XPR1: a regulator of cellular phosphate homeostasis rather than a Pi exporter.

Phosphate (Pi) is an essential nutrient, and its plasma levels are under tight hormonal control. Uphill transport of Pi into cells is mediated by the two Na-dependent Pi transporter families SLC34 and SLC20. The molecular identity of a potential Pi export pathway is controversial, though XPR1 has recently been suggested by Giovannini and coworkers to mediate Pi export. We expressed XPR1 in Xenopus oocytes to determine its functional characteristics. Xenopus isoforms of proteins were used to avoid species incompatibility. Protein tagging confirmed the localization of XPR1 at the plasma membrane. Efflux experiments, however, failed to detect translocation of Pi attributable to XPR1. We tested various counter ions and export medium compositions (pH, plasma) as well as potential protein co-factors that could stimulate the activity of XPR1, though without success. Expression of truncated XPR1 constructs and individual domains of XPR1 (SPX, transmembrane core, C-terminus) demonstrated downregulation of the uptake of Pi mediated by the C-terminal domain of XPR1. Tethering the C-terminus to the transmembrane core changed the kinetics of the inhibition and the presence of the SPX domain blunted the inhibitory effect. Our observations suggest a regulatory role of XPR1 in cellular Pi handling rather than a function as Pi exporter. Accordingly, XPR1 senses intracellular Pi levels via its SPX domain and downregulates cellular Pi uptake via the C-terminal domain. The molecular identity of a potential Pi export protein remains therefore elusive.

Significant Variations in Double-Stranded RNA Levels in Cultured Skin Cells.

Endogenous double-stranded RNA has emerged as a potent stimulator of innate immunity. Under physiological conditions, endogenous dsRNA is maintained in the cell nucleus or the mitochondria; however, if protective mechanisms are breached, it leaches into the cytoplasm and triggers immune signaling pathways. Ectopic activation of innate immune pathways is associated with various diseases and senescence and can trigger apoptosis. Hereby, the level of cytoplasmic dsRNA is crucial. We have enriched dsRNA from two melanoma cell lines and primary dermal fibroblasts, including a competing probe, and analyzed the dsRNA transcriptome using RNA sequencing. There was a striking difference in read counts between the cell lines and the primary cells, and the effect was confirmed by northern blotting and immunocytochemistry. Both mitochondria (10-20%) and nuclear transcription (80-90%) contributed significantly to the dsRNA transcriptome. The mitochondrial contribution was lower in the cancer cells compared to fibroblasts. The expression of different transposable element families was comparable, suggesting a general up-regulation of transposable element expression rather than stimulation of a specific sub-family. Sequencing of the input control revealed minor differences in dsRNA processing pathways with an upregulation of oligoadenylate synthase and RNP125 that negatively regulates the dsRNA sensors RIG1 and MDA5. Moreover, RT-qPCR, Western blotting, and immunocytochemistry confirmed the relatively minor adaptations to the hugely different dsRNA levels. As a consequence, these transformed cell lines are potentially less tolerant to interventions that increase the formation of endogenous dsRNA.

Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting.

Apart from increased fluid intake, patients with kidney stone disease (KSD) due to renal phosphate wasting require specific metaphylaxis. NaPi2a, NaPi2c, and NHERF1 regulate plasma phosphate concentration by reabsorbing phosphate in proximal kidney tubules and have been found altered in monogenic hypophosphatemia with a risk of KSD. In this study, we aimed at assessing the combined genetic alterations impacting NaPi2a, NaPi2c, and NHERF1. Therefore, we screened our hereditary KSD registry for cases of oligo- and digenicity, conducted reverse phenotyping, and undertook functional studies. As a result, we identified three patients from two families with digenic alterations in NaPi2a, NaPi2c, and NHERF1. In family 1, the index patient, who presented with severe renal calcifications and a bone mineralization disorder, carried digenic alterations affecting both NaPi transporter 2a and 2c. Functional analysis confirmed an additive genetic effect. In family 2, the index patient presented with kidney function decline, distinct musculature-related symptoms, and intracellular ATP depletion. Genetically, this individual was found to harbor variants in both NaPi2c and NHERF1 pointing towards genetic interaction. In summary, digenicity and gene dosage are likely to impact the severity of renal phosphate wasting and should be taken into account in terms of metaphylaxis through phosphate substitution.

