Sebastian Roka

Do we need HER-2/neu testing for all patients with primary breast carcinoma?

HER‐2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER‐2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER‐2/neu status.

Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer

ZusammenfassungHintergrundDie Bestimmung einer HER2/neu-Überexpression im Gewebe eines Mammakarzinoms gibt Aufschluss über einen wichtigen prognostischen und prädiktiven Marker. Eine Überexpression von HER2/neu ist beim Mammakarzinom mit einer schlechten Prognose assoziiert. Da die Nadelbiopsie zunehmend in der Diagnostik des Mammakarzinoms angewandt wird, war es unser Ziel die Zuverlässigkeit der HER2/neu-Bestimmung in der Nadelbiopsie bei Patientinnen mit primärem Mammakarzinom zu evaluieren.Patienten und MethodenWir untersuchten an 325 Patientinnen mit primärem Mammakarzinom die Genauigkeit der immunhistochemischen HER2/neu-Bestimmung in der Nadelbiopsie verglichen mit dem Operationspräparat. Bei Patientinnen mit stark positivem HER2/neu Status wurde zusätzlich eine Fluoreszenz in situ Hybridisierung (FISH) der Nadelbiopsie durchgeführt.ErgebnisseDie Genauigkeit der HER2/neu-Bestimmung in der Nadelbiopsie verglichen mit dem Operationspräparat durch Immunhistochemie alleine war 92% und konnte durch zusätzliche FISH Analyse auf 96% und werden (gewichteter Kappa Koeffizient: 0,86).DiskussionWir konnten an diesem großen Patientenkollektiv zeigen, dass die Bestimmung von HER2/neu in der Nadelbiopsie beim Mammakarzinom verlässlich ist. Bei immunhistochemisch stark positivem HER2/neu Status in der Nadelbiopsie sollte dies durch FISH überprüft werden, um die Zahl der falsch positiven Ergebnisse zu minimieren.SummaryIntroductionThe assessment of HER2/neu overexpression in tissue provides information about one of the most relevant prognostic and predictive markers in breast cancer: overexpression of HER2/neu is associated with worse prognosis in primary breast cancer. Since core needle biopsy is increasingly used for the diagnosis of breast cancer, the purpose of this study was to assess the reliability of HER2/neu evaluation using this technique in patients with primary breast cancer.Patients and methodsWe investigated the accuracy of immunohistochemical assessment of HER2/neu in core needle biopsies compared with surgically obtained specimens in 325 patients with primary breast cancer. In patients strongly positive for HER2/neu, additional fluorescence in situ hybridization (FISH) analysis of needle biopsies was performed.ResultsUsing immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in relation to surgically removed specimens was 92% and increased to 96% with additional FISH analysis (weighted Kappa coefficient: 0.86).DiscussionAs proven with this large series of patients, the assessment of HER2/neu status by core needle biopsy in breast cancer is accurate. Notwithstanding, in order to minimize the number of false-positive results, strongly positive core needle biopsies identified using immunohistochemistry should be confirmed by FISH analysis.

Sentinel Lymph Node Biopsy After Preoperative Chemotherapy for Breast Cancer: Findings from the Austrian Sentinel Node Study Group

BackgroundSentinel lymph node biopsy (SLNB) has become an accurate alternative to axillary lymph node dissection for early breast cancer. However, data are still insufficient as regards the combination of SLNB with preoperative chemotherapy (PC).MethodsThe Austrian Sentinel Node Study Group investigated 167 patients who underwent SLNB and axillary lymph node dissection after 3 to 6 courses of PC. SLNB was limited to patients with a clinically negative axilla after PC. Blue dye was used in 29 cases (17%), and tracers were used in 20 (12%). A combination of the two methods was applied in most patients (n = 120; 72%).ResultsAt least 1 sentinel lymph node (SLN) was identified in 144 patients (identification rate, 85%): in 86% by blue dye alone, in 65% by tracers alone, and in 88% by a combination of methods. The SLN was positive in 70 women (42%) and was the only positive node with otherwise negative axillary nodes in 39 patients (23%). In 6 cases, the SLN was diagnosed as negative although tumor infiltration was detected in an upper node of the axillary basin (false-negative rate, 8%; 6 of 76 patients; sensitivity, 92%). At least 62 patients (37%) were free of tumor cells in the SLN and in the axillary nodes.ConclusionThe results of SLNB after PC are comparable to the results of SLNB without PC. Further investigation in a prospective setting is warranted to confirm these promising results.

Influence of neoadjuvant therapy with epirubicin and docetaxel on the expression of HER2/neu in patients with breast cancer.

