Photodynamic Therapy of Necrobiosis Lipoidica - A Multicenter Study of 18 Patients

Background: Necrobiosis lipoidica (NL) is a granulomatous skin disease of unknown origin, and no reliably effective treatment option exists to handle this often disfiguring disease. Recently, a patient with long-lasting NL was reported to be cured by topical photodynamic therapy (PDT). Objective: To evaluate the overall potential of PDT in the treatment of NL on the lower legs. Methods: Retrospective study of 18 patients (aged 16 - 62 years) from 3 European university departments of dermatology treated with PDT for NL. Methyl aminolevulinate or 5-aminolevulinic acid were used as topically applied photosensitizers. Illumination followed with red light-emitting diode light. Results: Complete response was seen in 1/18 patients after 9 PDT cycles, and partial response in 6/18 patients (2 - 14 PDT cycles) giving an overall response rate of 39% (7/18). Conclusion: Although almost 40% of the cases showed some degree of response, PDT cannot currently be recommended as first-line therapy of NL. Subpopulations of therapy-resistant NL patients may, however, benefit from PDT. Copyright (C) 2008 S. Karger AG, Base

Comparison of guidelines for the management of patients with high‐risk and advanced cutaneous squamous cell carcinoma – a systematic review

The management of high‐risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high‐risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high‐risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high‐risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC

High-Definition Optical Coherence Tomography for the in vivo Detection of Demodex Mites

Background: Demodex mites are involved in different skin diseases and are commonly detected by skin scrape tests or superficial biopsies. A new high-definition optical coherence tomography (HD-OCT) with high lateral and axial resolution in a horizontal (en-face) and vertical (slice) imaging mode might offer the possibility of noninvasive and fast in vivo examination of demodex mites. Methods: Twenty patients with demodex-related skin diseases and 20 age- and gender-matched healthy controls were examined by HD-OCT. Mites per follicle and follicles per field of view were counted and compared to skin scrape tests. Results: HD-OCT images depicted mites in the en-face mode as bright round dots in groups of 3-5 mites per hair follicle. In the patients with demodex-related disease, a mean number of 3.4 mites per follicle were detected with a mean number of 2.9 infested follicles per area of view compared to a mean of 0.6 mites in 0.4 infested follicles in the controls. The skin scrape tests were negative in 21% of the patients. Conclusion: The innovative HD-OCT enables fast and noninvasive in vivo recognition of demodex mites and might become a useful tool in the diagnosis and treatment monitoring of demodex-related skin diseases. Copyright (C) 2012 S. Karger AG, Base

Quantitative analysis of cell types during growth and morphogenesis in Hydra

Tissue maceration was used to determine the absolute number and the distribution of cell types in Hydra. It was shown that the total number of cells per animal as well as the distribution of cells vary depending on temperature, feeding conditions, and state of growth. During head and foot regeneration and during budding the first detectable change in the cell distribution is an increase in the number of nerve cells at the site of morphogenesis. These results and the finding that nerve cells are most concentrated in the head region, diminishing in density down the body column, are discussed in relation to tissue polarity

Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition

In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-X-L 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

In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-X-L 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

Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma

Background: The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. Patients and Methods: Allele frequencies of BRAFV600 mutations were analyzed byultra-deepnext-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. Results: Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. Conclusions: BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors

Geo-statistical methods to analyse changes in pre-Hispanic settlement patterns in the Río Ica catchment, Peru

Within arid regions allochthonous rivers as a main source of fresh water play a significant role in the spatial organisation of human occupation.This study aims at a comprehensive view on changes in the prehistoric occupation patterns within the Río Ica catchment on the southern coast of Peru. Results of different research projects are integrated. The heterogeneous character of the catchment allows us to define three sub-sections which differ greatly in terms of vegetation, relief and water regime.Based on quantitative geo-statistical methods we analyse spatio-temporal changes in human occupation from the Early Horizon (c. 1000–200 BC) through to the Inca Late Horizon (AD 1450–1532) in the context of environmental conditions, as well as socio-economic processes. Examining known archaeological sites we are able to assess the significance of environmental location factors for pre-Hispanic settlements. In addition, areas of high human interaction are identified on the basis of a classification of archaeological sites according to their function (craft/industry, cult, cooperation and trade). We thereby transfer the concept of central place theory to the spatial distribution of archaeological remains, introducing a novel approach to identifying central functions in a spatially explicit way.Our results crystallise the changing character of occupation in the study area over more than two millennia. They contribute to the ongoing debate on the decline of the Nasca culture, endorsing a complex combination of natural and socio-economic reasons. Furthermore, the results support the concept of a more widespread exchange and cooperation during ‘Horizon’ periods in the study area and likewise indicate that the disappearance of a supra-regional administrative polity during ‘Intermediate’ periods might have led to higher human activity in smaller scale societies, as reflected in a more diverse spatial organisation in terms of geomorphometric units and central areas