Make an impact: going full circle together.

Sport diversification provides opportunities for individuals to develop physical literacy, establish a growth mindset, become more agile in varied environments, and develop robust strategies to improve performance. One could say the same for biomechanists, who study the control and dynamics of human movements in the context of sport. Through the lens of sport, we have focused on the ongoing interaction between the nervous system, musculoskeletal system, and the environment by using integrated experimental and modelling approaches to study well-practiced, goal-directed tasks in controlled laboratory and realistic field settings. By integrating multiple sources of information in real time to provide timely, relevant, usable, and easy to understand (TRUE) feedback during skill acquisition, we have found these resources also support learning and opportunities for self-discovery of proficiencies by coaches and athletes. Managing multimodal data acquired with emerging technological advances has also benefited from the use of FAIR data management principles, where data are findable, accessible, interoperable, and reusable. By listening, clarifying goals, and exploring together with coaches and athletes, we can bridge the gaps between what we know and what we do.

Diagnostic and prognostic classification of atypical spitzoid tumours based on histology and genomic aberrations: A prospective cohort study with long-term follow-up.

BACKGROUND: Histological classification of atypical spitzoid tumours (ASTs) is unreliable, and categorisation of these lesions into benign and malignant is poorly reproducible. Here, we classified ASTs based on histology and chromosomal aberrations and explored the prognostic significance of genomic aberrations in a prospective cohort with a long-term follow-up. PATIENTS AND METHODS: Histologically equivocal ASTs from 76 patients were analysed by array comparative genomic hybridisation (aCGH). Tumours were histologically assessed by a panel of dermatopathologist before and after aCGH and classified as benign, ambiguous or malignant. Chromosomal aberrations were correlated with an outcome. RESULTS: Chromosomal aberrations were detected in 45 (59%) of 76 ASTs (median age: 16 years, range: 0-74; median follow-up: 90 months, range: 13-153). The initial histological diagnosis was changed upon presentation of aCGH results in 36 of 76 cases (47%). The final diagnostic interpretation classified 61% of the lesions as benign, 18% as ambiguous and 21% as malignant. Positive sentinel lymph node biopsies (6+/29) occurred at similar rates in all diagnostic groups (P = 0.83) and were not associated with an unfavourable outcome. Two patients had local recurrences, but none of the patients developed metastasis beyond the sentinel lymph node. CONCLUSIONS: All ASTs had an excellent prognosis, even in cases with worrisome morphology and chromosomal aberrations. With no distant metastasis or death in long-term follow-up of 76 patients, no correlation between chromosomal aberrations and prognosis was possible. However, it seems likely that in larger cohorts, metastases would arise in cases with complex aberrations and these patients should undergo clinical follow-up.

Metaplastic spiradenocarcinoma: Report of two cases with sarcomatous differentiation.

Spiradenocarcinoma (SC) is a very rare malignant skin adnexal tumor with sweat gland differentiation that develops from a pre-existing spiradenoma, cylindroma, or hybrid tumor called spiradenocylindroma, or arises de novo. We present two exceptionally rare SC cases showing sarcomatous differentiation; we also discuss the clinicopathologic features of SC, as well as its differential diagnoses and available therapeutic modalities. Given the aggressive behavior of SC, rapid diagnosis and complete removal of the tumor with tumor-free margins is mandatory. Owing to the marked morphological heterogeneity of individual SC cases, dermatopathologists must be familiar with the different possible histopathologic manifestations of this neoplasm.

Bowen disease with matrical differentiation: Report of an exceptional histopathologic presentation.

Matrical differentiation is the distinctive feature of pilomatricoma and other purely matrical adnexal neoplasms; additionally, foci of matrical differentiation have been also described in hybrid cysts of Gardner syndrome, as well as in a wide variety of benign and malignant cutaneous tumors, including basal cell carcinoma. We report an exceptional case of Bowen disease exhibiting multiple foci of matrical differentiation, as confirmed by means of immunohistochemical studies. Several types of divergent, non-squamous differentiation have been exceptionally reported in cutaneous squamous cell carcinoma in situ (cSCCIS), including sebaceous, mucinous/glandular, poroid, tricholemmal, and neuroendocrine differentiation; matrical differentiation may be added to this list. Our findings further emphasize the undifferentiated nature of neoplastic cells in cSCCIS.