AbstractBackground. In primary breast cancer, the expression levels of biological markers relevant to the progression of the disease may be altered by administration of anticancer drugs. Since neoadjuvant chemotherapy with epirubicin and docetaxel is increasingly used in advanced breast cancer, our purpose was to assess the influence of this neoadjuvant chemotherapy on the expression of the growth factor receptor HER2/neu. Patients and methods. We investigated changes of HER2/neu status by immunohistochemistry (IHC) and applied additional fluorescence in situ hybridization (FISH) in patients with potential modulation of HER2/neu status after administration of neoadjuvant chemotherapy with docetaxel and epirubicin in 97 breast cancer patients. The influence of neoadjuvant chemotherapy on HER2/neu expression was calculated by correlation of HER2/neu status before and after chemotherapy. Results. The accuracy of HER2/neu assessment before and after neoadjuvant chemotherapy by IHC combined with FISH analysis in selected cases was 100%. The evaluation of HER2/neu status in these patients by IHC alone yielded accuracy of 93%. Neoadjuvant chemotherapy with epirubicin and docetaxel caused no significant modulation of HER2/neu status (p = 0.66). Discussion. The administration of epirubicin and docetaxel in the neoadjuvant setting is not associated with significant changes of HER2/neu status in primary breast cancer. As a consequence, drug resistance or sensitivity is not induced by modulation of HER2/neu expression. Moreover, the time of assessment of the HER2/neu status is not a critical factor under neoadjuvant therapy with epirubicin and docetaxel.

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Purpose: Colorectal cancer patients receiving neoadjuvant treatment with bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor (VEGF), may suffer from wound healing complications after surgery as the antibody persists in patient blood. We characterized the systemic angiogenic balance in the perioperative period to evaluate its effect on physiologic angiogenesis. Experimental Design: Nineteen patients receiving combination chemotherapy and bevacizumab for six neoadjuvant cycles were compared with 14 patients receiving chemotherapy without bevacizumab. Plasma from perioperative days −1, +1, +7, and +21 was analyzed for VEGF, thrombospondin-1 (TSP-1), and PD-ECGF concentrations. The angiogenic capacity was further tested in an in vitro assay of endothelial cell proliferation and migration. Results: On day +1, the onset of wound healing was reflected in a change of balance, i.e., an increase of proangiogenic factors VEGF and platelet-derived endothelial cell growth factor compared with low TSP-1 inhibitor levels in both treatment groups. Patients with bevacizumab therapy showed significantly higher blood levels of total VEGF throughout the evaluation period. However, most VEGF molecules were inactive, i.e., complexed with antibody. Nevertheless, the capacity to stimulate endothelial growth was higher for these plasma samples and was reflected in low TSP-1 levels and an altered TSP-1 sensitivity. When purified TSP-1 protein was added, plasma samples of the bevacizumab but not the chemotherapy group showed reduced endothelial growth. Conclusions: Feedback mechanisms of bevacizumab therapy are not restricted to VEGF expression but seem to involve additional factors, such as TSP-1, which influences the systemic angiogenic balance and permits endothelial growth.

Aneuploidy of chromosome 8 as detected by interphase fluorescence in situ hybridization is a recurrent finding in primary and metastatic breast cancer.

Previous work from our laboratory demonstrated aneuploidy for several chromosomes by interphase fluorescence in situ hybridization (FISH) in a high proportion of breast cancer specimens. In the literature, only limited data are available concerning chromosome 8 anomalies in breast cancer. To determine chromosome 8 ploidy status in primary and metastatic specimens from 81 breast cancer patients, FISH analysis with a DNA probe recognizing chromosome 8 centromeres was performed. In all primary tumor specimens (n=30), significant proportions of cells were aneuploid exhibiting gain of chromosome 8 copy numbers; in 75% of effusion specimens previously classified as malignant by cytology and/or FISH for various chromosomes (n=40), cell populations aneuploid for chromosome 8 were detected; effusions previously classified non-malignant (n=11) were diploid in 10 cases, whereas one specimen contained rare hyperdiploid cells. Among these cells complex chromosomal aneuploidy could be demonstrated by two-color FISH, suggesting malignancy. Trisomic and tetrasomic clones were predominant in the majority of samples, but a marked intratumor cytogenetic heterogeneity was observed in most cases. Primary tumors and corresponding positive axillary lymph nodes revealed similar distributions of chromosome 8 copy numbers, analogous to previous findings with other chromosomes. This implies that, by using suitable FISH probes after examination of the respective primary tumor, an efficient search for (micro)metastasis might be feasible.