Midterm clinical outcome of uncemented short-stem reversed shoulder arthroplasty.

INTRODUCTION: While the incidence of reverse total shoulder arthroplasty (rTSA) is increasing constantly, newer implants with designs other than the classic Grammont geometry are gaining importance. More anatomic inclination angles and lateralization are supposed to have a positive impact on clinical results and complication rates. Presentation of midterm results therefore is important to support these assumptions. The aim of this study was to report the midterm clinical outcome of primary rTSA with an uncemented humeral short-stem prosthesis (USSP) with a humeral inclination angle of 145° and the analysis of different variables on the outcome. METHODS: This is a retrospective study of all patients with primary rTSA using an USSP and a combined humeral inclination angle of 145° (Ascend™ flex, Stryker) with a minimum clinical follow-up of 2 years. The implant combines a 132.5° inclination for the humeral stem with an additional 12.5° for the polyethylene inlay. Primary outcomes were patient-reported outcome measures: ASES score, simple shoulder test (SST) and subjective shoulder value (SSV). Secondary outcomes were complication and revision rates. We analyzed different variables: preoperatively gender, age, indication for surgery and status of rotator cuff. Also, the glenoid morphology was classified according to Walch and a proximal humerus cortical bone thickness measurement (CBT avg) of 6 mm was used as a threshold for osteoporosis. Postoperatively, we analyzed different radiologic parameters: filling ratio, distalization and lateralization angles according to Boutsiadis. RESULTS: A total of 84 out of 99 (85%) patients with a mean FU of 46.7 months (range 24-80 months) could be included: 62 women and 22 men with a mean age of 74.7 years. Mean ASES score significantly increased from 47 preoperatively to 85.8 at the last follow-up (p = 0.001). The postoperative SST reached an average of 65.3 and the mean SSV was 83%. None of the variable parameters analyzed could be identified as a risk factor for a lower outcome defined as a SSV < 70. Three patients (3.6%) had a complication: one incomplete lower plexus lesion, one dislocation and one major hematoma. Surgical revision was needed in two cases (2.4%). CONCLUSION: The midterm clinical outcome of primary reverse total shoulder arthroplasty (rTSA) with an uncemented humeral short stem and a humeral inclination angle of 145° showed good-to-excellent results with a low complication and revision rate independent from a wide range of pre- and postoperative variables. PROMs are comparable to those reported for anatomic TSA with a low complication rate, different to historical studies especially with the Grammont design. LEVEL OF EVIDENCE: Treatment study, Level IV.

Seroprevalence of SARS-CoV-2 IgG Antibodies and Factors Associated with SARS-CoV-2 IgG Neutralizing Activity among Primary Health Care Workers 6 Months after Vaccination Rollout in France.

