Sentinel lymph node biopsy following previous axillary surgery in recurrent breast cancer.

INTRODUCTION: Ipsilateral breast recurrence or second primary breast cancer can develop in patients who have undergone breast conserving surgery (BCS) and axillary surgery. The purpose of this study was to examine the feasibility of a reoperative sentinel lymph node biopsy (SLNB) as a repeated axillary staging procedure. PATIENTS AND METHODS: From August 2014 through January 2017 patients with locally recurrent breast cancer or with BRCA mutation requiring risk reduction mastectomy as a second surgical procedure, underwent repeat SLNB in three Hungarian Breast Units with a radiocolloid (and blue dye) technique. RESULTS: Hundred and sixty repeat SLNBs were analysed, 80 after previous SLNB and 80 after previous total or partial axillary lymph node dissection (ALND). SLN identification was successful in 106 patients (66%); 77/80 (77.5%) and 44/80 (55%) in the SLNB and ALND groups, respectively. (p < 0.003). Extra-axillary lymph drainage was more frequent in the ALND group (19/44, 43,2% versus 7/62, 11,3%; p < 0.001). Lymphatic drainage to the contralateral axilla was observed in 14 patients (11 in the ALND group, p = 0.025), isolated parasternal drainage was detected in 4 patients (p = 0.31). Only 9/106 patients with successful repeat SLNB (8,8%, all with 1 SLN removed) had SLN metastases CONCLUSIONS: Repeat SLNB is feasible in patients with ipsilateral breast tumor recurrence or new ipsilateral primary tumor after previous BCS and axillary staging. Repeat SLNB should replace routine ALND as the standard axillary restaging procedure in recurrent disease with a clinically negative axilla. Preoperative lymphoscintigraphy is important to explore extra-axillary lymphatic drainage in this restaging setting.

Eight-year follow up result of the OTOASOR trial: The Optimal Treatment Of the Axilla - Surgery Or Radiotherapy after positive sentinel lymph node biopsy in early-stage breast cancer: A randomized, single centre, phase III, non-inferiority trial.

INTRODUCTION: The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer. PATIENTS AND METHODS: Patients with primary invasive breast cancer (cN0 and cT ≤ 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment. CONCLUSIONS: The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT ≤ 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases.

Objective decision making between conventional and oncoplastic breast-conserving surgery or mastectomy: An aesthetic and functional prospective cohort study.

BACKGROUND: Breast-conserving surgery (BCS) is considered the standard treatment for early-stage breast cancer. However, fair to poor cosmetic outcomes following conventional BCS have been observed in as many as one-third of cases. The aim of this study was to determine the critical tumor-to-breast volume ratio for each quadrant of the breast beyond which conventional BCS would no longer offer acceptable cosmetic and functional results or satisfactory quality of life for the patient. METHODS: A prospective cohort study was performed between December 2011 and December 2013 involving 350 patients younger than 70 years with early-stage unifocal (T ≤ 30 mm) breast cancer who underwent wide excision and axillary sentinel lymph node biopsy followed by whole-breast irradiation. Using validated panels and software (the Breast Cancer Treatment Outcome Scale [BCTOS], EORTC Cancer Quality of Life Questionnaire number C30-BR23, and Breast Cancer Conservative Treatment - cosmetic results [BCCT.core] software), quality of life and aesthetic and functional parameters and their changes in correlation to the percentage of breast volume excised were statistically analyzed. RESULTS: The maximum percentages of breast volume that were resectable by conventional BCS without resulting in unacceptable aesthetic and functional outcomes or decreased quality of life were 18-19% in the upper-outer quadrant (p < 0.0001), 14-15% in the lower-outer quadrant (p < 0.0001), 8-9% in the upper-inner quadrant (p < 0.0001), and 9-10% in the lower-inner quadrant (p < 0.0001). CONCLUSION: Aided by the calculated cut-off values for each breast quadrant, breast surgeons might render more objective decisions regarding performing conventional BCS, using oncoplastic techniques or choosing mastectomy with immediate reconstruction.

Comparison of immunophenotypes of primary breast carcinomas and multiple corresponding distant metastases: an autopsy study of 25 patients.

