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author:("hofstede, F")
1.  Guideline Concordant Therapy Prolongs Survival in HER2-Positive Breast Cancer Patients: Results from a Large Population-Based Cohort of a Cancer Registry 
BioMed Research International  2014;2014:137304.
Even though randomized controlled clinical trials demonstrated improved survival by adjuvant trastuzumab treatment of HER2-positive breast cancer patients, data on its effect in clinical routine are scarce. This study evaluated the use and efficacy of trastuzumab in routine treatment of HER2-positive breast cancer patients. Data from the clinical cancer registry Regensburg (Germany) were analyzed. The present study investigated 6,991 female patients with primary invasive breast cancer. In premenopausal HER2-positive patients a considerable increase of trastuzumab therapy was observed from 58.1% in 2006 to 90.9% in 2011, whereas in postmenopausal patients trastuzumab was rather used on a constant rate of 49.1%. Best overall survival (OS) was found in HER2/steroid hormone receptor-positive patients receiving guideline concordant treatment with trastuzumab plus chemotherapy (CHT) plus antihormone therapy (AHT) with a 7-year OS rate of 96% compared to the non-trastuzumab group with a 7-year OS rate of 92%. In multivariable analysis, HER2-positive patients treated with CHT or AHT who did not get trastuzumab, had a worse 7-year OS (65%, P = 0.006 versus 79%, P = 0.017) than the control groups. This population-based study demonstrated that guideline concordant use of adjuvant trastuzumab improves OS for HER2-positive breast cancer patients treated in routine clinical care.
doi:10.1155/2014/137304
PMCID: PMC3977430  PMID: 24779005
2.  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.
doi:10.1007/s10549-013-2560-8
PMCID: PMC3669503  PMID: 23674192
Ki-67; Primary breast cancer; Cancer Registry; Prognostic factor; Disease-free survival; Overall survival
3.  Direct improvement of quality of life using a tailored quality of life diagnosis and therapy pathway: randomised trial in 200 women with breast cancer 
British Journal of Cancer  2012;106(5):826-838.
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.
doi:10.1038/bjc.2012.4
PMCID: PMC3305975  PMID: 22315052
quality of life (QoL); breast cancer; definitive RCT; complex intervention; effectiveness of the QoL system
4.  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 
British Journal of Cancer  2008;99(3):415-422.
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.
doi:10.1038/sj.bjc.6604505
PMCID: PMC2527812  PMID: 18665187
quality of life; implementation; breast cancer; exploratory trial; patient–doctor agreement; positivity criterion
5.  Dupuytren's contracture is associated with sprouting of substance P positive nerve fibres and infiltration by mast cells 
Annals of the Rheumatic Diseases  2006;65(3):414-415.
doi:10.1136/ard.2005.044016
PMCID: PMC1798044  PMID: 16474037
Dupuytren's contracture; mast cells; nerve fibres; substance P; inflammation
6.  Morphological characterisation of Crohn’s disease fistulae 
Gut  2004;53(9):1314-1321.
Background: Fistulae are a common complication in up to 35% of all patients with Crohn’s disease. Their therapy is difficult and frequently unsatisfactory. To date, no histological comparison of Crohn’s disease fistulae with non-inflammatory bowel disease fistulae has been performed. In addition, Crohn’s disease fistulae have not been well characterised morphologically.
Methods: Eighty four fistulae from Crohn’s disease patients were compared with 13 fistulae from controls. Haematoxylin-eosin staining, electron microscopy, and immunohistochemistry for panCytokeratin (epithelial cells), CD20 (B cells), CD45R0 (T cells), and CD68 (macrophages) were performed according to standard techniques. In addition, histopathological findings were compared with clinical and laboratory data.
