Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

Impact of laparoscopic versus open surgery on humoral immunity in patients with colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Laparoscopic surgery (LS) is hypothesized to result in milder proinflammatory reactions due to less severe operative trauma, which may contribute to the observed clinical benefits after LS. However, previous systematic reviews and meta-analyses on the impact of LS on immunocompetence are outdated, limited and heterogeneous. Therefore, the humoral response after laparoscopic and open colorectal cancer (CRC) resections was evaluated in a comprehensive systematic review and meta-analysis. METHODS: Included were randomized controlled trials (RCTs) measuring parameters of humoral immunity after LS compared to open surgery (OS) in adult patients with CRC of any stage. MEDLINE, Embase, Web of Science (SCI-EXPANDED), Cochrane Library, Google Scholar, ClinicalTrials.gov and ICTRP (World Health Organization) were systematically searched. Risk of bias (RoB) was assessed using the Cochrane RoB2 tool. Weighted inverse variance meta-analysis of mean differences was performed for C-reactive protein (CRP), interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)α and vascular endothelial growth factor (VEGF) using the random-effects method. Methods were prospectively registered in PROSPERO (CRD42021264324). RESULTS: Twenty RCTs with 1131 participants were included. Narrative synthesis and meta-analysis up to 8 days after surgery was performed. Quantitative synthesis found concentrations to be significantly lower after LS at 0-2 h after surgery (IL-8), at 3-9 h (CRP, IL-6, IL-8, TNFα) and at postoperative day 1 (CRP, IL-6, IL-8, VEGF). At 3-9 h, IL-6 was notably lower in the LS group by 86.71 pg/ml (mean difference [MD] - 86.71 pg/ml [- 125.05, - 48.37], p < 0.00001). Combined narratively, 13 studies reported significantly lower concentrations of considered parameters in LS patients, whereas only one study reported lower inflammatory markers (for CRP and IL-6) after OS. CONCLUSION: The increase in postoperative concentrations of several proinflammatory parameters was significantly less pronounced after LS than after OS in this meta-analysis. Overall, the summarized evidence reinforces the view of a lower induction of inflammation due to LS.

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

PURPOSE: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. METHODS: In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. RESULTS: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). CONCLUSION: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Roles of Tetratricopeptide Repeat Proteins in Biogenesis of the Photosynthetic Apparatus.

Biosynthesis of the photosynthetic apparatus is a complex operation, which includes the concerted synthesis and assembly of lipids, pigments and metal cofactors, and dozens of proteins. Research conducted in recent years has shown that these processes, as well as the stabilization and repair of this molecular machinery, are facilitated by transiently acting regulatory proteins, many of which belong to the superfamily of helical repeat proteins. Here, we focus on one of its families in photoautotrophic model organisms, the tetratricopeptide repeat (TPR) proteins, which participate in almost all of these steps and are crucial for biogenesis of the thylakoid membrane.

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG.

E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were co-expressed in 80% of AML (n=30) and 40% in T-ALL (n=30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were co-stimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

Sex determination diversity and sex chromosome evolution in poeciliid fish.

Poeciliids, a family of live-bearing freshwater fish, including among others platyfish, swordtails and guppies, fully illustrate the diversity of genetic sex determination mechanisms observed in teleosts. Besides unisexuality, a variety of sex-determining systems has been described in this group of fish, including male and female heterogamety with or without autosomal influence, as well as more complicated situations such as multichromosomal and polyfactorial sex determination. Due to the presence of different mechanisms in closely related species or even between populations within a same species, poeciliids are a very attractive model to study the evolutionary dynamics of sex determination. For one species, the Southern platyfish Xiphophorus maculatus, positional cloning of the master sex-determining gene has been initiated through the construction and sequencing of bacterial artificial chromosome contigs covering the region differentiating the X from the Y chromosome. Initial analysis revealed a high plasticity of the sex-determining region and the absence of synteny with other fish and vertebrate sex chromosomes, indicating an independent evolutionary origin.

Medical informatics and the quality of health: new approaches to support patient care - findings from the IMIA Yearbook of Medical Informatics 2003.

OBJECTIVES: The Yearbook of Medical Informatics is published annually by the International Medical Informatics Association (IMIA) and contains a selection of excellent papers on medical informatics research which have been recently published (http://www. yearbook.uni-hd.de). The 2003 Yearbook of Medical Informatics took as its theme the role of medical informatics for the quality of health care. In this paper, we will discuss challenges for health care, and the lessons learned from editing IMIA Yearbook 2003. RESULTS AND CONCLUSIONS: Modern information processing methodology and information and communication technology have strongly influenced our societies and health care. As a consequence of this, medical informatics as a discipline has taken a leading role in the further development of health care. This involves developing information systems that enhance opportunities for global access to health services and medical knowledge. Informatics methodology and technology will facilitate high quality of care in aging societies, and will decrease the possibilities of health care errors. It will also enable the dissemination of the latest medical and health information on the web to consumers and health care providers alike. The selected papers of the IMIA Yearbook 2003 present clear examples and future challenges, and they highlight how various sub-disciplines of medical informatics can contribute to this.