Factors affecting identification rate and positivity of the sentinel node in breast cancer in 1567 patients, using blue dye and99mTc-labelled colloid, based on a multicentre database project in Austria

SummaryBackground: In several studies sentinel node biopsy has been determined to be a predictive indicator of the axillary nodal status in patients with breast cancer. Although the acceptance of this procedure is growing worldwide, no consensus has yet been reached on the methodology. The aim of this analysis was to evaluate a nationwide standardized central database as an instrument of quality control for sentinel node biopsy in patients with breast cancer and to elucidate factors associated with identification rate, positivity of the sentinel node and the axillary specimen in a prospective nationwide multicentre program. Methods: Since 1996, patient data from nine departments in Austria have been collected. Both blue dye and99 mTc-labelled colloid were used, either alone or in combination. Identification methods varied but had to be consistent within one department. Inclusion criteria and pathological examination of the sentinel node corresponded with national guidelines. Collected data also included the learning period of every centre. Data were coded and transferred to a central database per e-mail Results: Data on 1567 patients were eligible. Identification rate was 87.3%. Multivariate analysis showed age, tumour size, learning period and the department to be significant factors in identification, whereas large tumour size, histological type and palpability of the tumour were significant for a histologically positive sentinel node. Conclusions: Sentinel node biopsy is an accurate and feasible staging method for axillary nodal status if it is performed in a standardized setting. A central database is helpful in gaining nationwide optimal quality control.ZusammenfassungGrundlagen: In diversesten Studien wurde die Sentinel Lymphknoten Biopsie beim Mammakarzinom bereits als geeignetes Instrument zum axillären Staging beschrieben. Obwohl die Methode weltweit bereits große Akzeptanz besitzt, gibt es noch keinen Konsensus über die Art der Durchführung und Anwendung. Ziel dieser Untersuchung war die Evaluierung einer standardisierten Datenbank als Instrument zur Qualitätskontrolle anhand einer prospektiven österreichweiten Multicenterstudie und die Analyse von Faktoren, die die Identifikationsrate und die Positivität des Wächterlymphknotens beeinflussen. Methodik: Seit 1996 wurden Daten von 9 österreichischen Abteilungen zusammengeführt. Als Identifikationsmethoden wurden Blaufarbstoff und die Lymphoszintigraphie, sowohl alleine als auch in Kombination, angewendet. Die Identifikationsmethoden variierten von Abteilung zu Abteilung, Einschlusskriterien und histologische Untersuchung erfolgten nach festgelegten Empfehlungen für Österreich. Die Daten wurden anonymisiert und via e-mail an die zentrale Datenbank transferiert. Die Erfassungszeit schließt die Lernphase der einzelnen Abteilungen ein. Ergebnisse: Daten von 1 567 Patienten wurden analysiert. Die Identifikationsrate betrug 87.3%. Die multivariate Analyse zeigte, dass Patientenalter, Tumorgröße, Lernphase und die operierende Abteilung signifikant die Identifikationsrate beeinflussen, wohingegen die Tumorgröße, die Histologie und die Tastbarkeit des Tumors die Positivität des Sentinel Lymphknotens beeinflussen. Schlußfolgerungen: Die Wächterlymphknoten Biopsie ist eine genaue und gut praktikable Methode zum axillären Staging, wenn sie in einem standardisierten und kontrollierten Setting durchgeführt wird. Eine zentrale Datenbank im Rahmen eines landesweiten Programms ist hilfreich zur optimalen Qualitätskontrolle.

