Correction to: The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.

Screening-relevant age threshold of 70 years and older is a stronger determinant for the choice of adjuvant treatment in breast cancer patients than tumor biology.

PURPOSE: The 70-year threshold determines whether patients are eligible or not for the breast cancer screening program in Germany. It is not known whether this age threshold also influences the choice of adjuvant treatment and ultimate outcome. METHODS: 3463 patients were analyzed from the clinical cancer registry Regensburg (Germany) with primary, non-metastatic invasive breast cancer diagnosed between 2000 and 2012. The distribution of tumor biological subtypes was evaluated in breast cancer patients both in those eligible for screening (ESG, 50-69 years) and those not eligible for screening (NESG, ≥70 years). Local and systemic therapies in different subtypes as well as overall survival (OS) were analyzed. RESULTS: 2171 patients (62.7%) pertained to the ESG and 1292 patients (37.3%) referred to the NESG. The distribution of the common subtypes Luminal A, Luminal B, HER2-like, and Basal-like was comparable in both groups. Treatment varied considerably with less systemic therapies in all subtypes in patients in the NESG. Regarding local therapies, patients in the NESG also received less surgery and less radiotherapy. As to Luminal A patients, best OS was seen in patients receiving endocrine therapy (ET) (7-year OS of 95.6%) and CHT plus ET (7-year OS of 93.1%) in the ESG. In the NESG, best OS was seen in patients receiving CHT plus ET (7-year OS of 95.2%), whereas patients receiving only ET had a 7-year OS of 73.9%. CONCLUSIONS: Despite similar tumor biology, elderly patients are undertreated regarding both systemic and local therapies compared to younger patients, leading to reduced OS.

[Autopsy in oncology : Treatment validation in cancer centers and clinical cancer registries]. / Obduktion bei Tumorerkrankungen : Behandlungsstrategien in Tumorzentren und klinischen Krebsregistern.

The legal recognition of autopsy as a tool of quality assurance will strengthen its importance especially in the care of cancer patients. However, this confidence is relativized by the consideration of the assessment of the autopsy in various effective nonlegislative regulations. This consideration shows that in contrast to earlier years autopsy does not play a major role in the most important programs for the certification of cancer centers or for clinical cancer registration. If clinical autopsy is to play a more important role in the future, then in addition to improving and standardizing its quality the implementation into these systems of quality management is indispensable.

4-IHC classification of breast cancer subtypes in a large cohort of a clinical cancer registry: use in clinical routine for therapeutic decisions and its effect on survival.

The aim of the present study was to evaluate to what extent the combination of standard histopathological parameters determines the biology of breast cancer and the effect on therapy and prognosis. The Clinical Cancer Registry Regensburg (Bavaria, Germany) included n = 4,480 female patients with primary, non-metastatic (M0) invasive breast cancer diagnosed between 2000 and 2012. Immuno-histochemical analyses, i.e., estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 (4-IHC), defined the tumor biological subtypes Luminal A, Luminal B, HER2-like, and Basal-like. Subtype-related differences in therapies and overall survival (OS) were analyzed using multivariable statistical methods. 4344 patients (97.0 %) could be classified into the four common tumor biological subtypes. The two most frequent entities were Luminal A (48.4 %), Luminal B (24.8 %), HER2-like (17.8 %), and Basal-like subtype (9.0 %). A multivariable Cox regression model showed that the best 7-year OS was seen in Luminal A patients and that OS of Luminal B and HER2-like patients was comparable (HR = 1.59, P < 0.001 versus HR = 1.51, P = 0.03). Lowest OS was seen in patients with Basal-like tumors (HR = 2.18, P < 0.001). In conclusion, the classification of tumor biological subtypes by the ER, PR, HER2, and Ki-67 biomarkers is practical in routine clinical work. Providing that quality assurance of these markers is ensured, this classification is useful for making therapy decisions in the routine clinical management of breast cancer patients.

The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence.