Prurigiform Angiomatosis: Reactive Angioproliferation in the Skin and Vascular Endothelial Growth Factors.

BACKGROUND: Cutaneous benign angioproliferations can be diagnostically challenging and may mimic vascular tumors. Keratinocytes express vascular endothelial growth factors (VEGFs). We studied the angiogenic factor expression pattern in cutaneous lesions with a distinctive pattern of remarkable dermal angiomatosis underlying prurigo-like epidermal changes. METHODS: Cases were selected retrospectively from 2012 to 2018, and their VEGF staining pattern was compared with normal skin and other reactive skin conditions. RESULTS: Thirty-eight patients, median age 76 years, mostly men (74%), presented with asymptomatic patches or plaques, most commonly located on the buttocks (n = 17) and/or intergluteal fold (n = 12), often eliciting concern for neoplasia (n = 19). Microscopically, all cases featured a prominent proliferation of dilated capillaries and postcapillary venules, underneath epidermal changes resembling prurigo or lichen simplex chronicus. In one-third, a subepidermal lymphocytic infiltrate was present. Immunostaining with VEGF was positive in the upper 4/5 of the epidermis overlying the angioproliferation, in contrast with nonlesional skin, where VEGF positivity was limited to the stratum granulosum. Receptor VEGFR-2 was expressed in the endothelia of neovessels. CONCLUSIONS: We propose the term prurigiform angiomatosis for the morphological picture of prurigo/lichen simplex chronicus-like epidermal hyperplasia with prominent dermal angioproliferation. Mechanical injury and inflammation are the likely triggers of this reactive angiogenesis pattern, driven by epidermal VEGF expression.

Endocrine mucin-producing sweat gland carcinoma: Clinicopathologic, immunohistochemical, and molecular analysis of 11 cases with emphasis on MYB immunoexpression.

BACKGROUND: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare low-grade primary cutaneous sweat gland carcinoma with predilection for the periorbital skin in elderly female patients. METHODS: We describe 11 cases of EMPSGC using a broad panel of immunohistochemical markers including BerEP4, cytokeratin 7, CAM 5.2, synaptophysin, chromogranin, cytokeratin 20, Ki67, progesterone receptor, and estrogen receptor. Calponin (1A4) and p63 were used to detect surrounding myoepithelial cells. We also examined staining with a relatively new marker, MYB. Previous studies of MYB on EMPSGC remain limited. As mucin-rich basal cell carcinoma (BCC) represents a main differential diagnosis and primary cutaneous mucinous carcinoma (PCMC) could appear synchronous with EMPSGC, these lesions were also stained for MYB. RESULTS: We found strong and homogenous nuclear MYB-expression in 10 EMPSGC cases stained for MYB. MYB staining was not performed in one case. Furthermore, PCMC and mucin-rich BCCs did not express MYB. CONCLUSION: The strong nuclear MYB-positivity in EMPSGC could be useful as a new surrogate marker, especially in mucin-poor EMPSGC cases. Additionally, the staining of PCMC revealed absent MYB-expression leading to the conclusion that EMPSGC might not represent a precursor lesion for primary cutaneous mucinous carcinoma.

Dermoscopic appearance of an amelanotic mucosal melanoma.

BACKGROUND: Hypomelanotic or amelanotic melanomas are challenging to identify, especially at mucosal sites. The dermoscopic clues to the diagnosis of mucosal melanomas have been reported to be structureless zones with the presence of blue, gray, or white colors. CASE: A female in her seventies noted a new lesion on the inside of her right labia that first appeared two months prior. Her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. After no response to two weeks of local treatment for suspected herpes simplex infection, her gynecologist performed a skin biopsy. Based on the histopathological diagnosis of an amelanotic melanoma (Breslow thickness of 1.3 mm) the patient was referred to dermatology for further assessment. Polarized dermoscopy revealed a distinct asymmetric, sharply demarcated homogenous white papule (4 × 5 mm) as well as polymorphous vessels. CONCLUSION: Dermoscopy may aid in the diagnosis of amelanotic mucosal melanomas. Our case revealed a structureless white area and polymorphous vessels. Additional clues to the diagnosis were the advanced age of the patient and the clinical presentation of a new lesion.

Screening for skin cancer in bank and insurance employees: risk profile and correlation of self and physician's assessment.

