The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis.

INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Identification of Aspergillus and Mucorales in formalin-fixed, paraffin-embedded tissue samples: Comparison of specific and broad-range fungal qPCR assays.

Establishing the etiology of invasive fungal infections is important to guide therapeutic options and for epidemiologic purposes. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven invasive fungal infections are valuable to determine the etiology of systemic fungal infections. We compared different polymerase chain reaction (PCR) amplification strategies from FFPE tissue blocks to identify agents of invasive fungal infections. We found that specific PCR assays show superior sensitivity in the identification of DNA of Mucorales and Aspergillus and mixed infections caused by both as compared to broad-range PCR assays. Shorter amplicon lengths and less detection of contaminating fungal DNA are potential factors involved. However, detection of fungal DNA by highly sensitive specific PCR assays in the absence of demonstration of fungal elements in tissue suggests that PCR results should be interpreted in the context of the histopathology and clinical findings.

[Vascularized tumor of the retroauricular skin]. / Gefäßreicher Tumor der retroaurikulären Haut.

An 84-year-old female patient with loss of hearing and otorrhoea went to an otolaryngologist. On examination, a polypoid mass in the auditory canal and a retroauricular skin lesion, possibly seborrheic keratosis, were found. Only the skin was submitted for histological examination and showed a cutaneous highly vascular lesion with an associated "zellballen" of clear cells without atypia. The initial diagnosis was that of a cutaneous glomangioma. Immunohistochemical findings favored diagnosis of a paraganglioma. Additional clinical information revealed a large mastoid tumor mass. Therefore, the findings were compatible with an jugulotympanic paraganglioma with infiltration of the overlying skin. This possibility was initially not considered in differential diagnosis, as cutaneous glomangiomas are relatively common (typically located on the hands). Cutaneous paragangliomas, however, are not reported.

Critical insolation-CO2 relation for diagnosing past and future glacial inception.

The past rapid growth of Northern Hemisphere continental ice sheets, which terminated warm and stable climate periods, is generally attributed to reduced summer insolation in boreal latitudes. Yet such summer insolation is near to its minimum at present, and there are no signs of a new ice age. This challenges our understanding of the mechanisms driving glacial cycles and our ability to predict the next glacial inception. Here we propose a critical functional relationship between boreal summer insolation and global carbon dioxide (CO2) concentration, which explains the beginning of the past eight glacial cycles and might anticipate future periods of glacial inception. Using an ensemble of simulations generated by an Earth system model of intermediate complexity constrained by palaeoclimatic data, we suggest that glacial inception was narrowly missed before the beginning of the Industrial Revolution. The missed inception can be accounted for by the combined effect of relatively high late-Holocene CO2 concentrations and the low orbital eccentricity of the Earth. Additionally, our analysis suggests that even in the absence of human perturbations no substantial build-up of ice sheets would occur within the next several thousand years and that the current interglacial would probably last for another 50,000 years. However, moderate anthropogenic cumulative CO2 emissions of 1,000 to 1,500 gigatonnes of carbon will postpone the next glacial inception by at least 100,000 years. Our simulations demonstrate that under natural conditions alone the Earth system would be expected to remain in the present delicately balanced interglacial climate state, steering clear of both large-scale glaciation of the Northern Hemisphere and its complete deglaciation, for an unusually long time.

TRPA1 and TRPV1 are differentially involved in heat nociception of mice.

BACKGROUND: Two transient receptor potential (TRP) channels, TRPV1 and TRPA1, have been physiologically studied with regard to noxious heat transduction. Evidence argues against these channels as sole transducers of noxious heat or cold, respectively. Moreover, in submammalian species the TRPA1 orthologue shows heat sensitivity. METHODS: In vitro, single-fibre and compound action potential recordings from C-fibres as well as measurements of stimulated cutaneous CGRP release are combined with behavioural experiments to assess heat responsiveness in wild type mice, TRPA1 and TRPV1 as well as double-null mutants. RESULTS: Heat thresholds of cutaneous C-mechano-heat sensitive fibres were significantly higher in TRPA1-/- (43 °C) than +/+ (40 °C) mice, and averaged heat responses were clearly weaker, whereas TRPV1-/- showed normal heat thresholds and responses (up to 46 °C). Compound action potential recordings revealed much less activity-dependent slowing of conduction velocity upon noxious heat stimulation in TRPA1-/- and a delayed deficit in TRPV1-/- in comparison to controls. Heat-induced calcitonin gene-related peptide release was reduced in TRPV1-/- but not TRPA1-/- animals. Paw withdrawal latencies to radiant heat were significantly elevated in TRPA1-/-, more so in TRPV1-/- animals. In general, double-null mutants were similar to TRPV1-/- except for the single-fibre heat responses which appeared as weak as in TRPA1-/-. CONCLUSIONS: Our results indicate that in addition to TRPV1, TRPA1 plays a role in heat nociception, in particular in definition of the heat threshold, and might therefore serve as a therapeutic target in acute inflammatory pain.