PURPOSE: To predict biochemical recurrence respecting the natural course of pT2 prostate cancer with positive surgical margin (R1) and no adjuvant/neoadjuvant therapy. METHODS: A multicenter data analysis of 956 patients with pT2R1N0/Nx tumors was performed. Patients underwent radical prostatectomy between 1994 and 2009. No patients received neoadjuvant or adjuvant therapy. All prostate specimens were re-evaluated according to a well-defined protocol. The association of pathological and clinical features, in regard to BCR, was calculated using various statistical tests. RESULTS: With a mean follow-up of 48 months, BCR was found in 25.4 %. In univariate analysis, multiple parameters such as tumor volume, PSA, Gleason at positive margin were significantly associated with BCR. However, in multivariate analysis, Gleason score (GS) of the prostatectomy specimen was the only significant parameter for BCR. Median time to recurrence for GS ≤ 6 was not reached; 5-year BCR-free survival was 82 %; and they were 127 months and 72 % for GS 3+4, 56 months and 54 % for GS 4 + 3, and 27 months and 32 % for GS 8-10. The retrospective approach is a limitation of our study. CONCLUSIONS: Our study provides data on the BCR in pT2R1-PCa without adjuvant/neoadjuvant therapy and thus a rationale for an individual's risk stratification. The data support patients and physicians in estimating the individual risk and timing of BCR and thus serve to personalize the management in pT2R1-PCa.

[Clinical and epidemiological cancer registries: two complementary sources of information on cancer incidence]. / Klinische und epidemiologische Krebsregister : Zwei sich ergänzende Informationsquellen zum Krebsgeschehen.

The law for the development of early cancer detection and quality assurance by clinical cancer registries regulates the duties, the funding, and the functions of the clinical cancer registries and thereby the cooperation between epidemiological and clinical registries. The necessary regulations and interfaces are described here. The progress in new concepts of cancer registration is triggered by fundamental changes in oncological care such as the increasing use of high-quality guidelines and the certification of oncological health-care units.

Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry.

The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, who had been diagnosed between 2005 and 2011, in 3,658 cases Ki-67 was routinely determined. Thus, a total of 3,658 patients with invasive breast cancer were included in the present study and used for statistical analysis. Ki-67 expression was associated with the common histopathological parameters. The strongest correlation was found between grading and Ki-67 (P < 0.001). In terms of survival analyses, Ki-67 was categorized into five categories (reference category Ki-67 ≤15 %) due to a nonlinear relationship to overall survival (OS). In multivariable analysis, Ki-67 was an independent prognostic parameter both for disease-free survival (DFS) (Ki-67 > 45 %, HR = 1.96, P = 0.001) as well as for OS (Ki-67: 26-35 %, HR = 1.71, P = 0.017; Ki-67: 36-45 %, HR = 2.05, P = 0.011; Ki-67 > 45 %, HR = 2.06, P = 0.002) independent of common clinical and histopathological factors. The 5-year DFS (OS) rate was 86.7 % (89.3 %) in patients with a Ki-67 value ≤15 % compared to 75.8 % (82.8 %) in patients with a Ki-67 value >45 %. Based on the data from a large cohort of a clinical cancer registry, it was demonstrated that Ki-67 is frequently determined in routine clinical work. Ki-67 expression is associated with common histopathological parameters, but is an additional independent prognostic parameter for DFS and OS in breast cancer patients. Future work should focus on standardization of Ki-67 assessment and specification of its role in treatment decisions.

Utility of immunohistochemistry markers in the interpretation of post-high-intensive focussed ultrasound prostate biopsy cores.

