Prognostic and Clinicopathological Correlations of Cell Cycle Marker Expressions before and after the Primary Systemic Therapy of Breast Cancer.

We aimed to analyze the expression of cell-cycle regulation markers - minichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) - in pre-treatment core-biopsy samples of breast carcinomas in correlation with known predictive and prognostic factors. Totally 52 core biopsy samples obtained prior to neoadjuvant therapy were analyzed. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, the presence of tumor infiltrating lymphocytes (TIL), pathological tumor response rate to the neoadjuvant therapy and patient survival. All investigated markers showed higher expression in high grade and in triple negative tumors (p < 0.01 and p < 0.05, respectively). Hormone receptor negative tumors showed significantly higher expression of Ki-67 (p < 0.01), MCM2 (p < 0.01) and Cyclin A (p < 0.01) than hormone receptor positive ones. Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04). Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher rate of pathological complete remission. Tumors with early relapse (progression-free survival ≤2 years) and shortened overall survival also show a higher rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify tumors with worse prognosis, but with a favorable response to primary systemic therapy. The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to be further substantiated in larger patient cohorts.

LAPTM4B gene copy number gain is associated with inferior response to anthracycline-based chemotherapy in hormone receptor negative breast carcinomas.

PURPOSE: To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas. PATIENTS AND METHODS: Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.). RESULTS: In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups. CONCLUSION: Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR- breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

Breast carcinoma subtypes show different patterns of metastatic behavior.

The aim of our retrospective study was to analyze patterns of subtype specific metastatic spread and to identify the time course of distant metastases. A consecutive series of 490 patients with breast cancer who underwent surgery and postoperative treatment at Semmelweis University, Hungary, and diagnosed between the years 2000 and 2007 was identified from the archives of the 2nd Department of Pathology, Hungary. Molecular subtypes were defined based on the 2011 St. Gallen recommendations. Statistical analysis was performed with SPSS Statistics for Windows, Version 22.0. Distant metastasis free survival (DMFS) was defined as the time elapsed between the first pathological diagnosis of the tumor and the first distant metastasis detection. Distant metastases were detected in 124 patients. Mean time to develop metastasis was 29 months (range 0-127 months). The longest DMFS was observed in the Luminal A (LUMA) subtype (mean 39 months) whereas the shortest was seen in the HER2-positive (HER2+) subtype (mean 21 months; p = 0.012). We confirmed that HER2+ tumors carry a higher risk for distant metastases (42.1%). LUMA-associated metastases were found to be solitary in 59% of cases, whereas HER2+ tumors showed multiple metastases in 79.2% of cases. LUMA tumors showed a preference for bone-only metastasis as compared with HER2+ and triple negative breast cancer (TNBC) cases, which exhibited a higher rate of brain metastasis. The most frequent second metastatic sites of hormone receptor (HR) positive tumors were the lung and liver, whereas the brain was the most affected organ in HR-negative (HR-) cases. Tumor subtypes differ in DMFS and in pattern of distant metastases. HER2+ tumors featured the most aggressive clinical course. Further identification of subtype-specific factors influencing prognosis might have an impact on clinical care and decision-making.

[Latest international guidelines for screening, prevention and treatment of familial breast cancer - implications for the relevant practice in Hungary]. / Az örökletes emlorák szurésének, megelozésének és kezelésének új nemzetközi irányvonalai - hazai vonatkozásokkal.

INTRODUCTION: Screening, prevention and treatment of familial breast cancer require a multidisciplinary approach. New guidelines were published in the United Kingdom for the management of familial breast cancer. AIM: The authors summarise these new guidelines and analyse the relevant practice in Hungary. METHOD: Relevant guidelines of the National Institute for Health and Care Excellence and Familial Breast Cancer Report (NHS Scotland) are described. RESULTS: New guidelines will increase the number of genetic tests as well as genetic counselling. An increase in the number of breast magnetic resonance imaging is expected, too. Chemoprevention can be offered for individuals with medium risk and above. Promising trials are underway with platinum based chemotherapy and polyADP-ribose polimerase inhibitors for the systemic treatment of familial breast cancer. The increase in the number of genetic tests, counselling, and breast magnetic resonance imaging may have a significant impact on health care budget. CONCLUSIONS: These guidelines will change some aspects of the current management of familial breast cancer. Orv. Hetil., 2016, 157(28), 1117-1125.

[A giant myxoid leiomyoma mimicking an inguinal hernia]. / Lágyéksérvet utánzó gigantikus méretu myxoid leiomyoma.

Leiomyoma is a rare, smooth muscle tumour that can occur everywhere in the human body. The authors present the history of a 60-year-old female, who had a giant, Mullerian type myxoid leiomyoma in the inguinal region mimicking acute abdominal symptoms. After examination the authors removed the soft tissue mass in the right femoral region reaching down in supine position to the middle third of the leg measuring 335 × 495 × 437 mm in greatest diameters in weight 33 kg. Reconstruction of the tissue defect was performed using oncoplastic guidelines. During the follow-up time no tumour recurrence was detected and the quality of life of the patient improved significantly.

Stromal matrix protein expression following preoperative systemic therapy in breast cancer.