Results: In 31.0% of controls and 27.4% of Crohn’s disease specimens, fistulae had a lining of flattened intestinal epithelium without goblet cells or, in the case of cutaneous/perianal disease, narrow squamous epithelium. Non-epithelialised fistulae were covered by a thin layer of (myo)fibroblasts, focally forming a new basement membrane, as demonstrated by electron microscopy. All fistulae were surrounded by granulation tissue. Crohn’s disease fistulae presented with central infiltration by CD45R0+ T cells, followed by a small band of CD68+ macrophages and dense accumulation of CD20+ B cells. In contrast, in controls, there was dense infiltration by CD68+ macrophages with only few CD20+ B cells and CD45R0+ T lymphocytes.
Conclusions: Fistulae in Crohn’s disease differ markedly from non-Crohn’s disease fistulae with regard to their cellular composition. The presence of an epithelial lining in a subgroup of fistulae may be important for the therapeutic approach and healing process.
doi:10.1136/gut.2003.038208
PMCID: PMC1774207  PMID: 15306592
Crohn’s disease; fistulae; histology; immunohistochemistry; electron microscopy
7.  Alterations in p53 predict response to preoperative high dose chemotherapy in patients with gastric cancer 
Molecular Pathology  2003;56(5):286-292.
Aims: To evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy (HDCT) and survival of patients with advanced gastric cancer.
Methods: In a phase II trial, 25 patients with metastatic gastric cancer received preoperative tandem HDCT consisting of etoposide, cisplatin, and mitomycin, followed by autologous bone marrow transplantation to achieve surgical resectability. Samples before and after treatment, from normal and tumour tissue, were characterised histopathologically, and both p53 and BAX expression was analysed by immunohistochemistry. Pretreatment formalin fixed, paraffin wax embedded samples from normal and tumour tissue were microdissected, and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction. Detection of microsatellite instability (MSI) or loss of heterozygosity (LOH) was performed using markers for p53, BAX, BAT25, BAT26, D2S123, D17S250, and APC. Exons 5–9 of the p53 gene were sequenced directly on ABI 373.
Results: Four parameters were significantly associated with response to chemotherapy and prolonged overall survival: positive p53 immunostaining, positive p53 mutation status before chemotherapy, strong histological regression induced by preoperative HDCT, and surgical treatment. Patients’s sex or age, tumour location or stage, lymph node status, Lauren classification, MSI, or LOH did not influence duration of survival significantly in this high risk population.
Conclusion: Positive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT.
PMCID: PMC1187340  PMID: 14514923
gastric cancer; preoperative high dose chemotherapy; molecular parameters; histological regression; p53
8.  The combined effects of high-energy shock waves and cytostatic drugs or cytokines on human bladder cancer cells. 
British Journal of Cancer  1994;69(1):58-65.
The effects of shock waves generated by an experimental Siemens lithotripter in combination with cytostatic drugs or cytokines on several bladder cancer cell lines were examined in vitro. Proliferation after treatment was determined with the 3-4,5-dimethylthiazol-2,5 diphenyl tetrazolium bromide assay. Dose enhancement ratios were calculated for each drug and each shock wave application mode in order to characterise the sensitising effect of shock wave pretreatment. The influence of the time between shock wave and drug treatment as well as the effects of different sequences of shock wave and drug treatment or concomitant treatment were assessed for selected combinations of cell lines and drugs. It was found that shock wave treatment could render certain cell lines more susceptible to subsequent cis-platinum, mitomycin C or actinomycin D incubation. Cell lines sensitive to tumour necrosis factor alpha or interferon alpha were further sensitised to these cytokines by shock wave pretreatment. The enhanced sensitivity to cis-platinum and actinomycin D decreased rapidly during the first hours after shock wave treatment. The antiproliferative effect was most pronounced after concomitant shock wave and drug treatment. The sensitisation to interferon alpha diminishes more slowly after shock wave exposure. From the results presented in this study it is concluded that transient shock wave-induced permeabilisation of cell membrane not only enhances drug efficiency, but also causes damage to cell organelles and alterations in cellular metabolism.
PMCID: PMC1968790  PMID: 8286211

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