PURPOSE: To overcome the difficulties in the interpretation of postoperative tumor obtaining biopsy cores for patients who treated their prostate cancer with high-intensity focussed ultrasound (HIFU) therapy. METHODS: The H&E slides of 58 patients with residual prostate cancer after HIFU treatment were systematically reviewed. Correlation between the pathologist's findings and immunohistochemical expression of MIB-1, alpha-Methyl-Co-Racemase and 34ßE-12 staining was analyzed. RESULTS: Mean time from treatment to biopsy was 40.2 (8-208) weeks. The expert review of the H&E slides identified 40 patients with viable carcinoma in the post-HIFU biopsy cores. 18 patients were revised to necrosis-only-tumors. These biopsies were performed not later than 16 weeks after HIFU treatment (median 10.9 weeks, range 8-14). Both MIB-1 and AMACR staining displayed significant differential expression in viable carcinoma (p < 0.001) compared to necrosis tumors. Referring to viable carcinoma tissue, AMACR staining index was significantly rising, the longer treatment dated back from biopsy (p < 0.002). In this context, 34-ß-E12 stained negative through all tumor areas and positive in the majority (85%) of the surrounding non-neoplastic epithelium. CONCLUSIONS: AMACR and MIB-1 reliably differentiate viable carcinoma from a process of ongoing irreversible necrosis in early post-HIFU prostate biopsy cores and therefore proposed-in addition with 34 beta-E12-as useful markers exposing suspicious tumor foci in difficult cases.

Direct improvement of quality of life using a tailored quality of life diagnosis and therapy pathway: randomised trial in 200 women with breast cancer.

BACKGROUND: Despite thousands of papers, the value of quality of life (QoL) in curing disease remains uncertain. Until now, we lacked tools for the diagnosis and specific treatment of diseased QoL. We approached this problem stepwise by theory building, modelling, an exploratory trial and now a definitive randomised controlled trial (RCT) in breast cancer, whose results we report here. METHODS: In all, 200 representative Bavarian primary breast cancer patients were recruited by five hospitals and treated by 146 care professionals. Patients were randomised to either (1) a novel care pathway including diagnosis of 'diseased' QoL (any QoL measure below 50 points) using a QoL profile and expert report sent to the patient's coordinating practitioner, who arranged QoL therapy consisting of up to five standardised treatments for specific QoL defects or (2) standard postoperative care adhering to the German national guideline for breast cancer. The primary end point was the proportion of patients in each group with diseased QoL 6 months after surgery. Patients were blinded to their allocated group. RESULTS: At 0 and 3 months after surgery, diseased QoL was diagnosed in 70% of patients. The QoL pathway reduced rates of diseased QoL to 56% at 6 months, especially in emotion and coping, compared with 71% in controls (P=0.048). Relative risk reduction was 21% (95% confidence interval (CI): 0-37), absolute risk reduction 15% (95% CI: 0.3-29), number needed to treat (NNT)=7 (95% CI: 3-37). When QoL therapy finished after successful treatment, diseased QoL often returned again, indicating good responsiveness of the QoL pathway. CONCLUSION: A three-component outcome system including clinician-derived objective, patient-reported subjective end points and qualitative analysis of clinical relevance was developed in the last 10 years for cancer as a complex intervention. A separate QoL pathway was implemented for the diagnosis and treatment of diseased QoL and its effectiveness tested in a community-based, pragmatic, definitive RCT. While the pathway was active, it was effective with an NNT of 7.

[Precursor lesions: epidemiology--is there enough evidence?]. / Vorläuferläsionen: Epidemiologie--sind Aussagen möglich?

Exact knowledge of the incidence and prevalence of precursor lesions of malignant diseases would be of great value for the precise evaluation of their potential clinical-pathological progression and therefore for planning and intervention in individual cases and also for planning and evaluation of prevention and early detection strategies. Concerning these high expectations it is surprising that precise data on incidence, prevalence and the exact risk for progression are lacking. Sources of data (cancer registries, specific registries for precursor lesions, early detection programs and specific designed studies) are analyzed concerning their validity and reliability. Imprecise and redundant terminology represents a crucial reason for the lack of data availability.

Long-term effects of chondrospheres on cartilage lesions in an autologous chondrocyte implantation model as investigated in the SCID mouse model.

