Disease Management Project Breast Cancer in Hesse - 5-Year Survival Data: Successful Model of Intersectoral Communication for Quality Assurance.

Introduction: The Disease Management Project Breast Cancer (DMP Breast Cancer) was first launched in Hesse in 2004. The project is supported by the health insurance companies in Hesse and the Professional Association of Gynaecologists in Hesse. The aim is to offer structured treatment programmes to all women diagnosed with breast cancer in Hesse by creating intersectoral cooperations between coordinating clinics, associated hospitals and gynaecologists in private practice who registered in the DMP programme. Method: Between 1 January 2005 and 30 June 2011, 13 973 women were enrolled in the DMP programme. Results: After data cleansing, survival rates were calculated for a total of 11 214 women. The 5-year overall survival (OS) rate was 86.3 %; survival rates according to tumour stage on presentation were 92.2 % (pT1) and 82.3 % (pT2), respectively. The impact of steroid hormone receptor status on survival (87.8 % for receptor-positive cancers vs. 78.9 % for receptor-negative cancers) and of age at first diagnosis on survival (≤ 35 years = 91 %) were calculated. Conclusion: The project showed that intersectoral cooperation led to significant improvements in the quality of treatment over time, as measured by quality indicators and outcomes after treatment.

COMPliance and Arthralgia in Clinical Therapy: the COMPACT trial, assessing the incidence of arthralgia, and compliance within the first year of adjuvant anastrozole therapy.

BACKGROUND: This prospective study evaluated the relationship between arthralgia and compliance during the first year of adjuvant anastrozole therapy in postmenopausal women with hormone receptor-positive early breast cancer. PATIENTS AND METHODS: COMPliance and Arthralgia in Clinical Therapy (COMPACT) was an open-label, multicenter, noninterventional study conducted in Germany. Patients had started adjuvant anastrozole 3-6 months before the study start. The primary end points were arthralgia, compliance, and the relationship between compliance and arthralgia, assessed at specific time points. RESULTS: Overall, 1916 patients received upfront anastrozole. Mean arthralgia scores were increased from baseline at each visit up to 9 months. Compliance with anastrozole therapy gradually decreased over time from baseline to 9 months (P<0.001). At 9 months, investigators estimated that >95% of patients were compliant versus patient reports of <70%. There was a significant association between arthralgia mean scores and noncompliance at 6 months (P<0.0001), 9 months (P<0.0001), and overall (P<0.0001). Over time, new events or impairment of existing arthralgias were reported in 14% (3 months), 11% (6 months), and 9% (9 months) of patients. CONCLUSION: Arthralgia is important in the clinical management of women with early breast cancer and may contribute to noncompliance and clinical outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT00857012.

Crucial role of Plexin C1 for pulmonary inflammation and survival during lung injury.

Acute pulmonary inflammation during lung injury is initiated by the migration of neutrophils into the alveolar space. The severity of these inflammatory changes within the pulmonary tissue determines the severity of lung injury and ultimately patient outcome. Recent work has demonstrated that the guidance protein Semaphorin 7A propagates the infiltration of neutrophils into an hypoxic tissue site, yet the role of its target receptor Plexin C1 (PLXNC1) during lung injury is to date unknown. We demonstrate here that PLXNC1(+) neutrophils are present within the alveolar space and that PLXNC1 is induced in vitro and in vivo during lung injury. In a model of high-pressure ventilation PLXNC1(-/-) animals show decreased signs of alveolar inflammation and improved survival compared with wild-type controls. Studies employing chimeric animals identified the hematopoietic expression of PLXNC1 to be of crucial importance for the observed results. Functional inhibition of PLXNC1 resulted in improved survival and ameliorated the signs of inflammation within the lung. Furthermore, the injection of a peptide binding to PLXNC1 resulted in improved survival and attenuated pulmonary inflammation. As such we demonstrate here, that previously unknown PLXNC1 holds significant importance for degree of pulmonary inflammation and determines outcome during experimental lung injury.

[Molecular pathology of the lungs. New perspectives by next generation sequencing]. / Molekularpathologie der Lunge. Perspektiven durch neue Sequenzierformen.

