Long-term responders to trastuzumab monotherapy in first-line HER-2+ advanced breast cancer: characteristics and survival data.

BACKGROUND: The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. METHODS: This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. RESULTS: Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31-72) and of 18% (95%CI 10-30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. CONCLUSION: Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. TRIAL REGISTRATION: NCT00004935 ; first posted 27.01.2003, retrospectively registered.

Lesions with unclear malignant potential (B3) after minimally invasive breast biopsy: evaluation of vacuum biopsies performed in Switzerland and recommended further management.

BACKGROUND: Histopathological B3 lesions after minimal invasive breast biopsy (VABB) are a particular challenge for the clinician, as there are currently no binding recommendations regarding the subsequent procedure. PURPOSE: To analyze all B3 lesions, diagnosed at VABB and captured in the national central Swiss MIBB database and to provide a data basis for further management in this subgroup of patients. MATERIAL AND METHODS: All 9,153 stereotactically, sonographically, or magnetic resonance imaging (MRI)-guided vacuum-assisted breast biopsies, performed in Switzerland between 2009 and 2011, captured in a central database, were evaluated. The rate of B3 lesions and the definitive pathological findings in patients who underwent surgical resection were analyzed. RESULTS: The B3 rate was 17.0% (1532 of 9000 biopsies with B classification). Among the 521 lesions with a definitive postoperative diagnosis, the malignancy rate (invasive carcinoma or DCIS) was 21.5%. In patients with atypical ductal hyperplasia, papillary lesions, flat epithelial atypia, lobular neoplasia, and radial scar diagnosed by VABB, the malignancy rates were 25.9%, 3.1%, 18.3%, 26.4%, and 11.1%, respectively. CONCLUSION: B3 lesions, comprising 17%, of all analyzed biopsies, were common and the proportion of malignancies in those lesions undergoing subsequent surgical excision was high (21.5%).

Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN.

BACKGROUND: The tumor suppressor phosphatase and tensin homolog (PTEN) is a pleiotropic enzyme, inhibiting phosphatidyl-inositol-3 kinase (PI3K) signaling in the cytosol and stabilizing the genome in the nucleus. Nucleo-cytosolic partitioning is dependent on the post-translational modifications ubiquitinylation and sumoylation. This cellular compartmentalization of PTEN was investigated in lung neuroendocrine tumors (lung NET). METHODS: Tumor tissues from 192 lung NET patients (surgical specimens = 183, autopsies = 9) were investigated on tissue microarrays. PTEN was H-scored by two investigators in nucleus and cytosol using the monoclonal antibody 6H2.1. Results were correlated with immunoreactivity for USP7 (herpes virus-associated ubiquitin-specific protease 7) and SUMO2/3 (small ubiquitin-related modifier protein 2/3) as well as PTEN and p53 FISH gene status. Clinico-pathologic data including overall survival, proliferation rate and diagnostic markers (synaptophysin, chromogranin A, Mib-1, TTF-1) were recorded. RESULTS: The multicentre cohort included 58 typical carcinoids (TC), 42 atypical carcinoids (AC), 32 large cell neuroendocrine carcinomas (LCNEC) and 60 small cell lung carcinomas (SCLC). Carcinoids were smaller in size and had higher synaptophysin and chromogranin A, but lower TTF-1 expressions. Patients with carcinoids were predominantly female and 10 years younger than patients with LCNEC/SCLC. In comparison to the carcinoids, LCNEC/SCLC tumors presented a stronger loss of nuclear and cytosolic PTEN associated with a loss of PTEN and p53. Concomitantly, a loss of nuclear USP7 but increase of nuclear and cytosolic SUMO2/3 was found. Loss of nuclear and cytosolic PTEN, loss of nuclear USP7 and increase of cytosolic SUMO2/3 thus correlated with poor survival. Among carcinoids, loss of cytosolic PTEN was predominantly found in TTF1-negative larger tumors of male patients. Among SCLC, loss of both cytosolic and nuclear PTEN but not proliferation rate or tumor size delineated a subgroup with poorer survival (all p-values <0.05). CONCLUSIONS: Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. Both nuclear and cytosolic PTEN immunoreactivity should be considered for correlation with clinico-pathologic parameters.

Adenomyoepithelial tumours and myoepithelial carcinomas of the breast--a spectrum of monophasic and biphasic tumours dominated by immature myoepithelial cells.