Microtraumata often lead to articular cartilage lesions. Due to the bradytrophic character of hyaline cartilage, these lesions are hardly repaired by the organism. Autologous chondrocyte implantation (ACI) was established for restoring isolated structural cartilage defects in knee joints. However, results are not always convincing. Human chondrocytes from patients undergoing total knee arthroplasty were cultured in monolayer followed by condensing single chondrocytes to spheroids (chondrospheres). The integrative capacity of chondrospheres was examined by implanting them into lesions in human articular cartilage specimens and co-implanting them into SCID mice. Mice were sacrificed after 4, 12 and 24 weeks. HE and safranin O staining as well as immunohistochemistry using anti-S100, anti-collagen I and II antibodies were performed and analyzed using semiquantitative scores. Integration of the chondrospheres with the (native) cartilage matrix was analyzed by determining the percentage of adhering surface. With respect to long-term stability, the chondrocytes within chondrospheres showed a typical chondrocytic morphology. Immunohistochemically, a high collagen II production was detected. Over a time period of 24 weeks, an increasing content of collagen type II, glycosaminoglycans and collagenous fibers were found. Importantly, the newly synthesized cartilaginous matrix integrated continuously with the native cartilage lesion border. In conclusion, the presented data demonstrate that chondrospheres are able to restore and conserve their phenotype for at least 24 weeks under in vivo conditions. Moreover, chondrospheres adhere to full-thickness cartilage defects and appear to produce a cartilaginous extracellular matrix which fuses with native cartilage thus generating an autologous cartilage-like repair tissue.

[Renal pelvic carcinoma: a different urothelial tumor?]. / Nierenbeckenkarzinom: Ein anderer Urotheltumor?

Urothelial tumors of the renal pelvis and the ureter do not differ from those of the urinary bladder concerning histopathological phenotypes. However, with respect to tumor biology there are relevant differences between the two tumor locations. The originating tissue (urothelium) of the bladder and of the upper urinary tract varies significantly with respect to developmental origin, morphology and physiological function. Specific pathways of tumorigenesis (e.g. hereditary non-polyposis colorectal cancer, HNPCC) and tumor propagation (seeding) are described for tumors of the upper urinary tract. Clinical epidemiological data indicate specific correlations between the two tumor locations.

[41-year old patient with obscure diarrhea]. / 41-jähriger Patient mit unklarer Diarrhö

Chronic inflammatory diseases can induce further complications such as secondary amyloidosis. Being a rare but serious complication it affects typically the kidneys resulting in a nephrotic syndrome. Further sites of AA amyloid deposition are liver, heart and the autonomic nervous system. We report about a patient with congenital neutropenia, AA amyloidosis and chronic intestinal bowel inflammation due to amyloid deposition in the bowel.

Implementing a system of quality-of-life diagnosis and therapy for breast cancer patients: results of an exploratory trial as a prerequisite for a subsequent RCT.

A system for quality-of-life diagnosis and therapy (QoL system) was implemented for breast cancer patients. The system fulfilled the criteria for complex interventions (Medical Research Council). Following theory and modeling, this study contains the exploratory trial as a next step before the randomised clinical trial (RCT) answering three questions: (1) Are there differences between implementation sample and general population? (2) Which amount and type of disagreement exist between patient and coordinating practitioners (CPs) in assessed global QoL? (3) Are there empirical reasons for a cutoff of 50 points discriminating between healthy and diseased QoL? Implementation was successful: 74% of CPs worked along the care pathway. However, CPs showed preferences for selecting patients with lower age and UICC prognostic staging. Patients and CPs disagreed considerably in values of global QoL, despite education in QoL assessment by outreach visits, opinion leaders and CME: Zero values of QoL were only expressed by patients. Finally, the cutoff of 50 points was supported by the relationship between QoL in single items and global QoL: no patients with values above 50 dropped global QoL below 50, but values below 50 and especially at 0 points in single items, induced a dramatic fall of global QoL down to below 50. The exploratory trial was important for defining the complex intervention in the definitive RCT: control for age and prognostic stage grading, support for a QoL unit combining patient's and CP's assessment of QoL and support for the 50-point cutoff criterion between healthy and diseased QoL.