Lung cancer is one of the most frequent malignancies in the western world. Its frequent association with a wide spectrum of mutations in genes encoding various signal transducers that are often linked to therapy response, emphasizes the obvious need for improved, fast and highly efficient approaches in molecular pathology. Comprehensive analyses of the mutation status of progression and therapy relevant genes can be performed by the novel sequencing forms named next generation sequencing (NGS) providing extremely high capacities for ultra-deep sequence analyses. The 454 pyrosequencing method, the sequencing by synthesis and the semiconductor sequencing platform are now available for parallel sequencing approaches of multitudinous target genes linked to multiple tumor DNA applications. The "one molecule, one clone, one read" principle by the NGS approaches supplies not only information on allele frequencies and mutation rates but also has the advantage of a very sensitive detection of low frequency variants.

The effect of sildenafil on retinopathy of prematurity in very preterm infants.

OBJECTIVE: Sildenafil is occasionally used as rescue treatment for preterm infants with severe bronchopulmonary dysplasia and pulmonary arterial hypertension. In adults, sildenafil treatment has been associated with several ophthalmological adverse effects, including nonarteritic ischaemic optic neuropathy. We reviewed the effect of sildenafil on retinopathy of prematurity (ROP) in very preterm infants. STUDY DESIGN: Retrospective case-control study. Infants born <30 weeks gestation who had received sildenafil during their hospitalisation were included. A control group matched for gestation, birth weight, gender, and place of birth was identified from the departmental database. For every sildenafil case, three matched controls were studied. Baseline data, sildenafil therapy data, results of eye examinations and respiratory data were analysed. RESULT: 17 infants received sildenafil between 2004 and 2010. The median duration of sildenafil treatment was 52 days. Baseline characteristics were similar between groups. The odds ratio for an increase in ROP stage in the group treated with sildenafil was 1.35 (95% confidence interval 0.39-4.62, P-value 0.63). One infant in each group required laser treatment. CONCLUSION: Sildenafil treatment did not affect ROP progression or increase the need for laser treatment in this cohort.

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation.

Lysine (K)-specific demethylase 1A (LSD1/KDM1A) has been identified as a potential therapeutic target in solid cancers and more recently in acute myeloid leukemia. However, the potential side effects of a LSD1-inhibitory therapy remain elusive. Here, we show, with a newly established conditional in vivo knockdown model, that LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.

[Experimental corneal imaging and corneal surgery with non-amplified femtosecond laser pulses]. / Experimentelle Hornhautbildgebung und Hornhautchirurgie mit nicht verstärkten Femtosekundenlaserpulsen.

BACKGROUND: Non-amplified femtosecond laser was used to induce multiphoton effects for corneal tissue imaging and for tissue ablation. MATERIAL AND METHODS: A non-amplified titanium-sapphire laser was coupled to a laser scanning microscope in order to examine human and porcine cornea. Tissue was subjected to imaging and lesions were created using identical optical pathways at pulse energies below 2 nJ. RESULTS: Cellular components and the extracellular matrix were selectively imaged by applying autofluorescence and second harmonic generation at submicron resolution. Intrastromal linear scanning at higher power resulted in luminescent plasma along the scanning line. Lesion width decreased with increasing tissue depth and increased with increasing laser power at the target. Light microscopy showed intact stromal tissue around the area of the lesion. CONCLUSIONS: High-resolution images as well as high precision tissue lesions were created in the cornea using low energy femtosecond laser pulses. Easy switching between tissue imaging and ablation seems to be suitable for diagnostic and therapeutic applications.

Pregnancy in a woman with proportionate (primordial) dwarfism: a case report and literature review.

Primordial dwarfism is a rare form of severe proportionate dwarfism which poses significant challenges in pregnancy. A 27-year-old with primordial dwarfism (height 97 cm, weight 22 kg) and coexisting morbidities of familial hypercholesterolaemia and hypertension presented to our unit. Early pregnancy was complicated by difficult blood pressure control, sinus tachycardia, biochemical hyperthyroidism and insulin-requiring gestational diabetes. Delivery was indicated at 24 weeks with uncontrollable hypertension, progressive renal impairment and intrauterine growth restriction. A caesarean section was performed under general anaesthesia, resulting in the delivery of a 486 g male infant. This case highlights the difficulties of managing pregnancy in a woman with primordial dwarfism. Her limited capacity to respond to the physiological demands of pregnancy created a life-threatening situation, culminating in profound preterm birth.

Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography.