We aimed to investigate the immunoglobulin G response and neutralizing activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among primary health care workers (PHCW) in France and assess the association between the neutralizing activity and several factors, including the coronavirus disease 2019 (COVID-19) vaccination scheme. A cross-sectional survey was conducted between 10 May 2021 and 31 August 2021. Participants underwent capillary blood sampling and completed a questionnaire. Sera were tested for the presence of antibodies against the nucleocapsid (N) protein and the S-1 portion of the spike (S) protein and neutralizing antibodies. In total, 1612 PHCW were included. The overall seroprevalences were: 23.6% (95% confidence interval (CI) 21.6-25.7%) for antibodies against the N protein, 94.7% (93.6-95.7%) for antibodies against the S protein, and 81.3% (79.4-83.2%) for neutralizing antibodies. Multivariate regression analyses showed that detection of neutralizing antibodies was significantly more likely in PHCW with previous SARS-CoV-2 infection than in those with no such history among the unvaccinated (odds ratio (OR) 16.57, 95% CI 5.96-59.36) and those vaccinated with one vaccine dose (OR 41.66, 95% CI 16.05-120.78). Among PHCW vaccinated with two vaccine doses, the detection of neutralizing antibodies was not significantly associated with previous SARS-CoV-2 infection (OR 1.31, 95% CI 0.86-2.07), but was more likely in those that received their second vaccine dose within the three months before study entry than in those vaccinated more than three months earlier (OR 5.28, 95% CI 3.51-8.23). This study highlights that previous SARS-CoV-2 infection and the time since vaccination should be considered when planning booster doses and the design of COVID-19 vaccine strategies.

Standard radiological classification of glenohumeral osteoarthritis does not correlate with the complexity of the arthritic glenoid deformity.

BACKGROUND: The Samilson-Prieto classification (SPC) depending on the humeral osteophyte length on a-pX-rays today is widely used to classify glenohumeral osteoarthritis in general. For treatment planning and prognosis, the patho-morphology of the glenoid and static posterior subluxation of the humeral head classified according to Walch is of much higher importance. Here, usually a CT or MRI scan is required for a correct classification. A possible correlation between both classifications is poorly explored. Without it, the complexity of the case might be mis-interpreted using the SPC. The aim of this study was to investigate such a correlation, i.e. whether it correlates with the glenoid deformity and degree of humeral head subluxation. PATIENTS AND METHODS: Radiological datasets (X-ray and CT or MRI) of 352 patients with primary OA of the shoulder were evaluated by two observers experienced in shoulder surgery. For the Samilson-Prieto classification, true a-p shoulder radiographs and for the modified Walch classification CT or MRI scans in the axial plane were interpreted using a validated method. To investigate a correlation between both classifications, the Fisher's exact test was used. For the interobserver reliability, the weighted kappa coefficient κ was determined. RESULTS: For the Walch classification, both observers found a similar percentage for the different types, with decreasing numbers from normal (type A1) to severely altered glenoids In the Samilson-Prieto classification, OA grade I was predominant, while grade II and III showed a relatively equal distribution. Interobserver reliability was high both for the Walch classification with a κ 0.923 (95% confidence interval 0.892; 0.954) and) for the SPC with a κ 0.88 (95% confidence interval 0.843; 0.916). A correlation between the two classifications in Fischer's exact test could not be shown (p = 0.584). DISCUSSION: Since there is no correlation between both, using the Samilson-Prieto classification alone might miss relevant prognostic factors in gleno-humeral OA. Adequate imaging of the glenoid morphology also in the axial plane is absolutely mandatory to understand the complexity and chose the right treatment for each patient. LEVEL OF EVIDENCE: Study of Diagnostic Test-Level II.

Comparative study on tertiary contacts and folding of RNase P RNAs from a psychrophilic, a mesophilic/radiation-resistant, and a thermophilic bacterium.