Exploration of the APC/beta-catenin (WNT) pathway and a histologic classification system for pulmonary artery intimal sarcoma. A study of 18 cases.

APC, a tumor suppressor gene in the Wnt pathway, stabilizes beta-catenin and controls cell growth. Mutation of APC or beta-catenin leads to nuclear accumulation of beta-catenin and transcription of cyclin D1/cyclin A. Pulmonary artery sarcoma (PAS) were studied by morphologic, immunohistochemical, and molecular genetic methods of the Wnt pathway. Eighteen cases were included: mean age 52 years, primary intraluminal location with typical clinical presentation. PAS were classified as epithelioid (n = 4) or malignant fibrous histiocytoma (MFH; spindled/pleomorphic, n = 4), myxofibrosarcoma (n = 8), and one each hemangiopericytoma-like or malignant inflammatory myofibroblastic tumor-like. The tumor cells demonstrated vimentin, focal actins, and rare focal desmin positivity. All but one were grade 2 or 3 by FNCLCC grading. Alteration in chromosome 5q21 (APC) was found in 4/14 PAS by LOH, mostly epithelioid-type; an MFH-type case demonstrated microsatellite instability (MSI) and nuclear beta-catenin. Cyclin D1 was expressed in seven tumors, all myxofibrosarcoma-type. No mutations were detected in APC or beta-catenin. In summary, PAS are predominantly intermediate grade myxofibrosarcoma in middle-aged males, and fatal in two-thirds of patients. Despite myofibroblastic phenotype, APC/beta-catenin pathway changes are rare. Cyclin D1, only expressed in the myxofibrosarcoma-type, is likely transcribed via factors other than beta-catenin.

Murine models of anaemia of inflammation: extramedullary haematopoiesis represents a species specific difference to human anaemia of inflammation that can be eliminated by splenectomy.

In contrast to humans, mice physiologically exhibit extramedullary haematopoiesis in the spleen. In spite of this crucial species specific difference not much is known about the contribution of extramedullary haematopoiesis to overall erythropoiesis in models of anaemia of inflammation (AI). The objective of this study is to characterize murine AI with respect to extramedullary haematopoiesis and to develop a model more closely resembling human AI. Three different models of AI [caecal ligation and puncture (CLP), collagen induced arthritis (CIA) and DSS induced chronic colitis (DSSC)] were characterized with respect to red blood parameters, iron metabolism and extramedullary haematopoiesis. Arthritic animals were splenectomised to prevent extramedullary haematopoiesis. Anaemia caused by systemic inflammation was found in all three models. Splenic extramedullary haematopoiesis was markedly increased as reflected by increment in spleen weights and increase of the red pulp resulting in increased reticulocyte counts. Splenectomised arthritic animals did not show increased reticulocyte counts indicating that most of the reticulocytes were produced in the spleen. Our results demonstrate that murine AI differs from human AI with respect to increased splenic extramedullary haematopoiesis. Our data demonstrate that induction of AI in splenectomised mice represents a good way to model human AI.

[Urothelial carcinoma. Does surgical pathology learn from molecular pathology?]. / Urothelkarzinom. Lernt die Pathologie von der Molekularpathologie?

The question is raised whether the new theories about initiation and progression of urothelial carcinoma gained by molecular techniques show effects on the classification and histopathological diagnosis. As fundamental new concepts are considered: two pathways of tumor progression, clonality of synchronous and metachronous tumors, tumor-analogous molecular findings in flat lesions, and stromal invasion as dominant principle of molecular tumor classification.The dual pathogenesis of molecular pathology is reflected by the WHO 2004 classification by the differentiation into low and high grade malignancy, but diluted by the use of PUNLMP (papillary urothelial neoplasia of low malignant potential). The new concept of frequent oligoclonality should induce investigations about the mechanism of propagation of these migrating or metastasizing cells and whether they possess stem cell characteristics. The role of flat urothelial lesions must be revised from a molecular pathological view point, but the histological diagnosis does not gain profit till now. The expression signatures of stromal invasive tumors compared with non-invasive ones points to the major importance of an exact histopathological diagnosis in this area.