Axillary Recurrence after Sentinel Node Biopsy

SummaryBackground: Sentinel lymph node biopsy seems to be a promising new method for determining axillary status in breast cancer. The method helps to reduce morbidity, and an increased number of micrometastases are detected in the sentinel nodes by which patients with a less favourable outcome are identified. However, no long-term follow-up data is available. Methods: Data from 1567 breast cancer patients treated at nine institutions in Austria were collected in a centrally reviewed database. Included in this study were 383 patients with a negative sentinel node biopsy who were treated without axillary dissection. The median follow-up was 19.5 months. Results: Sentinel node biopsy was performed using blue dye (21.2 %), radiocolloid (24 %) or the combination of both methods (54.8 %). Two axillary recurrences were observed. Both patients developed distant disease synchronously or metachronously. Primary tumours of both patients showed high nuclear grading and negative hormone receptor status. Tumour size at primary diagnosis was 12 mm and 22 mm, respectively. Conclusions: The current results of sentinel node biopsy seem to confirm the accuracy of the method. There are only sporadic reports in the literature on axillary recurrence after sentinel node biopsy. The risk of treatment failure after sentinel node biopsy can only be determined after the completion of prospective randomized trials. Therefore, sentinel node biopsy should be performed within therapeutic concepts with quality control.ZusammenfassungGrundlagen: Die Wächterlymphknotenbiopsie stellt eine neue hoffnungsvolle Methode in der Therapie der Axilla beim Mammakarzinom dar. Die Vorteile der Methode sind eine geringere Morbidität und die höhere Detektion von Mikrometastasen, wodurch Patienten mit möglicherweise schlechterer Prognose identifiziert werden. Bis jetzt fehlen jedoch Langzeitergebnisse. Methodik: Die Daten von 1 567 Brustkrebspatientinnen, die an 9 Abteilungen Österreichs behandelt wurden, wurden in einer Datenbank zusammengefaßt. 383 Patientinnen hatten einen tumorfreien Wächterlymphknoten und es wurde auf eine Axilladissektion verzichtet. Das mediane Follow-up betrug 19,5 Monate. Ergebnisse: Zur Wächterlymphknotenbiopsie wurde die Blaumethode (21,2 %), die Radiokolloidmethode (24 %), oder die Kombination aus beiden (54,8 %) verwendet. Zwei axilläre Rezidive wurden beobachtet. Bei beiden Patientinnen traten Fernmetastasen synchron oder in weiterer Folge auf. Die Primärtumore beider Patientinnen hatten niedrigen Differenzierungsgrad und negative Hormonrezeptoren. Die Tumorgrößen waren 12 mm und 22 mm. Schlußfolgerungen: Die derzeitigen Ergebnisse scheinen die Genauigkeit der Methode zu beweisen. Nur einzelne Berichte über axilläre Rezidive nach Wächterlymphknotenbiopsie wurden bis jetzt publiziert. Das wirkliche Risiko einer falsch negativen Wächterlymphknotenbiopsie kann erst nach Abschluß prospektiver Studien beantwortet werden. Deshalb sollte die Wächterlymphknotenbiopsie nur unter qualitätskontrollierten Bedingungen durchgeführt werden.

Primary hyperparathyroidism: is there a role for imaging?

“The best means of localisation is an experienced surgeon.” Although this sentiment can sometimes be found in publications, preoperative localisation of pathological parathyroid glands is a permanent endeavour. The reasons are obvious. With correct preoperative localisation, quick and guided identification of parathyroid adenomas can be achieved by the surgeon. This is especially important for reoperative surgery or in the presence of ectopic glands. Furthermore, operative time and surgical trauma are minimised, in accordance with the general trend within endocrine and other branches of surgery towards minimally invasive surgical techniques. Nevertheless, bilateral exploration with identification of all four glands without biopsy remains the gold standard in parathyroid surgery. In a meta-analysis of 2,531 patients [1], normocalcaemia was achieved after the initial operation in 96.5%, while hypocalcaemia and persistent hyperparathyroidism were seen in only 1.4% and 2.1%, respectively. These results are optimal, even by today’s standards. The main argument for performing bilateral exploration is the possibility of multiple gland disease, which occurs in up to 17.3% of patients [1]. With the philosophy of bilateral exploration, the importance of preoperative localisation consists in identifying ectopic glands, which occur in up to 20% of cases [2]. Various terms have been employed for minimally invasive parathyroid surgery (minimal access, directed surgery or unilateral surgery) [3–6]. The operative procedure is performed on only one side of the neck. In these cases the value of preoperative localisation is to identify the diseased gland on the correct side. Surgical success has to be confirmed intraoperatively by a fall in the blood parathyroid hormone (PTH) level (via PTH monitoring). Recommendations for these procedures are still under debate. In the event of recurrence, reoperation or recurrent nerve palsy, the advantages of minimally invasive surgery are obvious. In these cases, correct preoperative localisation is essential. Four diagnostic procedures are routinely used for preoperative localisation, and the clinical value of each has been assessed.

Anale HPV-Infektionen

Anogenitale Infektionen mit humanen Papillomaviren (HPV) verzeichnen in den letzten Jahren gerade in jüngeren Generationen durch frühe sexuelle Aktivität eine steigende Inzidenz. Neue Erkenntnisse der ätiologischen, epidemiologischen und pathophysiologischen Zusammenhänge erfordern eine Überarbeitung der proktologischen Position HPV-assoziierter Erkrankungen der Analregion. Dies ist auch aufgrund der ansteigenden Inzidenz präkanzeröser und invasiver Neubildungen nötig. In Ermangelung großer, kontrollierter Studien stellt dieser Konsensusbericht über weite Strecken die Expertenmeinung der auf dem Gebiet der HPVInfektion erfahrenen Autoren aus den Gebieten Proktologie, Dermatologie, Gynäkologie, Radiologie, Strahlentherapie und Pathologie dar. Anale HPV-Infektionen1