BACKGROUND: Adenomyoepithelial tumours and myoepithelial carcinomas of the breast are primarily defined by the presence of neoplastic cells with a myoepithelial immunophenotype. Current classification schemes are based on purely descriptive features and an assessment of individual prognosis is still problematic. METHODS: A series of 27 adenomyoepithelial tumours of the breast was analysed immunohistochemically with antibodies directed against various cytokeratins, p63, smooth muscle alpha-actin (SMA) and vimentin. Additionally, double immunofluorescence and comparative genomic hybridisation (CGH) was performed. RESULTS: Immunohistochemically, all the tumours showed a constant expression of high molecular weight cytokeratins (Ck) Ck5 and Ck14, p63, SMA and vimentin. With exception of one case diagnosed as myoepithelial carcinoma, all tested tumours expressed low molecular weight cytokeratin Ck18 in variable proportions of cells. Even in monophasic tumours lacking obvious glandular differentiation in conventional staining, a number of neoplastic cells still expressed those cytokeratins. Double immunofluorescence revealed tumour cells exclusively staining for Ck5/Ck14 in the presence of other cell populations that co-expressed high molecular weight Ck5/Ck14 as well as either low molecular weight Ck8/18 or SMA. Based on morphology, we assigned the series to three categories, benign, borderline and malignant. This classification was supported by a stepwise increase in cytogenetic alterations on CGH. CONCLUSION: Adenomyoepithelial tumours comprise a spectrum of neoplasms consisting of an admixture of glandular and myoepithelial differentiation patterns. As a key component SMA-positive cells co-expressing cytokeratins could be identified. Although categorisation of adenomyoepithelial tumours in benign, borderline and malignant was supported by results of CGH, any assessment of prognosis requires to be firmly based on morphological grounds. At present it is not yet clear, if and to what extent proposed Ck5-positive progenitor cells contribute to the immunohistochemical and morphological heterogeneity of these neoplasms of the breast.

Standardization for Ki-67 assessment in moderately differentiated breast cancer. A retrospective analysis of the SAKK 28/12 study.

BACKGROUND: Proliferative activity (Ki-67 Labelling Index) in breast cancer increasingly serves as an additional tool in the decision for or against adjuvant chemotherapy in midrange hormone receptor positive breast cancer. Ki-67 Index has been previously shown to suffer from high inter-observer variability especially in midrange (G2) breast carcinomas. In this study we conducted a systematic approach using different Ki-67 assessments on large tissue sections in order to identify the method with the highest reliability and the lowest variability. MATERIALS AND METHODS: Five breast pathologists retrospectively analyzed proliferative activity of 50 G2 invasive breast carcinomas using large tissue sections by assessing Ki-67 immunohistochemistry. Ki-67-assessments were done on light microscopy and on digital images following these methods: 1) assessing five regions, 2) assessing only darkly stained nuclei and 3) considering only condensed proliferative areas ('hotspots'). An individual review (the first described assessment from 2008) was also performed. The assessments on light microscopy were done by estimating. All measurements were performed three times. Inter-observer and intra-observer reliabilities were calculated using the approach proposed by Eliasziw et al. Clinical cutoffs (14% and 20%) were tested using Fleiss' Kappa. RESULTS: There was a good intra-observer reliability in 5 of 7 methods (ICC: 0.76-0.89). The two highest inter-observer reliability was fair to moderate (ICC: 0.71 and 0.74) in 2 methods (region-analysis and individual-review) on light microscopy. Fleiss'-kappa-values (14% cut-off) were the highest (moderate) using the original recommendation on light-microscope (Kappa 0.58). Fleiss' kappa values (20% cut-off) were the highest (Kappa 0.48 each) in analyzing hotspots on light-microscopy and digital-analysis. No methodologies using digital-analysis were superior to the methods on light microscope. CONCLUSION: Our results show that all methods on light-microscopy for Ki-67 assessment in large tissue sections resulted in a good intra-observer reliability. Region analysis and individual review (the original recommendation) on light-microscopy yielded the highest inter-observer reliability. These results show slight improvement to previously published data on poor-reproducibility and thus might be a practical-pragmatic way for routine assessment of Ki-67 Index in G2 breast carcinomas.

CGH analysis shows genetic similarities and differences in atypical fibroxanthoma and undifferentiated high grade pleomorphic sarcoma.

