Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

[From myxomas of the skin to LVAD implantation : A 28-year-old female patient with Carney complex]. / Von Hautmyxomen zur LVAD-Implantation : Eine 28-jährige Patientin mit Carney-Komplex.

Multiple skin lesions, endocrine dysfunction and cardiac myxomas are characteristic symptoms of Carney complex. This case report gives an overview about the major and minor criteria of Carney complex and presents the course of a female patient who developed severe cardiac insufficiency with multiple organ failure because of recurring heart operations leading to implantation of a left ventricular assist device (LVAD).

[Inherited retinal or optic nerve disorders ­ five steps to diagnosis]. / Erbliche Netzhaut- und Sehbahnerkrankungen ­ 5 Schritte zur Diagnose.

An early diagnosis of inherited retinal or optic nerve disorders is often delayed due to unspecific clinical signs, multiple clinical manifestations and striking genetic heterogeneity of the underlying molecular defects. This study represents a retrospective analysis of findings in 4,021 patients with inherited retinal or optic nerve disorders seen between 1986 and 2014 (1,171 with follow-up). In addition to the basic ophthalmological examination, electrophysiological tests (ERG, n = 2,088, since 1986; EOG, n = 381, since 1986; VEP n = 595, since 1986; mfERG, n = 819, since 1998) and non-invasive retinal imaging (fundus autofluorescence (FAF, n = 1,784, since 2002), near-infrared autofluorescence (NIA, n = 1,091, since 2006), spectral domain OCT (SD-OCT, n = 848, since 2008) and three-wavelengths multicolour spectral reflection imaging (MC, n = 366, since 2013) were performed at least once. Molecular DNA testing was done in 383 patients between 2006 and 2014. Based on these data an efficient diagnostic strategy is suggested: 1) inclusion of inherited retinal and optic nerve disorders into the differential diagnosis of visual loss or visual field defects with undefined causes; 2) non-invasive retinal imaging; 3) electrophysiological tests; 4) DNA testing to confirm the initial clinical diagnosis; 5) examination in specialised centres, therapy and follow-up. In recent years, the spectrum of diagnostic techniques has continuously expanded. Importantly, non-invasive retinal imaging has become the primary diagnostic tool and DNA testing based on state-of-the-art high throughput techniques increases the identification of associated gene mutations. In conclusion, a structured process in the diagnostic procedure of inherited retinal and optic nerve disorders greatly reduces a diagnostic delay, enables an earlier counselling and therapy and avoids further unnecessary diagnostic tests.

[Evidence-based diagnostic approach to inherited retinal dystrophies 2009]. / Evidenzbasierte Diagnostik hereditärer Netzhautdystrophien 2009.

BACKGROUND: Hereditary retinal dystrophies comprise a heterogeneous group of inherited retinal disorders with variable clinical presentation and multiple associated genes. Clinical diagnosis and differential diagnosis are difficult. The purpose of the current paper is to provide guidelines for an effective diagnostic approach. METHODS: A literature search was carried out and our own data on clinical (n = 3200) and molecular genetic (n = 4050) diagnosis of patients with retinal dystrophies were evaluated. RESULTS: For an early diagnosis it is of importance to include inherited retinal dystrophies in the differential diagnosis of unexplained visual disturbances. The most important clinical test is the full-field electroretinogram (ERG), which allows detection or exclusion of generalised retinal dystrophies. If the full-field ERG is normal, a multifocal ERG will distinguish macular dystrophies. Fundus autofluorescence, near-infrared autofluorescence and high resolution optical coherence tomography improve the early diagnosis because morphological alterations can be detected prior to their ophthalmoscopic visibility. In addition, these non-invasive imaging techniques reveal new phenomena which are important for the differential diagnosis and follow-up of retinal dystrophies as well as for an improved understanding of their pathogenesis. Routine molecular genetic diagnosis is available for an increasing number of retinal dystrophies. A succinct clinical diagnosis is a prerequisite to allow selection of the gene(s) to be analysed. If genetic testing is indicated, a human geneticist should be involved for counselling of the patient and possibly further family members and initiation of the necessary steps for DNA testing. CONCLUSION: The combination of electrophysiological testing, retinal imaging and molecular genetic analysis allows a differentiated diagnosis of inherited retinal dystrophies and an individual counselling of patients. If inherited retinal dystrophies are suspected, a detailed examination in a retinal centre specialised on inherited retinal dystrophies is recommended.

In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-XL and Mcl-1 but in the absence of active BH3-only proteins.

Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl-2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules. All anti-apoptotic Bcl-2 proteins were targeted via RNA interference alone or in combinations of two in primary human fibroblasts. Simultaneous targeting of B-cell lymphoma-extra large and myeloid cell leukemia sequence 1 led to apoptosis in several cell types. Apoptosis depended on Bak whereas Bax was dispensable. Activator BH3-only proteins were not required for apoptosis induction as apoptosis was unaltered in the absence of all BH3-only proteins known to activate Bax or Bak directly, Bcl-2-interacting mediator of cell death, BH3-interacting domain death agonist and p53-upregulated modulator of apoptosis. These findings argue for auto-activation of Bak in the absence of anti-apoptotic Bcl-2 proteins and provide evidence of profound differences in the activation of Bax and Bak.

Differences of ploidy status in progression of head and neck melanomas.

Thirty-three common naevi, 26 dysplastic naevi, 58 primary melanomas of facial skin, 24 oral melanomas, 32 lymph nodes and 12 distant melanoma metastases were stained using Feulgen method to evaluate the ploidy status by image analysis GAS-200 system. Eight percent of common naevi, 22% of dysplastic naevi, 43% of facial melanomas, 65% of oral melanomas, 40% of lymph nodes with melanoma metastases and 66% of distant melanoma metastases were classified as aneuploid. In facial melanomas the percentage of aneuploid cases increased with Clark level. Survival time of patients was significantly shorter for aneuploid cases as compared to euploid ones (p <0.01).