Phenotypical change in metastatic breast carcinoma has widely been accepted as an inherent biological feature rather than technical fault. We analyzed the immunohistochemical phenotype and histopathological features of 25 primary breast carcinomas and 90 corresponding distant metastases in 23 organs retrospectively. Histological slides were reviewed for prognostic and predictive factors. Overall, metastases were more similar to each other and often differed from the primary tumor. We created a 3-step grouping system based on the localization of metastases. Regions: tumors metastasizing to the abdominal region were likely to lose ER (p = 0.002); we detected loss of PR in metastases to the thorax (p = 0.039) and abdomen (p < 0.001). Organ systems: loss of ER and PR was observed in metastases to the gastrointestinal system (p = 0.026 and p = 0.001, respectively), in the respiratory system only the loss of PR was significant (p = 0.05). Individual organs: the primaries were likely to lose the hormone receptors in liver metastases (ER p = 0.026; PR p = 0.004). In lung metastases only loss of PR was apparent (p = 0.049). We did not observe significant change in HER2 status, regarding Ki67 change occurred only in bone metastases compared to the primary (p = 0.048). 7/25 patients' distant metastases had heterogeneous immunoprofiles. The later the metastasis was discovered the more likely it had a differing IHC profile compared to the primary tumor, patients who had longer OS had a higher chance to develop a discordant metastasis. Immunoprofile of metastases may differ from primary breast cancer and from each other, probably resulting in different response to therapy.

Does breast screening offer a survival benefit? A retrospective comparative study of oncological outcomes of screen-detected and symptomatic early stage breast cancer cases.

INTRODUCTION: Mammography screening reduces breast cancer mortality by up to 32%. However, some recent studies have questioned the impact of non-palpable breast cancer detection on mortality reduction. The aim of this study was to analyse the clinicopathological and long-term follow-up data of early stage screened and symptomatic breast cancer patients. PATIENTS AND METHOD: The institutional prospectively led database was systematically analysed for breast cancer cases diagnosed via the mammography screening program from 2002 to 2009. As a control group, symptomatic early stage breast cancer patients were collected randomly from the same database and matched for age and follow-up period. All medical records were reviewed retrospectively. RESULTS: Data from 298 breast cancer patients were collected from 47,718 mammography screenings. In addition, 331 symptomatic breast cancer patients were randomly selected. The screened group presented a significantly lower median tumour size (P < 0.00001). The incidence of negative regional lymph nodes was significantly higher in the screened group (P < 0.0006). The incidence of chemotherapy was 17% higher in the symptomatic group (P = 4*10-5). At the median follow-up of 65 and 80 months, the screened group did not exhibit better overall (P = 0.717) or disease-free survival (P = 0.081) compared to the symptomatic group. CONCLUSION: Our results do not suggest that mammography screening does not reduce breast cancer mortality but the mammography screening did not bring any significant improvement in patient overall or disease-free survival for the early stage breast cancer patients compared to the symptomatic group. The drawback of symptomatic early stage tumours compared to non-palpable tumours could be equalized by modern multimodality oncology treatments.

Accuracy of the determination of S100B protein expression in malignant melanoma using polyclonal or monoclonal antibodies.

AIMS: To compare the routinely used polyclonal anti-S100 and a mouse monoclonal anti-S100B antibody for their accuracy in the detection of the S100B expression profile (pattern and intensity) in a series of 67 primary (n = 37) and lymph node metastatic (n = 30) melanoma tissues. S100B is the lineage marker of malignant melanoma. Antibodies routinely used for melanoma diagnosis are not necessarily specific for this protein. Furthermore, clinical monitoring of melanoma progression is mostly based on the determination of serum S100B protein levels without knowing the actual expression level in the primary and/or metastatic tissue. METHODS AND RESULTS: The profile of expression patterns (focal, heterogenous and diffuse) as well as intensity ranges (+, ++ and +++) were similar for the two antibodies in melanoma tissues. However, comparison of the patterns and intensities on the basis of individual cases revealed a high frequency of discrepancies (50.7 and 58.2%, respectively). Severe discrepancy between the two antibodies in the determination of the S100B protein expression pattern (focal versus diffuse or focal versus heterogeneous) was relatively frequent; 13.4 and 11.9%, respectively. Furthermore, a similar rate of severe discrepancy was observed between the two antibodies in the determination of the intensity of S100B expression levels (+ versus +++ or + versus ++); 19.4 and 8.9%, respectively. Separate analysis of the primary tumours and metastases gave similar results. CONCLUSION: For the accurate determination of S100B protein expression in malignant melanoma it is highly recommended that a monospecific antibody is used.