In most bacterial type A RNase P RNAs (P RNAs), two major loop-helix tertiary contacts (L8-P4 and L18-P8) help to orient the two independently folding S- and C-domains for concerted recognition of precursor tRNA substrates. Here, we analyze the effects of mutations in these tertiary contacts in P RNAs from three different species: (i) the psychrophilic bacterium Pseudoalteromonas translucida (Ptr), (ii) the mesophilic radiation-resistant bacterium Deinococcus radiodurans (Dra), and (iii) the thermophilic bacterium Thermus thermophilus (Tth). We show by UV melting experiments that simultaneous disruption of these two interdomain contacts has a stabilizing effect on all three P RNAs. This can be inferred from reduced RNA unfolding at lower temperatures and a more concerted unfolding at higher temperatures. Thus, when the two domains tightly interact via the tertiary contacts, one domain facilitates structural transitions in the other. P RNA mutants with disrupted interdomain contacts showed severe kinetic defects that were most pronounced upon simultaneous disruption of the L8-P4 and L18-P8 contacts. At 37°C, the mildest effects were observed for the thermostable Tth RNA. A third interdomain contact, L9-P1, makes only a minor contribution to P RNA tertiary folding. Furthermore, D. radiodurans RNase P RNA forms an additional pseudoknot structure between the P9 and P12 of its S-domain. This interaction was found to be particularly crucial for RNase P holoenzyme activity at near-physiological Mg2+ concentrations (2 mM). We further analyzed an exceptionally stable folding trap of the G,C-rich Tth P RNA.

Endogenous Double-Stranded RNA.

The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation of repetitive elements in the genome. The transcription of endogenous retroviruses as well as long and short interspersed elements is not only essential for evolving lncRNAs but is also a significant source of double-stranded RNA (dsRNA). From an lncRNA-centric point of view, the latter is a minor source of bother in the context of the entire cell; however, dsRNA is an essential threat. A viral infection is associated with cytoplasmic dsRNA, and endogenous RNA hybrids only differ from viral dsRNA by the 5' cap structure. Hence, a multi-layered defense network is in place to protect cells from viral infections but tolerates endogenous dsRNA structures. A first line of defense is established with compartmentalization; whereas endogenous dsRNA is found predominantly confined to the nucleus and the mitochondria, exogenous dsRNA reaches the cytoplasm. Here, various sensor proteins recognize features of dsRNA including the 5' phosphate group of viral RNAs or hybrids with a particular length but not specific nucleotide sequences. The sensors trigger cellular stress pathways and innate immunity via interferon signaling but also induce apoptosis via caspase activation. Because of its central role in viral recognition and immune activation, dsRNA sensing is implicated in autoimmune diseases and used to treat cancer.

SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models.

Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7) is the intranuclear accumulation of mutant, misfolded ataxin-7 (polyQ-ATXN7). Here, we show that endogenous ATXN7 is modified by SUMO proteins, thus also suggesting a physiological role for this modification under conditions of proteotoxic stress caused by the accumulation of polyQ-ATXN7. Co-immunoprecipitation experiments, immunofluorescence microscopy and proximity ligation assays confirmed the colocalization and interaction of polyQ-ATXN7 with SUMO2 in cells. Moreover, upon inhibition of the proteasome, both endogenous SUMO2/3 and the RNF4 ubiquitin ligase surround large polyQ-ATXN7 intranuclear inclusions. Overexpression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7 and, upon proteasomal inhibition, led to a marked increase in the polyubiquitination of polyQ-ATXN7. This provides a mechanism for the clearance of polyQ-ATXN7 from affected cells that involves the recruitment of RNF4 by SUMO2/3-modified polyQ-ATXN7, thus leading to its ubiquitination and proteasomal degradation. In a SCA7 knock-in mouse model, we similarly observed colocalization of SUMO2/3 with polyQ-ATXN7 inclusions in the cerebellum and retina. Furthermore, we detected accumulation of SUMO2/3 high-molecular-mass species in the cerebellum of SCA7 knock-in mice, compared with their wild-type littermates, and changes in SUMO-related transcripts. Immunohistochemical analysis showed the accumulation of SUMO proteins and RNF4 in the cerebellum of SCA7 patients. Taken together, our results show that the SUMO pathway contributes to the clearance of aggregated ATXN7 and suggest that its deregulation might be associated with SCA7 disease progression.

Screening for distress in patients with intracranial tumors during the first 6 months after diagnosis using self-reporting instruments and an expert rating scale (the basic documentation for psycho-oncology short form - PO-Bado SF).