PURPOSE: Stromal alterations are observed following preoperative systemic therapy in breast cancer. The aim of the present study was to analyze the qualitative and quantitative changes of representative tumor stroma proteins in the context of neoadjuvant therapy and the response of patients undergoing preoperative systemic therapy. EXPERIMENTAL DESIGN: Fifty women receiving preoperative systemic therapy were evaluated for clinical and pathologic parameters. Clinical response was defined according to International Union against Cancer (UICC) criteria, whereas pathologic responses to preoperative systemic therapy were defined according to the Chevallier and Sataloff classifications. The expression of tenascin-C, syndecan-1, collagen IV, and smooth muscle actin proteins was investigated using morphometric analysis of immunohistochemical reactions. Quantitative reverse transcription-PCR was done to evaluate the mRNA expression level of syndecan-1 and tenascin-C. The data were compared with 20 breast cancer samples of patients not treated with preoperative systemic therapy. RESULTS: According to UICC criteria, the expression levels of collagen IV were up-regulated in all preoperative systemic therapy-treated patients (P = 0.002). Collagen IV was up-regulated in the preoperative systemic therapy group in both Chevallier and Sataloff classifications compared with the control cases (P = 0.025 and P = 001, respectively). There were no significant differences in the expression of smooth muscle actin between the treated and nontreated groups. The syndecan-1 proteoglycan level was significantly down-regulated in the preoperative systemic therapy group (Chevallier classes P = 0.015, Sataloff classes P = 0.015). Tenascin-C was up-regulated in women with progressive disease (P = 0.005). CONCLUSION: We have observed that the stromal component of breast carcinomas following preoperative systemic therapy differs from the nontreated tumors, which can be evaluated with the analysis of the above mentioned proteins.

[Immunohistochemical phenotype of breast carcinomas predicts the effectiveness of primary systemic therapy]. / Az emlodaganatok primer szisztémás kemoterápiára adott válasza az immunhisztokémiai fenotípus tükrében.

The purpose of the study was to identify breast cancer subtypes by immunohistochemistry likely to respond to neoadjuvant chemotherapy and to analyze the used chemotherapy regimen and the range of response rates. Analysis of a collected database was performed. Ninety-two patients were identified in our files who received neoadjuvant chemotherapy between 1998 and 2009. We used immunohistochemical profiles (ER, PgR, HER2, Ki-67 and p53) of NCB, FNAB and surgical breast specimens to subclassify the tumors. Pathological response rates were assessed following surgical removal of tumors by using the Chevallier classification. DFS and OS was measured in 88 cases from the date of definitive surgery to the date of last follow-up or death. Pathological complete or near-complete remission (pCR = Chevallier I and II) was observed in 13 of 92 cases (14.1%). According to the preoperative characteristics of the 13 tumors achieving pCR, 9 of the cases were triple negative, one of 13 was ER-/HER2+ and three of 13 ER+/HER2+. Twenty-four of 92 patients received taxane based neoadjuvant chemotherapy, 30 of 92 anthracycline based neoadjuvant chemotherapy, 33 of 92 taxane + anthracycline regimen and 2 of 92 CMF regimen. In the taxane treated group of patients the pCR rate was 29.1%, in the anthracycline group 6.6% and in the taxane + anthracycline treated group 12.1%. Concerning DFS, significant difference was observed between the Chevallier III and IV groups (p=0.006), and less events were observed in the pCR group (not significant). pCR was associated with significantly better OS (p=0.050). It seems that even limited, routinely used immunohistochemical profiling of tumors is able to predict the likelihood of pCR to neoadjuvant chemotherapy. Patients with triple negative and HER2-positive cancers are likely to achieve pCR after neoadjuvant chemotherapy.

[Failure of diagnosing pancreatic tumors in the course of laparoscopic cholecystectomy: surgical lessons]. / Laparoszkópos cholecystectomia kapcsán fel nem ismert pancreasrák, mutéti tanulságok.

INTRODUCTION: In Hungary surgeons perform approximately 24000 cholecystectomies per year. Nowadays the choice of treatment of uncomplicated cholelithiasis is laparoscopic cholecystectomy. The advantages and popularity of the procedure are well known; otherwise the exploration of the abdominal cavity is not so complete than during open surgery. In the course of laparoscopic surgery the surgeon has minimal chance to find the preoperatively not diagnosed tumour. AIMS: In our retrospective study we analysed those complains and clinical signs, when we suspect the presence of a pancreas tumour. PATIENTS AND METHODS: We analysed the clinical data of patients who were operated on with pancreatic tumor and before the surgery, laparoscopic cholecystectomy had been performed in the previous 24 month. RESULTS: In the period of 1996-2003 we operated 1515 patients with pancreatic tumor, at our clinic. 21 patients (1.39%) had laparoscopic cholecystectomy in the last 24 month, before the surgery. The age of the patients was between 50-78 (average age 65), the rate of the female and male patients was 15/6. Most of the patients had weight loss (in 11 cases it was considerable, 5.4 kg in one month) and the uncertain abdominal pain, feeling of discomfort, meteorism was also characteristic of these patients. In 16 cases (76%) the blood glucose level had been elevated. The ultrasound examination before the cholecystectomy in these cases was focused to the gall bladder. After the cholecystectomy, complains did not disappear definitely and further diagnostic steps verified the pancreatic tumour. The average time between the laparoscopic cholecystectomy and the open surgery was 10 month. In 4 cases we were able to remove the tumor, but in 17 cases only palliative operation was performed. CONCLUSIONS: If the patient is over the age of 50, especially if he is male, has weight loss and if the symptoms are not characteristic of gallbladder disease, further diagnostic steps are necessary before cholecystectomy. Complains remaining after laparoscopic cholecystectomy must be indication for urgent diagnostic steps. The life expectancy of patients with advanced pancreatic tumor is very poor.