BACKGROUND: Multiphoton tomography (MPT) is a novel non-invasive imaging method in dermatology allowing the depiction of the epidermis with sub-cellular resolution. Here, we present a descriptive characterization of unaffected human epidermis, morphometric data on human keratinocytes and some epidermal parameters in vivo and a morphological characterization of keratinocyte changes in actinic keratoses. METHODS: In a clinical setting, 57 volunteers of different age groups were examined using MPT. RESULTS: The morphological appearance of keratinocytes showed polygonal cells in the horny layer, a granular cytoplasm in the stratum granulosum, smaller prickle cells in the stratum spinosum and hyperpigmented small round basal cells. Actinic keratoses presented remarkable differences including widened inter-cellular spaces, heterogeneity in cellular fluorescence and shape as well as an increased ratio of nuclear to cellular size. Finally, the thickness of the epidermis was significantly increased in actinic keratoses compared with the control. CONCLUSION: In vivo MPT provides high-resolution images allowing the identification and quantification of cellular morphometric parameters. First observations of morphology and morphometry of actinic keratoses are reported.

[Multiphoton microscopy and in vivo tomography in dermatologic imaging]. / Multiphotonenmikroskopie und In-vivo-Multiphotonentomographie in der dermatologischen Bildgebung.

Multiphoton microscopy (MPM) and in vivo multiphoton tomography (MPT) are non-invasive examination techniques that allow for the evaluation of cellular as well as extra-cellular structures by working at a subcellular resolution level. These techniques are thus appropriate not only for clinical diagnostics but also for scientific issues in basic and applied research. MPM and MPT are based on the stimulation of biogenic fluorophores by two or more long-wave, low-energy photons and the evocation of second harmonic generation (SHG). Thus, the evaluation quality of cell clusters and tissues is similar to histological sections. At the same time the dermal fiber network can be assessed. MPT was developed further for the application in non-invasive in vivo diagnostics of skin diseases. This review presents the capabilities of multiphoton-based diagnostics in the evaluation of transcutaneous metabolism. In addition, the multiphoton techniques employed for the evaluation of physiologic and pathologic changes of the dermal fiber network as well as in the diagnosis of dermal and epidermal disorders by visual biopsy. Besides the morphological classification of benign and malignant skin tumors or allergic or inflammatory skin lesions, the techniques also allow for recording metabolic processes.

Two-photon microscopy of deep intravital tissues and its merits in clinical research.

Multiphoton excitation laser scanning microscopy, relying on the simultaneous absorption of two or more photons by a molecule, is one of the most exciting recent developments in biomedical imaging. Thanks to its superior imaging capability of deeper tissue penetration and efficient light detection, this system becomes more and more an inspiring tool for intravital bulk tissue imaging. Two-photon excitation microscopy including 2-photon fluorescence and second harmonic generated signal microscopy is the most common multiphoton microscopic application. In the present review we take diverse ocular tissues as intravital samples to demonstrate the advantages of this approach. Experiments with registration of intracellular 2-photon fluorescence and extracellular collagen second harmonic generated signal microscopy in native ocular tissues are focused. Data show that the in-tandem combination of 2-photon fluorescence and second harmonic generated signal microscopy as two-modality microscopy allows for in situ co-localization imaging of various microstructural components in the whole-mount deep intravital tissues. New applications and recent developments of this high technology in clinical studies such as 2-photon-controlled drug release, in vivo drug screening and administration in skin and kidney, as well as its uses in tumourous tissues such as melanoma and glioma, in diseased lung, brain and heart are additionally reviewed. Intrinsic emission two-modal 2-photon microscopy/tomography, acting as an efficient and sensitive non-injurious imaging approach featured by high contrast and subcellular spatial resolution, has been proved to be a promising tool for intravital deep tissue imaging and clinical studies. Given the level of its performance, we believe that the non-linear optical imaging technique has tremendous potentials to find more applications in biomedical fundamental and clinical research in the near future.

[Femtosecond laser ablation and scanning microscopy of the internal retinal limiting membrane: an experimental study].

The investigation was undertaken to study whether femtosecond laser ablation and microscopy might be used in the internal retinal borderline membrane. Ablation of internal limiting membrane preparations removed using or not using indocyanine green was made by a low-energy femtosecond laser. Examination of the preparations by laser and electron microscopy revealed precision laser cuts of the internal retinal borderline membrane. The use of indocyanine green during laser ablation reduced laser irradiation parameters as compared to the dye not being applied. Low-energy femtosecond lasers enable precision contactless ablation of the internal borderline membrane to be carried out without collateral damage to the adjacent tissue. The parameters of laser impulses, particularly low ones used in the ablation of indocyanine green-stained preparations, prove the photosensitizing effect of the dye.