Medical Imaging Informatics and Medical Informatics: opportunities and constraints. Findings from the IMIA yearbook of Medical Informatics 2002.

OBJECTIVES: The Yearbook of Medical Informatics is published annually by the International Medical Informatics Association (IMIA) and contains a selection of recent excellent papers on medical informatics research (http://www.yearbook.uni-hd.de). The 2002 Yearbook of Medical Informatics took as its theme the topic of Medical Imaging Informatics. In this paper, we will summarize the contributions of medical informatics researchers to the development of medical imaging informatics, discuss challenges and opportunities of imaging informatics, and present the lessons learned from the IMIA Yearbook 2002. RESULTS AND CONCLUSIONS: Medical informatics researchers have contributed to the development of medical imaging methods and systems since the inception of this field approximately 40 years ago. The Yearbook presents selected papers and reviews on this important topic. In addition, as usual, the Yearbook 2002 also contains a variety of papers and reviews on other subjects relevant to medical informatics, such as Bioinformatics, Computer-supported education, Health and clinical management, Health information systems, Knowledge processing and decision support, Patient records, and Signal processing.

Glycosylation of proteins: a computer based method for the rapid exploration of conformational space of N-glycans.

Inspection of protein databases suggests that as many as 70% of proteins have potential N-glycosylation sites. Unfortunately glycoproteins often refuse to crystallize and NMR techniques do not allow an unambiguous determination of the complete conformation of the sugar part. Therefore, time-consuming complex simulation methods are often used to explore the conformational space of N-glycans. The generation of a comprehensive data base describing the conformational space of larger fragments of N-glycans taking into account the effects of branching is presented. High-temperature molecular dynamics simulations of essential N-glycan fragments are performed until conformational equilibrium has been reached. Free energy landscapes are calculated for each glycosidic linkage. All possible conformations for each N-glycan fragment are automatically assigned, ranked according to their relative population and stored in a database. These values are recalled for the generation of a complete set of all possible conformations for a given N-glycan topology. The constructed conformations are ranked according to their energy content. Since this approach allows to explore the complete conformational space of a given N-glycan within a few minutes of CPU-time on a standard PC, it is well suited to be used as a Web-Based application.

The information encrypted in accurate peptide masses-improved protein identification and assistance in glycopeptide identification and characterization.

Analytically useful information from accurate mass data for peptides with an error of

SWEET - WWW-based rapid 3D construction of oligo- and polysaccharides.

UNLABELLED: SWEET is a WWW-based tool which rapidly converts the commonly used carbohydrate sequence information directly into a preliminary but reliable 3D model which can be visualised and written to files in several ways. AVAILABILITY: SWEET is accessible via the Internet at http://www.dkfz-heidelberg.de/spec/. CONTACT: a. bohne@dkfz-heidelberg.de or w.vonderlieth@ dkfz-heidelberg.de SUPPLEMENTARY INFORMATION: The current version of SWEET generates only one conformation out of a manifold. Several authors have analysed possible conformations of high-mannose N-linked glycans using a combination of NMR methods and computational approaches showing that such molecules are rather flexible populating normally several conformations for each glycosidic linkage. The displayed model exhibits for all glycosidic linkages a conformation which is in accordance with the reported variations of Phi, psi and omega values for specific linkage (see http://www.dkfz-heidelberg. de/spec/sweet2/doc/input/sba_example.html).

[The nature of evoked potentials, recorded at neocortical transplants]. / Priroda vyzvannykh potentsialov, registriruemykh v neokortikal'nykh transplantatakh.

Evoked potentials (EP) recorded from a barrelfield of adult rats were compared with those recorded from neocortical embryonal grafts 4-6 month after their transplantation into the barrelfield of adult rats. EPs at the surface of the intact barrelfield started with a positive component followed by a negative wave. EPs reversed their polarity at a depth of 0.4-1.0 mm from the cortical surface. EPs registered from the surface of grafts has the same latency as those in the intact barrelfield, but consisted exclusively of a negative component. It is concluded that though the simultaneously activated grafted neurons can generate local field potentials, their detection during EP recording is prevented as a result of diffuse neuronal organization of the grafts and they can be masked by passive current spreading from the adjacent intact areas of the host brain.

[Neuronal responses of the rate somatosensory cortex transplanted into the vibrissae representation field of the neocortex to the electrical stimulation of the recipient brain]. / Otvety neironov somatosensornoi kory krys, transplantirovannoi v oblast' predstavitel'stva vibriss neokorteksa, na élektricheskuiu stimuliatsiiu mozga retsipienta.