Heterogenous S-100B protein expression patterns in malignant melanoma and association with serum protein levels.

OBJECTIVE: Serum S-100B is a reliable tumor marker of malignant melanoma, but efficient use is restricted to patients with metastatic disease. Therefore, the aim of our study was to assess serum S-100B levels at different stages of malignant melanoma and to compare these levels with the expression of the S-100B phenotype in primary tumors and lymph node metastases. METHODS: Fifty-nine patients were included in this study; serum S-100B protein was measured using an immunoluminometric assay while the expression pattern in the primary tumor was determined by immunohistochemistry using an anti-S-100B monoclonal antibody. RESULTS: Serum S-100B concentrations were significantly elevated in stage III (p = 0.01) patients, with normal levels in stage I-II. The most frequent S-100B protein expression pattern of the melanoma tissue was found to be diffuse staining observed in around half of the cases (52.5%) followed by heterogeneous (30.5%) and focal patterns (17%), being independent of the stage as well as the lymph node involvement. In stage I-II patients, the various staining patterns did not correlate with the serum concentration of the S-100B protein, while in stage III patients with heterogenous or diffuse S-100B staining patterns in tumor tissue, the serum marker concentration was significantly higher (p < 0.05) than in patients with focal staining. Furthermore, S-100B staining of the melanoma tissue also differed (low/negative, medium and strong staining), and serum marker concentrations corresponded to the pattern of the staining intensity. In stage I-II, only strong staining was associated with elevated serum S-100B concentrations while in stage III medium and strong staining was found to be associated with significantly higher serum marker concentrations compared to patients with tumors with low/negative staining (p < 0.05). CONCLUSIONS: In malignant melanoma characterized by focal and/or low S-100B staining in the tumor tissue determined by immunohistochemistry, S-100B monitoring in the serum may not suffice to detect disease progression.

[Morphological parameters of breast cancers detected by mammography with and without organized screening; a comparative study]. / Mammográfiával felismert rákok morphologiai paramétereinek összehasonlítása a területileg szervezett szürés során és alkalomszerüen vizsgáltaknál.

Some pathological findings and prognostic indices recorded in breast cancer cases, detected, on one hand, by a provider-initiated mammography screening program (Group 1), and, opportunistically, in self-referred symptomatic women (Group 2) on the other, are compared. In 8877 symptom-free women, aged 50-65 years, individually invited to attend the screening offered for the residents of the III., XII. and XIII. districts of Budapest, 67 cancer cases were detected (7.5 in 1000 screenees), in accordance with the cancer detection rate of the first, "prevalence" round of organised screening programmes. In the other group of 1593 symptomatic, self-referred women of the same age, 113 cancer cases were diagnosed by mammography. As far as the pathological parameters are concerned, the number of cases with invasive cancer less than 15 mm in diameter, and those with axillary nodes present was found to be significantly higher in the screened group as compared to the self-referred one (p < 0.01). In "small" cancers (i.e. less than 15 mm in diameter), no significant difference was found in the proportion of histologic grade III tumours among the two groups. In screen-detected cancers both the morphometric prognostic index (as calculated by Baak et al.) and the Nottingham Prognostic Index (NPI) proved to be more favourable, as compared to those in the self-referred group. The p-value as determined by Mann-Whithey test was 0.000003 in the screened group, and 0.000015 in the other one. These findings provide convincing evidence in support of the public health importance of provider-initiated, organised mammography screening for breast cancer, therefore, the introduction on service basis of organised breast screening into the health care system in Hungary is strongly recommended by the authors.

High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history.