OBJECTIVE: Psychosocial screening in brain tumor patients is of high importance. We applied The Basic Documentation for Psycho-Oncology Short Form (PO-Bado SF) in primary brain tumor patients and patients with metastasis. The aim was to evaluating consistency between physicians' perception and the results of the patients' self-assessment. MATERIALS AND METHODS: 140 patients with first diagnosis of a brain tumor were screened during their hospital stay (t1) using Distress Thermometer (DT) and Hornheide Screening Instrument (HSI), health-related quality of life was assessed by EORTC QLQ-C30 + BN20. After 3 (t2) and 6 months (t3), patients were re-evaluated. Attending neuro-oncologists completed the PO-Bado SF at all three time points (cut-off for being in need for support >8). RESULTS: At t1, the mean of the PO-Bado SF total score was 7.71 (SD = 4.08), at t2 8.22 (SD = 5.40) and at t3 7.62 (SD = 5.72).The proportion of patients reaching a total score >8 was at t1: 43%, at t2: 41% and at t3: 47% (t1-3). Discrimination of PO-Bado SF total score, between patients in (DT ≥6) and those not in distress was more sensitive (cut-off 8.5, AUC 0.772, sens. 71.3%, spec. 67.6%) than discrimination compared to the HIS (cut-off 9.5, AUC 0.779, sens. 65.1%, spec. 77.7%). Higher PO-Bado-SF total score correlated with higher DT scores (r = 0.6, p < 0.0001) and lower EORTC GHS scores (r = -0.55, p < 0.0001). CONCLUSION: Physicians' perception according to PO-Bado SF provides a different measure for psychosocial burden in patients with brain tumors, however does not completely reflect patients' wishes.

Effect of acute ambient temperature exposure on cardio-pulmonary and respiratory kinetics in men.

AIM: The goal of the study was to compare the kinetic responses of heart rate (HR) and pulmonary (V̇O2pulm) and muscular (V̇O2musc) oxygen uptake during dynamic leg exercise across different acute ambient temperature conditions in a climatic chamber. METHODS: Thirteen physically healthy, active, male volunteers demonstrated pseudorandom binary sequence (PRBS) work rate (WR) changes between 30 and 80 W at 15 °C, 25 °C and 35 °C, respectively. HR was measured beat-to-beat using an echocardiogram and V̇O2pulm by breath-by-breath gas exchange; V̇O2musc estimations were assessed by applying a circulatory model and cross-correlation functions. RESULTS: No significant differences were observed across the various temperature conditions in each case for HR, V̇O2pulm or V̇O2musc kinetics (p > 0.05). Baroreflex regulation based on HR kinetics does not seem to be influenced between ambient temperatures of 15 °C and 35 °C during dynamic exercise. CONCLUSIONS: The results imply that ambient temperatures of 15 °C, 25 °C and 35 °C have no effect on HR, V̇O2pulm or V̇O2musc kinetics during dynamic moderate exercise. The applied approach may be of interest for assessments of the cardio-pulmonary and respiratory health statuses of individuals working or performing sports in extreme temperature environments. Furthermore, differentiation between systemic (e.g. cardio-dynamic: HR) and specific (e.g. exercising tissues: V̇O2musc) determinants of the relevant physiological systems may improve the evaluation of an individual's health status.

Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression.

BACKGROUND: Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up-regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study. METHODS: PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistochemistry (PSCA antibody MB1) and tissue microarrays. RESULTS: PSCA-expression was detected in 94/405 patients (23%) and correlated with unfavorable histopathological grade (p=0.011) and increased Ki67 proliferation index (p=0.006). We observed a strong positive correlation between PSCA-protein expression and HER2/neu receptor status (p<0.001). PSCA did not provide prognostic information in the analyzed cohort. Interestingly, the distribution of PSCA-expression among triple negative patients was comparable to the total population. CONCLUSION: We identified a subgroup of PSCA-positive breast cancer patients, which could be amenable for a PSCA-targeted therapy. Moreover, given that we found a strong positive correlation between PSCA- and HER/neu expression, targeting PSCA may provide an alternative therapeutic option in case of trastuzumab resistance.

