Serbian consensus of neoadjuvant therapy for breast cancer: NeoPULSE.

Even though surgery is the primary treatment of operable breast cancer, it has been known for decades that the administration of postoperative adjuvant or preoperative neoadjuvant therapy is extremely important. Indications for neodjuvant therapy administration have been expanded over the years, and nowadays this kind of treatment represents an inevitable option in early breast cancer treatment. The NeoPULSE project, which gathered a group of experts in the field of breast cancer from five Serbian university centres, was formed with the aim to define optimal breast cancer diagnosis, indications for neoadjuvant therapy, therapeutic combinations in relation to molecular/biological parameters of breast cancer, as well as the treatment after neoadjuvant therapy. During two separate expert meetings involving surgeons, medical oncologists, radiation oncologists, a pathologist, and a "Blueprint" workshop, the project participants answered questions over the indications for neoadjuvant therapy. The first part covered local practice and referred to the existence and work of a multidisciplinary team, as well as commonly applied therapeutic regimens in the neoadjuvant setting. Experts analysed personal views regarding indications for the administration and benefits of neoadjuvant therapy, their perception on the correlation between achieving a pathological complete response (pCR) and the outcome of treatment, as well as the attitude towards controversies about this type of treatment, primarily regarding a possible change in the receptor status after therapy and therapeutic options after a suboptimal response. The analysis of the answers pointed to problems and deviations from recommendations in everyday clinical practice, based on which appropriate solutions were proposed. The establishment of such a panel and consensus is an attempt to modernize multidisciplinary teams in Serbia, achieve reaching uniform decisions of all subjects dealing with breast cancer, and therefore, at least in one segment, improve breast cancer treatment in Serbia.

Modulatory effect of neoadjuvant chemotherapy on the prognosis of patients with breast cancer.

PURPOSE: To evaluate the changes in biological markers ER, PR, HER2 and Ki67 in residual tumor after surgery for locally advanced breast cancer (LABC), and also to evaluate the outcome of breast cancer patients treated with neoadjuvant chemotherapy (NAC). METHODS: 144 breast cancer patients treated with NAC at the Oncology Institute of Vojvodina, Serbia from 2011 to 2015 were included in this study. Changes in biologic markers ER,PR, HER2/neu and Ki-67 were evaluated at diagnostic core biopsy and at the final surgery tissue specimens. RESULTS: Of 144 patients pathological complete response was achieved in 17 (12%) and these were excluded from the study. Evaluated were 127 patients with residual tumor after the final surgery. A change in hormone receptor status (ER,PR) occurred in 9.4% of the patients (ER in 5%, PR in 14.5%) and HER2 status in 4.7% of the patients. ER and PR status change from negative to positive was associated with better overall survival (OS), but without statistical significance (p=0.16). Patients with conversion of HER2 status from negative to positive lived longer (65 vs 42 months). Furthermore, it was determined that HER2 change from negative to positive was associated with better OS (p=0.03). Ki-67 changed in 17 (11.8%) patients. The decrease of Ki-67 expression after NAC was associated with better outcome. Median follow up was 37.5 months (range 16.2-76.8). CONCLUSION: Changes in hormone receptor status, HER2 status and Ki-67 occurred after NAC in patients with LABC. A change from negative to positive hormone receptor status and HER2 status offers new treatment options, like endocrine therapy, and/or trastuzumab therapy for breast cancer patients. The decrease of Ki-67 expression after NAC was associated with better outcome.

MIA, S100 and LDH as important predictors of overall survival of patients with stage IIb and IIc melanoma.

PURPOSE: Melanoma represents the most severe form of skin cancer. Detection of specific tumor markers is an important step in disease diagnosis and treatment, contributing to personalized therapy. The purpose of this study was to evaluate the potential of MIA, S-100 and LDH as biomarkers for the estimation of overall survival and disease-free survival rate in patients with stage IIa, IIb vs stage IIc melanoma. METHODS: Selected biomarkers MIA, S-100 and LDH were prospectively evaluated in 80 patients with melanoma. Patients were divided in two groups according to tumor thickness. The first group (group A) consisted of patients with primary tumor thickness between 2.0 - 4.0 mm (N=40), i.e. IIa and IIb stage of disease (16 males; 40%, and 24 females; 60%). The second group (group B) consisted of 40 patients with primary tumor thickness over 4.0 mm, i.e. IIc stage, which is considered as high risk group (26 males; 65%, and 14 females 35%). Statistical analyses were performed to estimate overall survival and disease-free survival in both patient groups. RESULTS: In group A a significant difference in overall survival was found among MIA1, MIA2 and MIA3 scores, while the other 2 markers didn't show significant differences. In group B statistically significant differences in overall survival were found regarding all three biomarkers. Statistically significant differences in disease-free survival were found for MIA1 score compared to MIA2 and MIA3 scores. Also, very significant difference was detected in patients with S-100 below 0.106 and above 0.106. The same was confirmed for normal and increased LDH level in group B for disease-free survival. CONCLUSION: MIA score, S100 protein and LDH in the IIC group B patients might be useful in the prediction of overall survival and disease free survival.