Treatment of Cutaneous Lupus Erythematosus: Review and Assessment of Treatment Benefits Based on Oxford Centre for Evidence-based Medicine Criteria.

The treatment of cutaneous lupus erythematosus is centered upon formulating a regimen of topical and systemic therapies designed to reduce disease activity and minimize cosmetic damage. Sun avoidance and sunscreen are important preventative measures proven to minimize cutaneous lupus erythematosus exacerbations. Limited disease is typically managed with topical corticosteroids or calcineurin inhibitors. Antimalarial therapy is the gold standard of systemic therapy. Many other treatments have been studied in patients with recalcitrant cutaneous lupus erythematosus, and their use must be evaluated based on individual risk-benefit concerns. R-salbutamol and pulsed dye laser therapy have proven to be effective topical alternatives. Additional systemic agents include retinoids, immunosuppressants, immunomodulators, biologics, and other experimental therapies with novel modes of action. According to the Oxford Centre for Evidence-based Medicine criteria for evaluating the strength of evidence supporting an individual treatment measure, no therapy for cutaneous lupus erythematosus has achieved Level 1 status. This demonstrates the need for randomized, controlled trials and systematic reviews of all cutaneous lupus erythematosus interventions in order to meet increasing standards and demand for evidence-based practice.

Increased future ice discharge from Antarctica owing to higher snowfall.

Anthropogenic climate change is likely to cause continuing global sea level rise, but some processes within the Earth system may mitigate the magnitude of the projected effect. Regional and global climate models simulate enhanced snowfall over Antarctica, which would provide a direct offset of the future contribution to global sea level rise from cryospheric mass loss and ocean expansion. Uncertainties exist in modelled snowfall, but even larger uncertainties exist in the potential changes of dynamic ice discharge from Antarctica and thus in the ultimate fate of the precipitation-deposited ice mass. Here we show that snowfall and discharge are not independent, but that future ice discharge will increase by up to three times as a result of additional snowfall under global warming. Our results, based on an ice-sheet model forced by climate simulations through to the end of 2500 (ref. 8), show that the enhanced discharge effect exceeds the effect of surface warming as well as that of basal ice-shelf melting, and is due to the difference in surface elevation change caused by snowfall on grounded versus floating ice. Although different underlying forcings drive ice loss from basal melting versus increased snowfall, similar ice dynamical processes are nonetheless at work in both; therefore results are relatively independent of the specific representation of the transition zone. In an ensemble of simulations designed to capture ice-physics uncertainty, the additional dynamic ice loss along the coastline compensates between 30 and 65 per cent of the ice gain due to enhanced snowfall over the entire continent. This results in a dynamic ice loss of up to 1.25 metres in the year 2500 for the strongest warming scenario. The reported effect thus strongly counters a potential negative contribution to global sea level by the Antarctic Ice Sheet.

Efficient foldover suppression using SENSE.

Parallel imaging techniques, which in principle represent procedures of unfolding a reduced dataset, are well known and well established in MR imaging. This paper presents a further application of one particular reconstruction method, the SENSE algorithm, considered from a different point of view to remove potential foldover in conventional images acquired with multiple receive coils. Based on the coil sensitivity information, a body coverage map in the excited plane is calculated. This is used together with the measured raw data in a SENSE-type reconstruction to optimize the signal-to-noise ratio (SNR) as well as to remove foldover reliably by unfolding the image to a larger field of view. The reconstruction is performed automatically, without any user interaction, and does not affect data acquisition. Based on phantom and in vivo studies, which retain high image quality after the removal, the potential and limits of this approach are discussed, also taking into account future scanner hardware that will support a large number of parallel receiver channels.