To determine the contribution of BRCA1 and BRCA2 mutations to the pathogenesis of male breast cancer in Hungary, the country with the highest male breast cancer mortality rates in continental Europe, a series of 18 male breast cancer patients and three patients with gynecomastia was analyzed for germ-line mutations in both BRCA1 and BRCA2. Although no germ-line BRCA1 mutation was observed, 6 of the 18 male breast cancer cases (33%) carried truncating mutations in the BRCA2 gene. Unexpectedly, none of them reported a family history for breast/ovarian cancer. Four of six truncating mutations were novel, and two mutations were recurrent. Four patients (22%) had a family history of breast/ovarian cancer in at least one first- or second-degree relative; however, no BRCA2 mutation was identified among them. No mutation was identified in either of the genes in the gynecomastias. These results provide evidence for a strong genetic component of male breast cancer in Hungary.

N-acetyl cysteine ameliorates ischemic renal failure.

Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.

The p53-independent activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal failure.

In three different models of acute renal failure (ischemia, ureteral obstruction, and cisplatin administration), the p21WAF1/CIP1/SDI1 gene, the protein product of which is associated with cell-cycle interruption, terminal differentiation, and cellular senescence, was activated in murine kidney cells. This transcription was localized in kidney only to cells of thick ascending limbs and distal convoluted tubules. Although the tumor suppressor protein, p53, can trans-activate the p21 gene in some cells, increased levels of nuclear p53 protein could be demonstrated only in the cisplatin model of acute renal failure. High levels of p21 mRNA were induced in kidney of p53 "null" mice, demonstrating that p21 gene activation was through a p53-independent pathway. We also present evidence that, in the cisplatin model, both p53-independent and p53-dependent induction of p21 mRNA occur simultaneously. We conclude that p21 gene activation is a general response to renal injury and could be a key determinant of cell fate in the cell in which it is expressed.

DNA synthesis is dissociated from the immediate-early gene response in the post-ischemic kidney.

The response of the kidney to ischemic injury includes increased DNA synthesis, which is preceded by rapid and brief expression of the c-fos proto-oncogene. While the timing of these two events would suggest that c-Fos participates in an immediate-early gene program leading to proliferation, no direct test of this hypothesis exists. The purpose of these studies was (1) to determine whether c-fos is expressed as part of a typical immediate-early (IE) gene response, which would require co-expression of c-jun and sensitivity to cycloheximide, and (2) to determine whether the cells expressing c-Fos are the same as those undergoing DNA synthesis. Northern analysis was performed on renal mRNA at different times following release of a 50 minute period of renal hilar clamping. c-jun and c-fos mRNA were rapidly and briefly expressed following renal ischemia and their expression was superinduced by cycloheximide in a manner typical of an immediate-early gene response. 3H-thymidine autoradiography performed on semi-thin sections from intravascularly perfusion fixed kidneys 24 hours following induction of ischemia showed labeled nuclei in cells lining the damaged proximal tubules of the outer stripe of the outer medulla, as well as proximal tubules in the cortex and interstitial cells throughout the kidney. However, immunohistochemical localization of c-Fos and c-Jun protein occurred predominantly in nuclei of the thick ascending limb, distal tubule and collecting duct cells. The studies demonstrate that c-fos and c-jun are expressed following renal ischemia as a typical immediate-early gene response, but they are expressed in cells that do not enter the cell cycle. The failure of the cells to enter the cell cycle may depend on the co-expression of jun-B and jun-D, which suppress the mitogenic activity of c-Jun in other cells. The data suggest that the IE response following renal ischemia is part of the stress response, which is antiproliferative rather than proliferative. The role of the stress response during renal ischemia and the fate of the cells undergoing it are unknown.

Non-isotopic in situ hybridization of human papilloma virus on histologic sections: an amended protocol.