BACKGROUND: Self-assessment and knowledge of individual risk factors can be a reasonable strategy to detect cutaneous malignancies in an early curable stage. METHODS: Bank and insurance employees were voluntarily screened for skin cancer. They had to fill in a questionnaire asking for their skin and hair color, ultraviolet exposure and tanning ability, number and size of typical and atypical nevi, immunosuppression or chemotherapy, and history of skin cancer. Afterwards dermatologists performed a whole body evaluation, including a total body nevi count, and calculated an individualized risk profile. RESULTS: A total of 1658 employees were evaluated. Most employees underestimated their total number of nevi. There was poor agreement between employees and dermatologists (weighted κ-value = 0.03); 45.5% of the employees were judged to be at low risk, 27.3% as intermediate risk, and 27.2% as high risk. Twenty-seven employees (3.7%) with suspicious lesions were transferred to the clinics for further evaluation. CONCLUSION: Screening for skin cancer in a working population reveals low numbers of suspicious lesions. The focus of mass screenings should be on education and teaching of self-examinations.

Serum S100B, lactate dehydrogenase and brain metastasis are prognostic factors in patients with distant melanoma metastasis and systemic therapy.

BACKGROUND: Prognostic factors of melanoma with distant metastasis and systemic treatment are only poorly established. This study aimed to analyse the impact of S100B, lactate dehydrogenase (LDH) and the type of treatment on survival in advanced patients receiving systemic treatment. PATIENTS AND METHODS: We analysed overall survival of 499 patients from the university department of dermatology in Tuebingen, Germany, with unresectable melanoma at the time point of initiation of first-line systemic therapy. Only patients who started treatment between the years 2000 and 2010 were included. Disease-specific survival was calculated by bivariate Kaplan Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: In univariate analysis LDH, S100B, the site of distant metastasis (soft tissue vs. lung vs. other visceral), the presence of brain metastases and the type of treatment (monochemotherapy, polychemotherapy, immunotherapy or biochemotherapy) were associated with overall survival (all p<0.001). In multivariate analysis LDH (Hazard ratio [HR] 1.6 [1.3-2.1]; p<0.001), S100B (HR 1.6 [1.2-2.1]; p<0.001) and the presence of brain metastases (HR 1.5 [1.1-1.9]; p = 0.009), but not the type of treatment had significant independent impact. Among those factors normal S100B was the best indicator of long-term survival, which was 12.3% after 5 years for this subgroup. CONCLUSION: Serum S100B is a prognostic marker predicting survival at the time of initiation of first-line treatment in unresectable melanoma patients. Compared to the other independent factors LDH and the presence of brain metastases it is most appropriate to predict long-term survival and requires further prospective investigation in patients treated with new and more potent drugs in metastatic melanoma.

S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma.

Vemurafenib is a highly efficient BRAF inhibitor for metastatic melanoma patients carrying the V600 mutation: progression-free survival is prolonged to ∼ 6 months and 50-80% of the patients show objective tumor responses. S100B and lactate dehydrogenase (LDH) are established tumor markers in routine melanoma follow-up. This study evaluated their potential as response and progression markers during vemurafenib treatment. A cohort of 44 patients with stage IV melanoma disease who were treated with vemurafenib was retrospectively analyzed. Staging was performed every 6-8 weeks comprising computed tomography scans and measurement of LDH and S100B levels. Response Evaluation Criteria In Solid Tumors (RECIST) criteria were used for standardized radiological response evaluations. The correlation between response or progression and LDH and S100B levels was analyzed using accuracy tests, Spearman's rank correlation ρ, and polynominal regression analyses. There was a good correlation between S100B and LDH decline and a RECIST-confirmed response, especially when S100B and/or LDH were elevated at baseline (accuracy, 81.2% for S100B and 85.7% for LDH). However, the accuracy in case of RECIST-confirmed progression and S100B/LDH levels was low - 30.3% for S100B and 32.4% for LDH. Neither Spearman's rank correlation ρ nor polynomial regression analyses showed a correlation between the clinical course and S100B/LDH levels. Measurement of S100B and LDH levels during treatment with vemurafenib indicates an initial response; however, this does not seem to be sufficient in detecting tumor progression and is thus not an alternative to monitoring with imaging examinations.

Repeated blast exposure alters open field behavior recorded under low illumination.