Cause-of-death registers in radiation-contaminated areas of the Russian Federation and Kazakhstan.

Since the early 1990s, information on radiation-exposed populations other than those exposed from the Chernobyl accident in 1986 has become increasingly available for international scientific research. It is essential to understand how the cohorts of exposed populations have been defined and what mechanisms can be used to study their health outcomes. Different international scientific research collaborations currently investigate four population groups chronically exposed to ionizing radiation during the late 1940s and early 1950s in the Russian Federation and in Kazakhstan. In this framework, collaborations have been established to develop cause-of-death registers in each of these four areas for future mortality follow-up purposes with the aim of studying the health effects of ionizing radiation. The emphasis of this effort is on assessing the information sources available, the mechanisms of data collection and coding, and the data quality and completeness of the information collected. One of the major challenges is the harmonization of all these aspects between the four different centers to the extent possible, taking into account that much of the actual data has been collected over many decades.

Benign lymphangioendothelioma manifested clinically as actinic keratosis.

Benign lymphangioendothelioma is an acquired lymphangiectatic lesion that must be recognized and differentiated from angiosarcoma, early Kaposi's sarcoma, and lymphangioma circumscriptum. We report the case of a 68-year-old woman with the clinical presentation of a possible actinic keratosis and the typical histologic findings of benign lymphangioendothelioma and an overlying actinic keratosis.

Superficial spreading (and disappearing) seborrheic keratosis.

A rapidly spreading plaque of seborrheic keratosis developed following liquid nitrogen treatment and involuted quietly after a dermatitis developed; polymerase chain reaction of the tissue did not demonstrate papillomavirus DNA. Seborrheic keratoses can both develop and involute from more than one cause.

Classic Kaposi's sarcoma as a second primary neoplasm.

Although the incidence of classic Kaposi's sarcoma (CKS) has been investigated, its occurrence following a primary neoplasm and its association with this first neoplasm need to be determined. We analyzed a series of 124 patients with a secondary CKS (8.4% of a total of 1485 incident cases) which occurred between 1961 and 1992 in the Jewish Israeli population. Data on first neoplasms and subsequent Kaposi's sarcoma were retrieved from the Israel Cancer Registry. Acquired-immune-deficiency-syndrome-related Kaposi's sarcomas were excluded from the case series. Four controls were randomly selected for each CKS case among all Cancer Registry cases free from a second neoplasm at the time of diagnosis of the CKS in the case, and matched on gender, year of birth and year of diagnosis of the first neoplasm. The average time lapse between first neoplasm and secondary CKS was 4.5 years, being shorter for prostate cancer and for hematopoietic malignancies. As compared with Israel-born Jews, the risk of a subsequent CKS was significantly increased in immigrants [odds ratio (OR) 3.0]; this risk was particularly high in immigrants from the former Soviet Union (OR 9.4) and Poland (OR 7.0). There was no clear trend with age at immigration; however, low age at immigration and a short length of stay in Israel endowed a higher risk of developing a secondary CKS, markedly among patients suffering from solid tumors as the first primary. There was an excess of secondary CKS following a non-Hodgkin's lymphoma (OR 5.3), a Hodgkin's lymphoma (OR 7.5), a leukemia (OR 5.3) or a breast cancer (OR 2.2). Cancer patients with a first primary in the lung, colon, stomach, larynx, liver, pancreas or kidney showed secondary CKS less frequently. Despite the lack of control of therapy for the first neoplasm, development of secondary CKS seems to be mediated by mechanisms similar to those for hematopoietic neoplasms and selected nonhematopoietic neoplasms, such as breast cancer. The trend toward increased risk after a short time lapse and the difference in risk among immigrants indicate that genetic susceptibility is part of the complex interplay between cellular proliferation and control systems.

Classic Kaposi's sarcoma in Jews living in Israel, 1961-1989: a population-based incidence study.