Decreased expression of MLH1, MSH2, PMS1 and PMS2 in pigmented lesions indicates accumulation of failed DNA repair along with malignant transformation and tumour progression.

The tumorigenesis of human nonpolyposis colorectal cancer was reported to be connected with the mutations in DNA mismatch repair genes. The main aim of this study was to check the epression of 4 proteins MLH1, MSH2, PMS1 and PMS2 responsible for mismatch DNA repair in naevi and melanomas. Fifty-one naevi, 78 primary melanomas, 30 lymphatic and 7 organ melanoma metastases were stained for the presence of MLH1, MSH2, PMS1 and PMS2. All proteins were preserved in 88% of naevi and only in 37% of primary melanomas, 17% of lymphatic metastases and in none of the distant metastases. The difference of expression of all 4 proteins between naevi and melanomas was highly significant (p<0.01). MLH1 and MSH2 correlated significantly with each other as well with the follow-up of patients. On the basis of our results one can conclude that the defect of mismatch DNA repair plays an important role in both tumorigenesis of melanoma and metastatic spread of tumour.

Analysis of ploidy status in progression of head and neck cancers by DNA image cytometry.

Eight cases of leukoplakia, 25 lingual cancers, 15 cancers of the floor of the oral cavity, 11 pharyngeal cancers and 14 lymph nodes with squamous cell cancer metastases were stained using the Feulgen method to evaluate the ploidy status and ploidy related parameters. All leukoplakias were euploid. Percentage of aneuploid cancers correlated with the grade of tumours. Significant differences between tumours with 3 different locations were not found. Metastatic carcinoma cells in lymph nodes had significantly more cells in S-phase as compared to primary tumours.

Analysis of the DNA content in Bowen's disease.

The aim of this study was to evaluate the DNA content in Bowen's disease in comparison to healthy epidermis applying image cytophotometry. The material investigated was derived from 50 patients with Bowen's disease and 10 patients with healthy skin. For comparison of both groups the Kruskal-Wallis test was applied. Slides were stained with Feulgen and were evaluated with CAS-200 image analyzer. Only 7/50 morbus Bowen cases represented euploid histogram. The others 43/50 were either conspicious to be aneuploid (29/50) or clearly aneuploid (14/50). In contrast, all normal epidermis (10/10) were clearly euploid. Morbus Bowen cases demonstrated significantly higher 5c exceeding rate (p=0.0012) and significantly more cells in the S-phase (p=0.017). High aneuploidy rate and increased proliferative activity in morbus Bowen cases support the classification of these lesion as carcinoma in situ.

Prognostic relevance of Ki-67 antigen and c-myc oncoprotein in malignant fibrous histocytoma.

47 cases of malignant fibrous histiocytoma were stained immunohistochemically for the presence of Ki-67 antigen and c-myc oncoprotein. Percentage of Ki-67 and c-myc positive cells correlated with each other and with grade of tumour, mitotic index, cellularity and survival time of patients, but not with the extent of necrosis. Differences of mean values of Ki-67 index between grade I and grade II tumours as well as between grade II and grade III tumours were highly statistically significant. All 3 parameters connected with c-myc expression (index, intensity and score) differed significantly between grade I and grade II tumours but not between grade II and grade III MFH. The possible differential role of Ki-67 antigen and c-myc oncoprotein for improvement of grading is discussed.

Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanomas.

Twenty nine benign naevi and 59 melanomas of different Clark level and locations were stained immunohistochemically for the presence of p53 and 3 members of Growth Arrest. DNA Damage inducible family: GADD 34, GADD 45 and GADD 153. All naevi were p53 negative and highly GADD positive. Differences in the expression of all 3 GADD proteins between naevi and melanomas were highly significant (p = 0.0001). The expression of p53 increased and the expression of GADD proteins decreased with the Clark level of melanoma thickness. The survival time of patients correlated negatively with p53 positivity and positively with GADD 45 and 153 expression. Prognostic significance for GADD 34 was not found. Our conclusion is that GADD proteins play an important role in the malignant transformation of naevus to melanoma and GADD 45 and GADD 153 proteins can influence patient survival.

Significance of P-53 antigen in malignant melanomas and naevi of the head and neck area.

DO-7 antibody against p-53 antigen was applied for investigation of melanomas of facial skin (25 cases), oral cavity (17 cases), eye (18 cases) and naevi (25 cases). The p-53 index value (% of p-53 positive cells) was correlated with the thickness of the tumour, the presence of metastases and survival time. The difference in p-53 index between naevi and melanomas was statistically significant (p < < 0.01). A significant correlation was found between the p-53 index value and the thickness of the tumour, the presence of metastases and follow-up for patients with skin, oral and ocular melanomas. The possible diagnostic and prognostic significance of p-53 antigen in melanomas and naevi of the head and neck area is discussed.

How can one explain aneuploidy status in fibromatous and lipomatous naevus cell naevus?

34 lightly fibromatous, 23 heavily fibromatous, 5 lipomatous and 10 naevus cell naevi were stained with Feulgen kit in order to evaluate their ploidy status with CAS 200 image analyzer. 26/34 lightly fibromatous, 18/23 heavily fibromatous, and 5/5 lipomatous naevi were either suspicious for aneuploidy (Auer III) or clearly aneuploid (Auer IV). In contrast all 10/10 naevus cell naevi were euploid. Proliferation (S-phase) was not increased in naevi fibromatously and lipomatously changed. The mechanisms leading to aneuploidy are discussed.