Neuronal responses of the rat somatosensory cortex grafted into damaged host barrel field to electrical stimulation of the host brain were investigated extracellularly in rats under light pentobarbital anaesthesia. The following structures of the host brain were stimulated: ventrobasal complex and posterior thalamic nuclei, ipsilateral area of vibrissae representation in the sensorimotor cortex and contralateral barrel field. Reactivity of the grafted neurones was lower, than in the intact barrel field, but the mean latencies of responses were not significantly different. Stimulation of the thalamic nuclei was more effective than that of the cortical areas both in grafted and intact barrel fields. Posttetanic depression after repetitive stimulation was often observed in the grafts, while posttetanic potentiation was more usual for the intact barrel field. The data show the sources of some functional afferent inputs to the grafts which may be responsible for neuronal reactions to somatosensory stimulation of the host animal.

Transplants of the embryonal rat somatosensory neocortex in the barrel field of the adult rat: responses of the grafted neurons to sensory stimulation.

The degree of participation of grafted neurons in sensory analysis was investigated in embryonal rat somatosensory neocortex transplanted into the cavity at the place of the barrel field in the neocortex (SI) of adult rats. The neurons were investigated extracellularly 3 to 6 months after grafting. In the majority of grafts the neurons had normal levels and patterns of spontaneous activity. Many of them (65%) responded to displacement of the whiskers with latencies insignificantly different (18 +/- 0.8 ms) from those for reactions in the intact barrel field (16 +/- 0.5 ms). The receptive fields of the grafted neurons were very large. None of the neurons responded to stimulation of a single vibrissa, as in intact cortex. As a rule, the same neuron responded to isolated deflections of several (up to 10-20) vibrissae. Many of them were responsive to stimulation of the small anterior vibrissae and tactile stimulation of nose, limbs and body surface. Nevertheless, there was some spatial gradient in the effectiveness of stimulation of the body surface at various distances from the vibrissal pad; among effective vibrissae, usually several adjacent ones (2-4) produced larger responses with shorter latencies than the other ones. All units responded to painful stimuli irrespective of their location. The data show that the grafted neurons receive and may transmit sensory signals. The grafts which were proved histologically to be isolated from the host's brain did not respond to sensory stimulation and were characterized by the presence of aperiodic hypersynchronous bursts in their background activity. Electrophysiological criteria may be used for intravital diagnosis on the degree of the graft morphofunctional integration.

[Electrophysiological indices of the degree of functional integration of a cortical transplant with the brain of the recipient]. / Elektrofiziologicheskie pokazateli stepeni funktsional'noi integratsii kortikal'nogo transplantata s mozgom retsipienta.

Pieces of the embryonal rat neocortex were grafted into the cavity at the place of the barrel-field of adult rats. Neuronal discharges and slow activity were recorded in 11 grafts 3-8 months after the grafting. Neurons of nine grafts responded to vibrissae deflection, their background activity consisted of randomly distributed discharges as in the normal cortex. The similar slow activity was observed in the responding grafts and in the host's intact contralateral barrel-field. Neurons of two grafts did not respond to vibrissae deflection. Hypersynchronous discharges prevailed in their background activity as well as slow delta-waves and epileptiform sharp spikes and waves. Complexes predominated in slow activity of these grafts. Histology revealed a close contact between responding grafts and host brain tissue. Nonresponding grafts were separated from the host brain by a thick glial scar which apparently prevented the axonal exchange between them.

Vitamin B12 absorption and exocrine pancreatic insufficiency in childhood.

The absorption of vitamin B12, labelled with radioactive 58Co, was measured in 19 patients with cystic fibrosis and one child with the Shwachman-Diamond syndrome using the whole body counting technique. We found vitamin B12 absorption reduced to 7.97 on average, compared to 59.2% for the control group. The low vitamin B12 absorption correlated well with the reduced fat retention coefficients. After adding 0.212 pancreatin to the radioactive vitamin B12 test dose, the absorption quotas improved in all cases, the average being 61%. A meal poor in vitamin B12 tended to increase the absorption of the radioactive test dose to 23% on average. As yet there is no satisfactory explanation for the effect of the diet on the absorption of vitamin B12 in exocrine pancreatic insufficiency. This could be the reason why the malabsorption of vitamin B12 in patients with EPI can go unnoticed for many years and could possibly explain why vitamin B12 malabsorption in exocrine pancreatic insufficiency does not cause symptoms and signs of vitamin B12 deficiency for many years.

[Radiographic findings in clinically edentulous sections of alveolar processes]. / Röntgenbefunde in klinisch zahnlosen Alveolarfortsatzabschnitten

In the absence of symptoms indicative of pathological processes in the region of clinically edentulous alveolar processes, primary radiographic examination is sometimes omitted. For this reason, the authors report the results from the evaluation of the radiographs of 2177 patients with clinically edentulous alveolar processes. 320 (14.7%) positive findings were obtained from 278 patients. The great number of positive findings justifies the demand for careful radiographic examination also in case of clinically edentulous alveolar processes prior to the planning of any stomatological treatment.