Seasonal patterns of birth in patients with glioblastoma.

Seasonal distribution of birth rates was only recently described in patients with high-grade gliomas. We analyzed 501 cases from the database of a Regional Cancer Center in Bavaria to assess annual periodicity in the birth dates of glioma patients. Prior to analysis, the number of births per month was normalized [number of births x 100,000/total number of births in Germany] to obtain birth rates per month. The approximation of the time series data by a one-year cosine model found that the glioblastoma birth rate exhibits a statistically significant annual variation, with the peak rate in January. Vitamin intake, infections, and other as-yet-unknown factors and exposures during pre- and perinatal early life may contribute to the seasonality of birth rate in patients with brain tumors.

[Histological and immunohistochemical investigations with capsular contracture after breast augmentation with smooth silicone gel implants]. / Histologische und immunhistochemische Untersuchungen bei Kapselkontraktur nach glatten Brustimplantaten.

INTRODUCTION: A prospective study was performed to analyse the cellular and molecular composition of fibrous capsules around silicone breast implants. The necessity of an exact histological classification for comparing objectively the different findings of capsular contracture is shown. PATIENTS AND METHODS: The prospective study (investigation time 1/2003 to 6/2005) included 24 female patients (average age: 40+/-12 years) with contracture after bilateral cosmetic breast augmentation with smooth silicone gel implants (Mentor). In each patient the baker score was determined preoperatively. Samples of capsular tissue from all patients were evaluated histologically and immunohistochemically and classified according to the histological classification introduced by Wilflingseder and co-workers. RESULTS: All capsules showed the same basic histological structure with a three-layer composition. For the correlation analysis we had to exclude one patient with repeated implant change. There was no correlation between the patient's age, time of implantation, length of implant period, and capsular contracture. Greater amounts of silicone particles were associated with increased degrees of capsular contracture (Baker: r = 0.687, n = 23, p < or = 0.001; Wilflingseder: r = 0.784, n = 23, p < or = 0.001). High silicone amounts were associated with an increased local inflammation (r = 0.489, n = 23, p , 0.05). A moderate to severe local inflammation was found in 23 patients (95.8%). In summary, there was a positive correlation (r = 0.797, n = 23; p , or = 0.001) between the clinical classification (Baker score I to IV) and the histological classification (Wilflingseder score I to IV). CONCLUSIONS: We demonstrated in our study, in spite of using implants with high gel cohesiveness (fourth generation), the presence of vacuolated macrophages with microcystic structures containing silicone and silicone particles in the capsular tissue. Greater capsular thickness was associated with an increased number of silicone particles ans silicone-loaded macrophages in the peri-implant capsule. The histological classification introduced by Wilflingseder and co-workers takes into consideration this pathogenetic mechanism of inflammatory reaction which seems to be one of the major key factors in the development of capsular contracture.

Sensitivities of monolayers and spheroids of the human bladder cancer cell line MGH-U1 to the drugs used for intravesical chemotherapy.

The in vitro cytotoxicities of the four drugs most frequently used for intravesical chemotherapy (Adriamycin, epodyl, mitomycin C, Thiotepa) and epirubicin were compared using monolayers and multicellular tumor spheroids of the human bladder cancer cell line, MGH-U1. Adriamycin and epirubicin were most cytotoxic against monolayer cultures, whereas mitomycin C killed more cells in spheroids. Epodyl was least cytotoxic against both two- and three-dimensional cultures. Thiotepa was the only drug more cytotoxic to three- than two-dimensional cultures. Topographic analysis of bromodeoxyuridine-stained nuclei using image analysis indicated that Adriamycin selectively removed or killed superficial cells in multicellular tumor spheroids, but had little effect on DNA synthesis within the spheroids. In contrast Thiotepa killed cells throughout the spheroids. These in vitro data appear to reflect clinical experience using intravesical chemotherapy to treat superficial bladder cancer.