BACKGROUND: The incidence of classic Kaposi's sarcoma (CKS) has been reported to be high in Jewish populations, mostly born in Eastern Europe. OBJECTIVE: To describe the incidence on CKS in Israeli Jews and to determine differences in incidence according to their geography origin. DESIGN: We analysed data on 1098 incident CKS cases with known country of origin occurring between 1961 and 1989 in the Jewish Israeli population. Reporting systems were the Israel Cancer Registry, the medical documentation of all-Kaposi's sarcoma cases and the registry of HIV-seropositive patients. Patients who were seropositive for HIV were excluded from the study population. Population figures for groups of migrants and natives were derived from census surveys (1961, 1972, 1983) and inter-census estimates based on the population registry. RESULTS: The overall age-standardized rate of CKS was 16.9 per million in men and 6.3 per million in women. The ratio between genders remained stable during the study period. In both genders, there was a steep increase in CKS incidence between the late 1960s (age-standardized rates per million: 8.0 in men and 2.2 in women) and the early 1970s (17.9 in men and 6.7 in women). No further increase was present after 1971. Overall, immigrants experienced a relative risk (RR) of 1.17 [95% confidence interval (CI) 0.90-1.521 compared with Jews born in Israel. Immigrants from Morocco, Algeria and Tunisia had the highest incidence (RR 2.01; 95% CI 1.52-2.65) compared with Jews born in Israel, followed by those born in Iraq (RR 1.74; CI 95% 1.27-2.37). The lowest incidence was experienced by immigrants from Iran (RR 0.37; CI 95% 0.18-0.77) and from Central European countries (RR 0.45; CI 95% 0.30-0.66). Immigrants from other countries in Asia, Africa, the Americas and Europe had similar rates as Jews born in Israel. CONCLUSIONS: Israeli Jews present one of the highest incidences of CKS reported from developed countries. The incidence varies according to geographical origin. Countries surrounding the Mediterranean sea represent the area of highest CKS incidence.

Contact sensitivities in palmar plantar pustulosis (acropustulosis).

Acropustulosis, or chronic palmar plantar pustulosis (PPP), is a phenomenon of recurrent sterile pustules, erythema, and scaling affecting the palms and soles. Its pathogenesis is unclear, and it is difficult to treat. The purpose of this study was to elucidate further the factors involved in causing PPP, thereby enhancing the ability to manage this disease. All cases of PPP seen at Mayo Clinic Scottsdale from 1987 to 1993 were reviewed. 21 patients with PPP were identified, 15 of whom had been patch tested. 9 of the 15 patients (60%) showed positive patch test results. Fragrance was the most common sensitivity, but nickel, formaldehyde, para-phenylenediamine, thiuram, neomycin, mercury, balsam of Peru, and cinnamic aldehyde sensitivities were demonstrated. Less important factors included atopy, fungal and bacterial infections, and irritation. Although the mechanism of this sterile pustulosis response does not depend solely on delayed hypersensitivity mechanisms, we believe that we have demonstrated such a large number of positive patch tests in this chronic pustular dermatosis that patch testing should be considered in the routine work-up of these patients.

Weber-Christian panniculitis: a review of 30 cases with this diagnosis.

BACKGROUND: More than 60 years ago, Christian described a panniculitis that was later termed Weber-Christian disease. OBJECTIVE: The purpose of this study was to investigate whether this is a specific disease or a nonspecific disease that embraces several specific conditions. METHODS: We studied 30 cases diagnosed as Weber-Christian panniculitis and found it possible to make a more specific diagnosis. RESULTS: In 12 patients, findings were compatible with erythema nodosum. Six patients had phlebitis or postphlebitic syndrome. Factitial panniculitis was diagnosed in five patients, and trauma had a role in the conditions of another three patients. Cytophagic panniculitis, lymphoma, and leukemia were recognized in one patient each. The lesion was lobular in almost all cases, and the presence of lipophagia was noted in 19 biopsy specimens. Granulomatous, neutrophilic, and lymphocytic pathologic changes were present in nine, eight, and eight tissue specimens, respectively. CONCLUSION: The recognition of distinct disease patterns of fat lesions as fat necrosis with pancreatic disease, alpha1-antitrypsin panniculitis, lupus and connective tissue disease panniculitis, involution lipoatrophy, lipomembranous panniculitis, factitial panniculitis syndromes, calcification panniculitis, lipophagic lipoatrophy, and cytophagic panniculitis has lessened the need for a less specific panniculitis category. All these diseases have been reported in the literature as "Weber-Christian disease." Because separate and distinct forms of fat lesions have been described, we believe that the eponym should be abandoned and that more specific diagnoses should be made on the basis of pathogenesis or cause.