Blast-induced traumatic brain injury (bTBI) can have devastating behavioral consequences. This study was designed to evaluate the behavioral consequences of single or repeated bTBI, as evaluated by an open field (OF) test conducted in near-darkness to avoid confounding effects of illumination and photophobia. Sprague-Dawley rats under isoflurane anesthesia were exposed to a series of 3 sub-lethal blasts into a compressed air-driven blast chamber separated by 2 week intervals (n=11). Sham controls received anesthesia but without blast exposure (n=11). OF tests were performed 1 or 7 days after each blast using a computerized video tracking system in near-darkness to monitor spontaneous activity. Spatial and temporal variables calculated for both blast and sham groups were: Distance moved (cm) and time (s) spent in the center or periphery zones of the field, total distance traveled, speed in center and periphery zones, rearing events and non-linear regressions of distance moved and rearing events on time. Results showed that the sham group expressed the expected decrease (habituation) in total distance walked, and distance walked as well as speed in center and periphery in successive exposures to the OF while the blast group did not, a sign of impaired learning. The blast group also walked more and faster and demonstrated more rearing behavior, both considered OF signs of anxiety. These results indicate that OF outcomes of bTBI in animals have resemblance to alterations observed in human subjects with this condition and might be useful in evaluating the response of behavioral outcomes of bTBI to experimental treatments.

Effective combination of photodynamic therapy and imiquimod 5% cream in the treatment of actinic keratoses: three cases.

BACKGROUND: The therapy for actinic keratoses includes photodynamic therapy (PDT) and imiquimod 5% cream. The sequential use of both could result in better clinical outcomes. OBJECTIVES: To enhance efficacy of therapies while improving tolerability, convenience, and patient adherence with a scheme combining two concomitant or sequential AK treatments. METHODS: All patients underwent one session of conventional PDT. Two weeks after, the PDT imiquimod 5% cream was applied to the treatment area once daily for three days per week. One course continued for four weeks followed by a clinical evaluation and decision about further treatment. Patients who had not cleared all of their AK lesions in the treatment area in course 1 participated in a second 4-week course of treatment. Limitations. Small size of population. RESULTS: Three participants were enrolled. Two patients showed complete clinical clearance of AKs. The effect was also noted after long-term followup, at months seven and eleven. No subject discontinued for an adverse event. There were severe local skin reactions in two participants which were severe erythema, scaling, and crusting. One patient showed no response to the therapy. CONCLUSIONS: Photodynamic therapy followed by imiquimod was well tolerated and improved reduction of actinic keratoses. This initial proof-of-concept should be studied in larger clinical trials.

Proliferative activity, chromosomal aberrations, and tumor-specific mutations in the differential diagnosis between blue nevi and melanoma.

Blue nevi are a clinically and pathologically heterogeneous group of benign pigmented dermal melanocytic tumors that may exhibit histologic overlap with malignant melanoma. This study evaluates the role of immunohistochemical and molecular analyses in the classification and differential diagnosis between blue nevi and melanoma. Twenty-three dermal melanocytic tumors, initially diagnosed as benign or ambiguous, were subjected to immunohistochemical staining for phosphohistone H3 and MIB-1 to evaluate mitotic activity, comparative genomic hybridization to detect chromosomal aberrations, and GNAQ, GNA11, BRAF, NRAS, and KRAS sequencing. Of 19 patients with follow-up information (median, 1.6 years), 3 developed recurrent or metastatic disease. Nevertheless, 11 of the 19 patients with follow-up had <2 years of follow-up. Nine of 23 patients showed chromosomal aberrations, including all 3 patients with tumor recurrence or progression. There was no significant correlation between mutation status (P = 0.6) or mitotic rate (P = 0.3) and outcome. In conclusion, three of nine patients with chromosomal aberrations developed tumor recurrence or progression. Patients with histologically ambiguous dermal melanocytic proliferations that exhibit copy number aberrations should undergo careful clinical follow-up.

Recurrent nodules in a periauricular plaque-type blue nevus with fatal outcome.