BACKGROUND: Atypical fibroxanthoma (AFX) and undifferentiated high grade pleomorphic sarcoma (UpS) are histologically very similar, if not identical. However, they differ significantly in clinical outcome. MATERIALS AND METHODS: We used comparative genomic hybridization (CGH) to screen 24 AFX and 12 UpS for genomic alterations. RESULTS: DNA copy number changes were observed in 20/24 AFX and in all UpS. The most frequent alterations occurring with comparable frequency in both tumors were deletions on chromosomes 9p and 13q. We also detected statistically significant differences of genetic alterations between the two tumors concerning deletions on 1q, 3p, 5q, 11p, 11q, gains on 7q, 12q and high level gains on 5p and 11q. CONCLUSION: Despite their very similar histology, AFX and UpS show clear differences in their genetic alterations. This might contribute to the different biological behavior of the two tumors. On the other hand the similarities in genetic alterations on chromosomes 9p and 13q might suggest a common pathogenetic pathway.

Increased detection rates of Barrett's oesophagus without rise in incidence of oesophageal adenocarcinoma.

QUESTIONS UNDER STUDY/PRINCIPLES: The incidence of oesophageal adenocarcinoma has quadrupled in the last 20 years. Barrett's oesophagus carries a 30- to 125-fold increased risk of developing adenocarcinoma. The purpose of this study was to evaluate the incidence and surveillance of Barrett's oesophagus, dysplasia and adenocarcinoma in Eastern Switzerland. METHODS: Histological reports of 3659 patients (5190 oesophageal biopsies) from the St. Gallen Institute of Pathology were searched for evidence of Barrett's oesophagus (period 1989-1999). After retrospective classification according to findings on endoscopy and histology, the data were analysed with regard to surveillance intervals and incidence rates of Barrett's oesophagus, dysplasia and adenocarcinoma. RESULTS: 742 patients with Barrett's oesophagus and 100 with oesophageal adenocarcinoma were identified and followed up for a mean 1.6 (1-11) years. The average incidence of Barrett's oesophagus rose from 8.5/10(5)/yr (CI-95%: 7.4-9.7) in the first to 15.5/10(5)/yr (CI-95% 14.0-17.0) in the second 5-year period. The incidence of adenocarcinoma in our study population was 0.5% (1/97 patient years). In 207 patients (25%) with follow-up of >1 year, 9% progressed to low grade and 1% to high grade dysplasia, and 5% to adenocarcinoma. Adequacy of surveillance in BE patients rose from 54% to 87% over the study period. CONCLUSIONS: There is an increasing incidence of Barrett's oesophagus, which is not accompanied by an increase in oesophageal adenocarcinoma, in Eastern Switzerland. Surveillance of Barrett's oesophagus is often inadequate in spite of relevant findings such as dysplasia.

Ex vivo evaluation of coronary atherosclerotic plaques: characterization with dual-source CT in comparison with histopathology.

BACKGROUND: Identification and differentiation of coronary atherosclerotic plaques may improve risk stratification for incident coronary events. OBJECTIVE: We investigated the ability of dual-source computed tomography (CT) to depict and characterize atherosclerotic coronary plaques. METHODS: Contrast-enhanced CT was performed in 25 human heart specimens with a total of 322 histologically determined plaques. Coronary plaques were classified on CT as (1) noncalcified, mixed, or calcified and (2) by CT attenuation values. Atherosclerotic plaques were histopathologically characterized according to the Stary classification. RESULTS: CT detected 79% (245/322) of all plaques. Lesions missed by CT were generally early lesions, type I (n = 31), type II (n = 38), or type III (n = 8), according to Stary. CT detected 29% of early (Stary I-III) and 100% of advanced (Stary IV-VIII) plaques. Plaque classification as noncalcified was sensitive (100%) and specific (72%) for early, whereas classification as mixed/calcified was sensitive (92%, 89%) and specific (100%) for advanced plaques. Calcified plaques on CT were detected with high sensitivity (80%) and specificity (95%). Other subtypes were not distinguishable with CT according to the presence or absence of calcification. CT density was significantly higher for advanced (306 ± 470 HU) than for early (42 ± 14 HU; P < 0.01) plaques. The mean CT density value of type VII plaques (512 ± 349 HU) was significantly higher than those of other plaques (34-101 HU; P < 0.001). CONCLUSIONS: CT reliably depicts advanced coronary plaques and allows for the differentiation between early and advanced plaques.