Asteroid bodies and other cytoplasmic inclusions in necrobiotic xanthogranuloma with paraproteinemia.

BACKGROUND: Necrobiotic xanthogranuloma (NXG) with paraproteinemia is a distinctive palisading granuloma of the skin. Extracutaneous lesions are rarely present. OBJECTIVE: The purpose of this study was to confirm the presence and significance of giant cell asteroid bodies and other cytoplasmic inclusions in NXG with paraproteinemia. METHODS: Skin biopsy specimens from 24 patients with NXG with paraproteinemia were reviewed; autopsy and lung biopsy specimens from two patients were stained for iron, calcium, and polysaccharide. RESULTS: Giant cell asteroid bodies were observed in skin biopsy specimens of 8 (33%) of the 24 patients. In addition, large acidophilic polygonal cytoplasmic inclusions were observed in myocardial tissue of one of the autopsy cases. Iron and calcium were not found. CONCLUSION: Asteroid bodies and other inclusions can be present in the giant cells of NXG with paraproteinemia. They are as frequent as, or more frequent than, in other granulomatous diseases and should be considered in the diagnosis of NXG with paraproteinemia.

Intravenous immunoglobulin in autoimmune chronic urticaria.

Histamine releasing autoantibodies play a central role in the pathogenesis of chronic urticaria (CU) in approximately 30% of affected patients. We investigated the therapeutic effect of high-dose intravenous immunoglobulin (IVIG) on disease activity in patients with severe CU of autoimmune aetiology. Autoimmune urticaria was diagnosed by the development of a weal-and-flare reaction to the intradermal injection of autologous serum and by serum-induced histamine release from the basophil leucocytes of healthy donors in vitro. Ten patients with severe, autoimmune CU, poorly responsive to conventional treatment, were treated with IVIG 0.4 g/kg per day for 5 days. The outcome on cutaneous wealing and itch was monitored using urticaria activity scores, visual analogue scales and autologous intradermal serum tests. Clinical benefit was noted in nine of 10 patients: three patients continue in prolonged complete remissions (3 years follow-up), two had temporary complete remissions, and symptoms in four patients improved subsequent to treatment. There was significant improvement in the urticaria activity scores and visual analogue scores at 2 (P < 0.01) and 6 weeks (P < 0.01) post-IVIG compared with the baseline values (Wilcoxon matched pairs). The diminution in urticarial activity in the majority of patients corresponded with a reduced weal-and-flare response to the intradermal injection of autologous post-treatment serum compared with the pretreatment serum. Minor side-effects were common, but there were no serious or long-term adverse effects. IVIG represents a novel therapeutic option in selected patients with recalcitrant CU associated with histamine releasing autoantibodies.

Solution structure of the recombinant oxidized rabbit uteroglobin using homonuclear and heteronuclear multidimensional NMR.

Rabbit uteroglobin (rab-UG) is a 16-kDa homodimeric secretory protein with potent anti-inflammatory/immunomodulatory properties. Its physiological role is still unclear, although it was observed that several small hydrophobic molecules bind to the oxidized and the reduced uteroglobin. It is suggested that the formation and/or disruption of the two disulphide bridges not only regulates this binding itself, but also the affinity to the ligand. The determination of the solution structure has been started with the assignment of 1H, 15N and 13C resonances of the oxidized rabbit uteroglobin, based on several two-dimensional and three-dimensional homonuclear and heteronuclear double and triple resonance experiments. The assignment was possible with the overproduction of the wild-type as well as of uniformly 15N-labeled and 15N/13C-labeled samples of the recombinant protein. A complete assignment of 1H, 15N and 13C resonances, the secondary-structure elements and the tertiary structure in solution is presented. The tertiary solution structure was found to be in good agreement with the previously determined crystal structure of rab-UG and with the solution structure of human uteroglobin (h-UG). h-UG and rab-UG are extremely stable proteins within a wide range of pH and temperatures. Some of the binding characteristics of ligands of rab-UG and a mutant with all cysteine residues exchanged to serine residues are discussed.