Plaque-type blue nevus is a rare variant of blue nevus characterized by grouped nodules displaying histomorphological features of a cellular blue nevus. We report the clinical, histopathologic and immunohistologic features of a patient with recurrent nodules in a periauricular plaque-type blue nevus with malignant transformation and fatal outcome. The nevus was characterized clinically by childhood onset, with slow enlargement during adolescence. At age 16, the patient presented with nodules located retroauricularly. Several surgical excisions with the intent of complete removal of the nodules and the nevus were performed. Histopathological, dermal and subcutaneous proliferations of pigmented melanocytes with melanophages were detected. The nodules showed some cellular atypia and few mitotic figures, (Ki67 estimated <1%). At age 20, the patient developed new nodules retroauricular, with histopathology similar to previous lesions; however, the proliferation rate was higher. A comparative genomic hybridization (CGH) showed chromosomal changes indicative of melanoma. At age 25, the patient developed multiple liver metastases and died after 4 weeks. A sequencing of the tumor DNA revealed a GNAQ Q209P mutation, whereas mutations of GNA11, BRAF, NRAS and cKIT were not detected. This case shows that nodules in plaque-type blue nevus may have malignant potential which may be uncovered by CGH.

Oncogenetics of melanoma: basis for molecular diagnostics and therapy.

Our understanding of oncogenetics and of the molecular mechanisms involved in melanoma development and signaling has dramatically changed in recent years. Today, melanomas are also classified based on molecular alterations. Emerging molecular therapies are targeted against specific mutations in melanoma. An example of targeted therapies is the successful treatment of KIT-mutant melanoma with the kinase inhibitor imatinib. Highly selective BRAF-inhibitors are likewise under clinical development and show encouraging clinical responses. An increasing number of targeted drugs will emerge in the coming years, based on molecular diagnostics and classification. The present article reviews signaling pathways in melanocytes and alterations in melanoma that are a prerequisite to understanding modern cancer therapies in melanoma.

Complete revascularization in patients undergoing multivessel PCI is an independent predictor of improved long-term survival.

BACKGROUND: The prognostic relevance of complete revascularization (CR) in patients with multivessel coronary artery disease (MV-CAD) has been established so far for surgical treatment strategies rather than for percutaneous coronary revascularization (PCI). In addition, different definitions of CR have further complicated the interpretation of clinical studies. METHODS: Procedural characteristics and long-term overall survival were assessed in 679 consecutive "all-comer" patients, who underwent PCI in at least two main vessels. We adapted three definitions of CR from the coronary artery bypass grafting (CABG) trials. CR was achieved if following MV-PCI one of the three criteria was met: (1) no residual stenosis in a main coronary vessel, (2) no residual stenosis in any coronary segment, or (3) no residual stenosis in the left anterior descending (LAD) and at least one further main branch. The main objective was the evaluation of predictors of incomplete revascularization and the prognostic impact of CR in MV-PCI patients. RESULTS: CR was achieved in 76%, 67%, and 95%, respectively, (definitions 1-3). Patients without CR were older, had a lower ejection fraction, and presented more often with acute coronary syndromes (ACS). Clinical long-term follow-up regarding survival was available in 664 patients (98%) with a mean follow-up of 2.5 +/- 1.6 years. Independent of the specific definition, CR was associated with a reduced long-term mortality by approximately 50%. After adjusting for relevant baseline parameters, only absence of residual stenosis in all coronary segments remained as an independent predictor of long-term prognosis (hazard ratio [HR]= 0.51, 95% confidence interval [CI]: 0.28-0.93; P = 0.025). CONCLUSIONS: CR of all coronary segments is associated with improved overall survival after MV-PCI.

Melanoma staging: facts and controversies.

The value of staging examinations remains controversial for the initial staging in melanoma patients at the time of the primary diagnosis and for surveillance. Issues concerning tumor recurrences and progression must be discussed separately for different risk groups. For low-risk patients (stage IA; tumor thickness less than 1 mm), staging examinations like sentinel lymph node biopsy (SLNB), blood tests, or imaging can generally be abandoned. Baseline staging with simple techniques is at the discretion of the physician. In intermediate-risk patients (stages IB and IIA), an initial staging examination involving SLNB and computed tomography (CT) scans is recommended. Further follow-up may be restricted to physical examinations, blood tests of tumor marker protein S100beta, and to lymph node ultrasonography. If findings are suspicious, further imaging procedures may be involved. In high-risk patients (stages IIB to III), an initial staging examination with CT is recommended, and regular follow-up every 6 months with whole body imaging by CT or magnetic resonance imaging seems useful. Physical examinations, blood tests of tumor marker protein S100beta, and lymph node ultrasound imaging should be routine. This intense follow-up may enable surgical treatments with complete removal of all recognizable metastases in about 15% to 25% of patients and improve their prognosis. The risk of recurrence or tumor progression is very high in stage IV patients, and their management is individualized.