recurrent disease, and on the disease-free period and general health of the patient. In conclusion, the decision on the treatment approach for invasive carcinoma of the uterine cervix should be individualized, based on numerous factors, such as disease stage, general health of the patient, cancer-related factors, in order to choose the best approach with minimal complications.

Risk factors for breast cancer: a hospital-based case-control study.

PURPOSE: The factors responsible for the genesis of breast cancer remain unclear. A case-control study was undertaken to investigate the possibility of an association between hypothesized risk factors and the development of breast cancer in Serbia. PATIENTS AND METHODS: This hospital-based case-control study comprised 120 new breast cancer cases and 120 hospital controls matched with respect to age (+/- 2 years). This study used a targeted and detailed questionnaire to obtain information from respondents. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from multivariate conditional logistic regression models. RESULTS: Five independent predictors of breast cancer were: delayed age at first birth (OR=6.1, 95% CI=4.2-12.4), alcohol consumption (OR=4.8, 95% CI=1.9-12.4), family history of breast cancer in 2nd degree relatives (OR=2.5, 95% CI=1.4-4.3), never having breastfed (OR=5.2, 95% CI=1.4-18.5) and maternal death in childhood (OR=3.3, 95% CI=1.2-8.6). CONCLUSION: The results of this study confirmed that the aetiology of breast cancer in Serbia, as elsewhere, is complex. More research is needed to understand the interactions between factors that could affect vulnerability to breast cancer.

Chemotherapy in carcinomas of unknown primary site.

PURPOSE: Carcinomas of unknown primary site (CUPS) are highly malignant diseases with a usually ominous prognosis. We report on the efficacy of chemotherapy in the treatment and survival of patients with CUPS. PATIENTS AND METHODS: The study involved 63 patients with metastatic CUPS. Following routine light microscopy, the histological findings were classified into 3 groups: squamous cell carcinoma - 8 patients; adenocarcinoma - 33 patients; and undifferentiated carcinoma - 22 patients. Combination chemotherapy with doxorubicin 50 mg/m(2) (day 1), cisplatin 60 mg/m(2) (day 1), and etoposide 120 mg/m(2)/day (days 1-3) every 3 weeks was administered to 32 patients (20 females and 12 males), aged 29-70 years (median 54 years) who met the inclusion criteria. All patients with stable disease (SD), partial response (PR) or complete response (CR) received 6 cycles of chemotherapy. RESULTS: CR was achieved in 3 (9.4%), PR in 12 (37.5%), and SD in 10 (31.2%) patients. Seven (21.9%) patients had progressive disease (PD). The overall response rate (RR) was 46.9% (15/32) and the median response duration of CR+PR was 11 months (range 4-43(+) months). The overall survival (OS) of patients treated with chemotherapy (n=32; 50.8%) was better compared with the OS of those not receiving chemotherapy (n=31; 49.2%/; p <0.01). Also the 2-year survival of patients with chemotherapy (40%) and without chemotherapy (0%) implies potential curability in a specific subset of these patients. CONCLUSION: The usage of the aforementioned doses and chemotherapy scheme appears to improve the outcome of patients with carcinoma of unknown primary site.

The role of endocrine therapy in early breast cancer: adjuvant treatment of preand postmenopausal patients.

Two major trends are evident from ongoing conferences and panels of experts on early breast cancer adjuvant treatment. The first strongly suggests the application of wellestablished standards of adjuvant treatment in everyday clinical practice. The second encourages participation in international adjuvant clinical studies of breast cancer. Our growing knowledge of the role of endocrine adjuvant therapy in early breast cancer has emerged from the findings of large adjuvant studies. Meta-analyses of numerous randomised trials have accumulated evidence that has been analysed on many occasions by international panels of experts and has become a major source of consensus recommendations. Nevertheless, many open questions still exist, and new ones arise. This paper reviews the current standards for the adjuvant treatment of endocrine-dependent breast cancer, as well as some perspectives emerging from ongoing clinical studies.

Sensitivity, specificity, positive and negative predictive value of serum S-100 beta protein in patients with malignant melanoma.