Trastuzumab and survival of patients with metastatic breast cancer.

INTRODUCTION: Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. METHODS: All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. RESULTS: Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). CONCLUSION: Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer.

Cation Interactions and Membrane Potential Induce Conformational Changes in NaPi-IIb.

Voltage-dependence of Na(+)-coupled phosphate cotransporters of the SLC34 family arises from displacement of charges intrinsic to the protein and the binding/release of one Na(+) ion in response to changes in the transmembrane electric field. Candidate coordination residues for the cation at the Na1 site were previously predicted by structural modeling using the x-ray structure of dicarboxylate transporter VcINDY as template and confirmed by functional studies. Mutations at Na1 resulted in altered steady-state and presteady-state characteristics that should be mirrored in the conformational changes induced by membrane potential changes. To test this hypothesis by functional analysis, double mutants of the flounder SLC34A2 protein were constructed that contain one of the Na1-site perturbing mutations together with a substituted cysteine for fluorophore labeling, as expressed in Xenopus oocytes. The locations of the mutations were mapped onto a homology model of the flounder protein. The effects of the mutagenesis were characterized by steady-state, presteady-state, and fluorometric assays. Changes in fluorescence intensity (ΔF) in response to membrane potential steps were resolved at three previously identified positions. These fluorescence data corroborated the altered presteady-state kinetics upon perturbation of Na1, and furthermore indicated concomitant changes in the microenvironment of the respective fluorophores, as evidenced by changes in the voltage dependence and time course of ΔF. Moreover, iodide quenching experiments indicated that the aqueous nature of the fluorophore microenvironment depended on the membrane potential. These findings provide compelling evidence that membrane potential and cation interactions induce significant large-scale structural rearrangements of the protein.

Impact of breast cancer subtypes and patterns of metastasis on outcome.

Clinical outcome of patients with stage IV breast cancer is dependent on tumor biology, extent, and localization of metastases. Routine imaging diagnostics for distant metastasis is not recommended by the national guidelines for breast cancer follow-up. In this study, we evaluated different patterns of metastases of cancer subtypes in order to generate hypotheses on individualization of follow-up after breast cancer in the adjuvant setting. Patients of the Regional Breast Cancer Center Dresden diagnosed within the years 2006-2011 were classified into the five intrinsic subtypes luminal A (ER+, Her2-, G1/2), luminal B/Her2 negative (ER+, Her2-, G3), triple positive (ER+, PR+, Her2+), Her2-enriched (ER-, Her2+), and triple negative (ER-, PR-, Her2-) and with a median follow-up of 45 months. Tumor stage at time of first diagnosis of breast cancer as well as time and site of metastasis at first diagnosis of distant metastatic disease was analyzed. Tumor specimen of 2284 female patients with primary breast cancer was classified into five subtypes. Distant recurrence-free survival at 3 years was most unfavorable in Her2-enriched (66.8 %), triple negative (75.9 %), and triple-positive breast cancer (81.7 %). The same subtypes most frequently presented with visceral metastases only at first presentation: Her2-enriched 46.9 %, triple negative 45.5 %, and triple-positive breast cancer 37.5 %. Longest median survival of 2.3 years was seen in luminal A and in Her2-enriched metastatic disease, respectively. Median survival was significantly better in the luminal A, Her2-enriched, and triple-positive subtype compared to triple-negative breast cancer (p < 0.005). Differences in time to metastatic disease, first localization of metastases, and overall survival after diagnosis of metastatic disease were shown. Considering new targeted therapies and the option of surgery of oligometastases, screening for visceral metastases might be reasonable after diagnosis of Her2-positive subtypes.

Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma".

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Screening for distress in routine oncological care-a survey in 520 melanoma patients.