Segmental cavernous carotid ectasia in a patient with cluster-like headache.

INTRODUCTION: Cluster headache (CH) is a primary headache with severe, unilateral periorbital or temporal pain lasting 15-180 min, accompanied with various cranial autonomic features. A diagnosis of cluster-like headache can be made whenever underlying cause of CLH is present. METHODS AND RESULTS: We report a case where an ectatic cavernous segment of the internal carotid artery triggered CHL, most probably due to compression of the ophthalmic nerve within cavernous sinus. The pathological substrate of a vessel ectasia is degeneration of the tunica intima as a consequence of atherosclerosis and hypertension. On the other hand, cavernous sinus is unique space where parasympathetic, sympathetic and nociceptive fibers are in intimate relationship which is of great importance for understanding of CH pathophysiology. CONCLUSION: Magnetic resonance imaging and MR angiography are mandatory imaging tools used for precise localization of pathological changes in the cavernous sinus, especially in the group of secondary headaches attributed to vascular disorders.

Young age and pathological features predict breast cancer outcome - report from a dual Institution experience in Serbia.

PURPOSE: The aim of this study was to investigate the influence of clinicopathological and biological characteristics on prognosis, disease free survival (DFS) and overall survival (OS), of very young patients (≤35 years of age) with breast cancer. METHODS: We retrospectively collected information of 150 women diagnosed with breast cancer, aged ≤35 years, who were operated and treated at two University Hospitals in Serbia between January 2009 and February 2011. RESULTS: After a median follow up of 44 months patients ≤30 had shorter DFS and OS compared to patients aged 31-35 years (p=0.004 and p=0.037, respectively). The differences in DFS and OS were significant with decreased survival associated with higher tumor grade (p=0.005 and p=0.0001, respectively). Tumor size and number of positive nodes were predictors of outcome with decreased survival associated with higher tumor size (p=0.0019 for DFS and p<0.0001 for OS) and increasing number of nodes (p<0.0001 for both). HER 2 receptor did not seem to have a prognostic influence while patients with hormonal receptors (HRs) positive tumors had a better DFS (p=0.034) and OS (p=0.046) than those with HRs negative tumors. In univariate survival analysis, a significant difference in DFS (p=0.0003) and OS (p=0.0003) was found between patients with vs without lymphovascular invasion (LVI). CONCLUSION: Diagnosis of breast cancer at very young age (<30) was associated with increased risk of death and shorter DFS than women aged 31-35. Negative impact on survival was seen in patients with presence of LVI, negative HRs and higher grade and stage at the time of presentation.

The efficacy of lapatinib in patients with metastatic HER2 positive breast cancer who received prior therapy with monoclonal antibodies and antibody-drug conjugate: a single institutional experience.