PURPOSE: To establish the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of serum S-100 beta protein (sSB) in patients with malignant melanoma (MM), based on its concentration in the peripheral blood and the likelihood ratio (LR) for the whole group of patients with MM, as well as for each separate clinical stage. PATIENTS AND METHODS: sSB was determined immunoluminometrically in 172 patients with histologically confirmed MM. Sera from 64 healthy subjects were used as controls. RESULTS: Increased values of sSB were detected in 65 out of 172 patients with MM, and in 5 cases among healthy subjects. Sensitivity, specificity, PPV and NPV were 38%, 92%, 93% and 35%, respectively. In stage I 1/29 patients had increased values of sSB, in stage II 3/34, in stage III 13/47 and in stage IV 48/62 patients. Sensitivity, specificity, PPV and NPV for stage I were 3%, 92%, 17% and 68%, respectively/ for stage II 9%, 92%, 37% and 65%, respectively; for stage III 28%, 92%, 72% and 63%, respectively; and for stage IV 77%, 92%, 91%, and 81%, respectively. The LR for sSB values of >13 mug/l was 5 for the whole group of patients with MM, 0.4 for stage I, 1 for stage II, 3 for stage III and 10 for stage IV. CONCLUSION: Based on our results we conclude that sSB is a reliable serum marker for the diagnosis of stage IV MM.

Adjuvant chemotherapy of premenopausal breast cancer patients and patients under 35 years of age.

Micrometastases in patients with primary breast cancer are the rationale for adjuvant systemic treatment. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) sequential studies have shown that adjuvant systemic therapy decreases recurrence and prolongs survival. According to tumour and patient-related prognostic factors, the risk for relapse could be evaluated. If the risk for relapse is over 10% for 10 years, adjuvant systemic therapy is indicated. Adjuvant chemotherapy is associated with a greater 15-year absolute reduction in death in premenopausal than in postmenopausal patients. Anthracycline- based regimens have demonstrated superiority over classic cyclophoshamide, methotrexate and 5- fluorouracil (CMF) combination chemotherapy, and the role of taxanes is questionable. Timing and duration of adjuvant chemotherapy plays an important role in its individualization. The need for tailored treatments in premenopausal patients is most pronounced in women under 35 years of age at diagnosis.

Epidemiology of breast cancer in the city of Nis, Serbia.

PURPOSE: Over the past 10 years, Serbia has been affected by a heavy economic and political crisis that in 1999 even led to war and bombardment. Numerous facts indicate that the crisis has resulted in low-level health protection, increasing mortality, as well as other deteriorating effects over the general health of the population. The aim of the study was to assess mortality trends in female breast cancer in the city of Nis prior to (1986-1993) and following (1995- 1999) the socio-economic crisis peak. MATERIALS AND METHODS: Population and hospital cancer registry data for the 1986-1999 period were used for analysis, as well as death certificate data for all women who lived and died in the city of Nis in the given period. Survival was calculated according to the Kaplan-Meier method. The rates were calculated per 100,000 inhabitants (1991 census) and were not standardized. RESULTS: A total of 455 women in the city of Nis died of breast cancer during 1986-1999. The polynomial trend in mortality revealed an increasing (1986-1992) and decreasing (1993-1996) tendency, although the first period showed a lower average mortality (28.7) than did the second one (30.45). Survival rates were calculated for the periods 1986- 1993 and 1995-1998. The 12-month survival rate was 84.7% in the first and 92% in the second period; the 24-month survival rate for the first period was 76.6% and 87.9% for the second; the 36-month survival was 67.7% in the first and 80.5% in the second period; the 4-year survival rate for 1986-1993 was 64.1% and 78.1% for 1995-1999. CONCLUSION: The socio-economic and political crisis has proved to affect breast cancer patients in Serbia. Overall, the mortality rate increased. Calculated upon division of the whole period into two, mortality shows an upward trend in the first period (1986-1992) and a downward trend in the second. Although 1993-1999 was more difficult for the Serbian and Yugoslavian population (manifested in the therapy of all diseases, including breast cancer), the diagnosis of breast cancer improved and the disease was detected at earlier stages, the result of which were better survival rates in the 1986-1992 period.