INTRODUCTION: Despite the increasing incidence of melanoma little is known about patients' emotional distress associated with this disease. Supplemented by the problem list (PL), the distress thermometer (DT) is a recommended screening instrument to measure psychosocial distress in cancer patients. Our objective was to explore the acceptance and the feasibility of the DT and PL as a concise screening tool in an ambulatory setting for routine care and to elucidate determinants of distress in melanoma patients with regard to sociodemographic and clinical variables. METHODS: Consecutive melanoma outpatients were asked to complete the DT with the PL prior to their scheduled consultation. Demographic and clinical data were obtained from the patients' charts. Clinical data included melanoma stage, time since diagnosis, previous treatment, current treatment, and other cancer disease. RESULTS: Out of 734 patients recruited into the study, 520 patients (71%) completed both the DT and the PL. Forty-seven percent met the ≥5 cut-off score for distress. Younger and employed patients reported higher distress than older and retired patients. A cut-off score of ≥5 was closely associated with self-reported emotional sources of distress, with practical problems, especially at work, family problems (dealing with the partner), and physical problems like pain, appearance, getting around, and nausea. Apart from higher distress under current systemic treatment, no associations were found between distress and clinical data. CONCLUSION: The DT together with the PL seems to be an economically reasonable screening tool to measure psychosocial distress in melanoma patients. In particular, younger melanoma patients who are currently employed are prone to experience distress at some point after diagnosis, but there appears to be almost no association between clinical data and the extent of distress. To characterize the impact of distress on disease outcome and quality of life in melanoma patients, further research is needed.

[KoMPASS--design, implementation and experiences concerning a structured communication skills training for physicians dealing with oncology]. / KoMPASS - Konzeption, Implementierung und Erfahrungen mit einem strukturierten Kommunikationstraining für onkologisch tätige Ärzte.

Goal of the KoMPASS project is to develop and test a training program that effectively improves oncologists' communication skills. The training draws with regard to concept, content and didactic methods to the specific challenges arising in interactions with cancer patients. Concept and didactical methods for an intensive training (KoMPASS Training) are being presented and complemented with experiences gathered during 39 trainings with 335 physicians, as well as findings from the training evaluation by participants. The participants' feedback after 4 months indicates successful transfer into clinical practice along with personal relief, improved self-efficacy, and communicative competencies. Even experienced practitioners ascribe high practical usefulness, and personal learning achievements to the KoMPASS training. The results of the concomitant study concerning self-efficacy, empathy, work-related stress and communicative competence will be published later.

Patient versus clinician symptom reporting: how accurate is the detection of distress in the oncologic after-care?

OBJECTIVE: The high prevalence of psychosocial distress in cancer patients is well known. The objective of this study was to investigate the agreement between the self-report of patients and the detection of distress by the treating physicians. METHODS: The participating patients were all enrolled in a structured 5-year after-care program in Palatinate, Germany. All tumor-free patients with a scheduled follow-up exam in a 3-month time frame were asked to fill in a questionnaire regarding their psychosocial distress. The treating physicians participating in the program are family doctors or specialized physicians working in general practices. Their assessment of the patients' distress is part of the program. Agreement was evaluated using the kappa statistic. RESULTS: The levels of psychosocial distress were very high in the self-rating of 2642 patients. Low concordance was observed between the ratings of the patients and the physicians, with all kappa values below 0.1. Only about every 10th patient reporting weak to severe problems with depression or anxiety was identified as such. Detection of problems by physicians was somewhat better for female than male patients and highest among breast cancer patients. CONCLUSIONS: Overall the results of our study show that the need for psychosocial support extends past the acute treatment phase. The recognition of psychosocial distress in their patients seems to be extremely low in the outpatient, follow-on care phase. The application of an efficient rating method should become a routine part of the follow-up exams with physicians being trained to improve their abilities to detect the distress in the patient.