The authors report on their experience with an HPV non-radioactive in situ hybridization kit and describe the favorable results gained with the amended protocol, which are as follows: 1. The application of a decreased amount of both the probe and the chromogen substrate did not alter the quality of reactions. Therefore we were able to make 60 reactions instead of the originally suggested 21. 2. The proteolytic enzyme digestion time could be prolonged by changing proteinase-K for pepsin which intensifies the signal of hybridization. 3. By changing the order of hybrid detection and posthybridization washing, we succeeded in removing the excess amount of probe-ABC-AP-BAAV-ABC-AP conglomerates without losing the target sequence. 4. Using alkaline phosphatase or ABC-AP-BAAV-ABC-AP complex instead of peroxidase it was possible to demonstrate a very low number of gene copies, even if they were not detectable following the original instructions.

[Sclerosing hemangioma of the lung]. / A tüdö úgynevezett sclerotisáló haemangiomája.

The authors review the theories of origin of the so-called sclerosing heamangioma of the lung. The results of immunohistochemical studies--epithelial membrane antigen positivity and vimentin and factor VIII. related antigen negativity--support the hypothesis of epithelial origin. The problems of clinical and pathological differential diagnosis are discussed.

[Value of computer tomography in the diagnosis of lung hamartomas]. / A computer tomographia jelentösége a tüdö hamartomák diagnosztikájában.

Detailed radiological examinations were undertaken in six cases of hamartochondromas verified by histopathology on surgical samples. It has been shown that examination of lung hamartochondromas by computer tomography provides a good approach for separation of different tissues constructing hamartochondromas. Thus cartilage, lose and dense and mixed forms of connective tissue, and adipose tissue can be well separated. The growth rate of hamartochondromas is very slow, characterized by doubling times of several hundred to several thousand hours.

Expression of the histone H3 gene in benign, semi-malignant and malignant lesions of the head and neck: a reliable proliferation marker.

To search for a reliable proliferation marker in epithelial head and neck lesions, we have analysed the expression of the histone H3 gene by in situ hybridisation and compared this with the immunoreactivity of the widely used monoclonal antibody Ki-67. In many lesions, the Ki-67 staining failed to delineate proliferation. In contrast, the H3 hybridisation signals were in accordance with the histopathology of the biopsies: in hyperplastic epithelia, significant H3 mRNA levels were only seen in areas with inflammation. Dysplastic cells showed distinctly elevated H3 expression. Benign and semi-malignant tumours, i.e. basal cell carcinomas, showed moderate H3 signals at the periphery. In squamous cell carcinomas, H3 expression was always high at the expanding zone of the tumour and was most extensive in undifferentiated carcinomas. Thus, the expression of the histone H3 gene closely reflected the dynamics of neoplastic growth within and around head and neck tumours.

[Cellular DNA determination and its significance in the identification of tumor recurrences, metastases and second primary tumors]. / A sejtenkénti DNS tartalom meghatározásának jelentösége daganat recidívák, metastasisok, illetve második primer tumorok azonosításában.

The DNA content of 30 malignant tumors and their metastases were compared. The DNA indices of tumors (expressed by the mean DNA content of G0.1-phase tumor cells and leukocytes) differ from each other, but in metastases they are almost the same with the values of primary tumors. It can also be observed, if a tumor consisted of more than one subpopulation of tumor cells, the metastatic potential of clones can be different. However, there is no significant relationship between the degree of ploidy and the occurrence of metastasis. The stability of DNA index in tumors and their metastases were used to distinguish two primary tumors even if their histological patterns were very similar. We present an example of the above mentioned phenomena in which the results of DNA analysis is supported by the results of mucin histochemistry and the follow up data.

DNA distribution pattern and comparison of quantitative data in breast tumours.

Aspiration cytology smears from 24 breast alterations were subjected to cytophotometry and TV image analysis. The smears were grouped according to histological diagnosis and cytological pattern. Cell cycle parameters and DNA indices were calculated from the decomposition of the DNA histograms. Based on quantitative morphometric features the TV image analyser distinguished the benign cells from the malignant ones. In benign cases its diagnostic accuracy is of 80%. Cytological Grades 1, 2 and 3 are also identifiable by this system. Cytophotometric measurements were also performed with 22 invasive breast cancers with known 5-year survival. The cell cycle parameters were related to the survival data. From the point of view of survival only the ratio of the S plus G2 phase cells of all the parameters examined proved to be significant.