The choice of the anti-HER2 agent depends on country-specific availability, the specific, previously administered anti-HER2 therapy and the relapse-free interval, although there is not much published data on the use of lapatinib after progression on pertuzumab and/or T-DM1. The aim of this research is to determine efficacy of lapatinib in this setting. This research included 111 patients with metastatic HER2 positive breast cancer who received lapatinib with capecitabine at The Oncology Institute of Vojvodina. Lapatinib was given to 83 patients after trastuzumab without prior exposure to pertuzumab or T-DM1 while 28 patients received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1. In order to determine efficacy of lapatinib in both groups, we measured progression free survival (PFS) and overall survival (OS), as well as by subsets: hormonal status (ER-positive and/or PR-positive tumours versus ER-negative and PR-negative tumours), the number of positive axillary lymph nodes (four or more positive axillary lymph nodes versus less than four positive axillary lymph nodes), marker of proliferation (Ki-67 ≥ 30 versus Ki-67 < 30), disease free interval (metastatic recurrence ≤ 1 year after initial diagnosis versus metastatic recurrence > 1 year after initial diagnosis or de novo metastatic disease. Median PFS was 5.6 months (95% CI 4.6-6.6) in the group of patients who received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM 1 and 7.4 months (95% CI 6.1-10.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.79; 95% CI 0.61-0.98; P = 0.09). The patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes, marker of proliferation Ki 67 ≥ 30 and metastatic recurrence ≤ 1 year after initial diagnosis, had a similar PFS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Median OS was 10.1 months (95% CI 8.6-NR) in the group that received lapatinib after exposure to trastuzumab, pertuzumab and/or T-DM1 and 16.3 months (95% CI 14.4-20.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.76; 95% CI, 0.59-0.94; P = 0.04). Patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes and marker of proliferation Ki 67 ≥ 30, had no distinctly worse OS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Lapatinib with capecitabine is an effective therapeutic option, especially in patients with negative prognostic factors, who have received prior chemotherapy, trastuzumab, pertuzumab, T-DM1 and remains an acceptable option for HER2 positive metastatic breast cancer until the novel drugs are approved in developing countries.

Concurrent chronic lymphocytic leukemia and merkel cell carcinoma in primary skin tumor and metastatic lymph node.

Association between chronic lymphocytic leukemia and other malignancies has been known for a long time. This epidemiological phenomenon is explained by immunosuppression caused by disease itself or by the applied therapy. Merkel cell carcinoma is a rare malignant tumor of the skin of neuroendocrine origin diagnosed almost exclusively in immunocompromised host. We presented an unique case of coexisting infiltration of chronic lymphocytic leukemia cells within primary cutaneous Merkel cell carcinoma and metastatic lymph node in young HIV-negative female patient.

Increasing frequency of soft tissue sarcomas in Vojvodina - comparison with the literature.

BACKGROUND: Soft tissue sarcomas (STS) represent 1% of all malignant lesions. In this study the authors analyzed the incidence of STS in Vojvodina (the north region of Serbia) in the period from 1985 to 2009. A number of studies conducted worldwide indicate that STS incidence rates are tending to increase. MATERIALS AND METHODS: On the basis of data from the Cancer Registry of Vojvodina, age standardized STS incidence rates were established as well as their linear trend, with data on histological structure, age, gender and STS distribution at specific locations. RESULTS: The total number of registered patients was 1,308. Average age standardized rate was 1.90/100,000 per year. The investigated period showed a slight increase in the incidence rate (average annual percent increase=0.77%). The most frequent histological type was sarcoma not otherwise specified-NOS (27%), followed by leiomyosarcoma (21%), liposarcoma (14%), rhabdomyosarcoma (11%) and malignant fibrous histiocytoma (9%). The male/female ratio was 0.73:1. Every fifth patient was younger than 39. CONCLUSIONS: Comparison among eight international STS epidemiology studies show that the incidence rate range is between 1.4/100,000-5.0/100,000, though our finding is closer to the lower limit. Furthermore, the incidence rate increase was lower than that characteristic for the half of the analyzed studies. A partial explanation for that should be looked for among changes in diagnostic criteria and STS classifications.

Treatment of acute hepatitis C in breast cancer patient: a case report.

Oncologists worldwide are often dealing with hepatitis C virus positive breast cancer patients, questioning adequate chemotherapy protocol, reduction of doses, delays, or even interruptions of treatment. We present a case of a woman in stage IIIB breast cancer, who after the completion of neoadjuvant treatment developed significant increase in liver enzymes and was diagnosed positive for HCV. She was treated with interferon and after the resolving of acute liver disease continued concomitant treatment with interferon, ribavirin, docetaxel, and trastuzumab. Grade 4 neutropenia and grade 3 hepatotoxicity occurred after the third cycle of chemo and 5 months of antiviral therapy. Interferon and chemotherapy were postponed for 1 week. There are no sufficient data in order to recommend the concomitant antiviral and antineoplastic therapy. Hepatitis C virus and antiviral therapy may increase the toxicities of antineoplastic treatment. However, when lifesaving oncologic treatment is necessary, concomitant antiviral therapy can be administered with more intensive follow up.