Sonohistology - ultrasonic tissue characterization for prostate cancer diagnostics.

A computer-aided diagnostic system for imaging prostate cancer has been developed in order to supplement today's conventional methods for the early detection of prostate carcinoma. The system is based on analysis of the spectral content of radiofrequency ultrasonic echo data in combination with evaluations of textural, contextual, morphological and clinical features in a multiparameter approach. A state-of-the-art, non-linear classifier, the so-called adaptive network-based fuzzy inference system, is used for higher-order classification of the underlying tissue-describing parameters. The system has been evaluated on radio-frequency ultrasound data originating from 100 patients using histological specimens obtained after prostatectomy as the gold standard. Leave-one-out cross-validation over patient data sets results in areas under the ROC curve of 0.86 +/- 0.01 for hypoechoic and hyperechoic tumors and of 0.84 +/- 0.02 for isoechoic tumors, respectively.

[Guideline for the Early Detection of Breast Cancer in Germany 2008. Recommendations from the short version]. / Stufe-3-Leitlinie Brustkrebs-Früherkennung in Deutschland 2008 : Auszug aus der Kurzfassung: Handlungsempfehlungen.

The updated 2008 German Guideline for Early Detection of Breast Cancer provides evidence-based and consensus-based recommendations of the knowledge gained by the German Society for Surgery and the German Society of Plastic, Aesthetic, and Reconstructive Surgeons together with 29 professional societies, associations, and nonmedical organizations. The guideline is meant to assist physicians, healthy women, and patients in medical decisions with recommendations regarding the diagnostic chain in early detection of breast cancer. In addition to these recommendations, the guideline also includes descriptions of quality assurance for resources, procedures, outcomes, and evaluation using a set of quality indicators. It updates the previous version from 2003. The guideline's recommendations are presented. They are described in detail in the full publication (in German) Geburtsh Frauenh 2008; 68:251-261. The long version of the Guideline, methods report, and evidence report are available on the internet at www.awmf-leitlinien.de (reg. no. 077/001) with free access.

Clinical two-photon microendoscopy.

Two-photon medical imaging has found its way into dermatology as an excellent method for noninvasive skin cancer detection without need of contrast agents as well as for in situ drug screening of topically-applied cosmetical and pharmaceutical components. There is an increasing demand to apply the multiphoton technology also for deep-tissue skin imaging as well as for intracorporal imaging. We report on the first clinical use of multiphoton endoscopes, in particular of a miniaturized rigid two-photon GRIN lens endoscope. The microendoscope was attached to the multiphoton tomograph DermaInspect and employed to detect the extracellular matrix proteins collagen and elastin in the human dermis of volunteers and patients with ulcera by in vivo second harmonic generation and in vivo two-photon autofluorescence.

[The angle stable locking-proximal-humerus-plate (LPHP) for proximal humeral fractures using a small anterior-lateral-deltoid-splitting-approach - technique and first results]. / Die winkelstabile Plattenosteosynthese (LPHP) proximaler Humerusfrakturen über den kleinen anterolateralen Delta-Splitting-Zugang - Technik und erste Ergebnisse.

The Locking-Proximal-Humerus-Plate (LPHP) was slided from proximally to distally through a small anterior-lateral-deltoid-splitting-approach following a closed reduction. Additional tension band wiring for the rotator cuff was fixed at the plate after screw insertion. The prospective study included 35 patients (age median: 63 years, range: 33-92; male: 13, female: 22) from 08/01-05/02. The follow-up period was set to 3 months postoperatively, whereas 29 patients were able to attend. The patient-group with 2-part fractures (n = 8) showed an average Constant score of 77.6 points (+/- 10.7, "good"), the patients with 3-part fractures (n = 16) an average score of 75.1 points (+/- 14.4, "good") and the patients with 4-part fractures (n = 5) an average score of 64.8 points (+/- 10. 4, "moderate"). Specific, approach-related problems were not observed. Almost all fractures revealed bony union during the first 3 months and only one loss of reduction was found. A screw loosening in 2 cases and a break of the plate in 3 cases were seen as implant related problems, and furthermore in 5 cases the screws placed in the humeral head were too long. Only one early re-osteosynthesis with the same plate was necessary due to an initial non-correct reposition. As demonstrated by these good short-term results, this technique seems to be a suitable procedure for displaced humeral head fractures.