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(a) High nuclear Twist expression (n = 5), (b) Low nuclear Twist expression (n = 29), (c) High nuclear Zeb1 expression (n = 10), (d) Low nuclear Zeb1 expression (n = 27), (e) High nuclear Slug expression (n = 27) and (f) Low nuclear Slug expression (n = 8). Patients with high nuclear Twist and low nuclear Zeb1 expression formed one group (Twist+/Zeb-), and low nuclear Twist and high nuclear Zeb1 formed another (Twist-/Zeb+) group. [Extracted from the article]

Merkel cell carcinoma (MCC) is a rare cutaneous carcinoma that has gained enormous interest since the discovery of Merkel cell polyoma virus, which is a causative oncogenic agent in the majority of MCC tumours. Increased research has focused on effective treatment options with immuno-oncology. In this study, we reviewed the real-world data on different treatments given to MCC patients in Finland in 1986-2016. We used the Finnish Cancer Registry database to find MCC patients and the Hospital Discharge Register and the Cause-of-Death Register to obtain treatment data. We identified 376 MCC patients and 33 different treatment entities and/or combinations of treatment. An increase was noted in the incidence of MCC since 2005. Therefore, the cohort was divided into two groups: the "early" group with time of diagnosis between years 1986 and 2004 and the "late" group with time of diagnosis between 2005 and 2016. The multitude of different treatment combinations is a relatively new phenomenon; before the year 2005, only 11 treatments or treatment combinations were used for MCC patients. Our data show that combining radiation therapy with simple excision provided a survival advantage, which was, however, lost after adjustment for stage or age. Our registry study serves as a baseline treatment efficacy comparison as we move into the age of immunotherapy in MCC. Standardizing the treatment of MCC patients in Finland requires more work on awareness and multidisciplinary co-operation.

Background: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging., Objectives: To develop a prognostic index for MF., Methods: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies., Results: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF., Conclusions: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex., (© 2018 British Association of Dermatologists.)

Background: Merkel cell carcinoma (MCC) tumor samples frequently express B-lymphoid lineage markers. However, the reasons for expression of specific B-lymphoid lineage markers are still unclear. We studied the expression of TdT and PAX5 (two B-cell lymphoid lineage markers) in a large pool of MCC tissue microarray samples., Methods: Immunoexpression and staining intensities of TdT and Pax-5 were statistically correlated with patient, tumor, Merkel cell polyomavirus (MCV), and disease-specific parameters., Results: In a cohort of 117 MCC patients and their corresponding tumor samples, TdT was expressed in 37 (31.6%) samples and PAX5 in 26 (22.2%). Simultaneous immunostaining for TdT and PAX5 was observed in 13 (11.1%) samples. A statistically significant relationship was observed between MCV virus copy number and positive TdT expression (P = 0.0056). Similarly, a significant relationship was also observed between positive TdT and tumor MCV virus positivity (P = 0.000495)., Conclusion: We observed frequent TdT and PAX5 immunoexpression in MCC tumor samples. However, simultaneous immunoexpression of these markers was scarce. TdT expression was statistically significantly associated with MCV positivity. The absence of a statistically significant association between tumor parameters and disease progression markers undermines the systemic use of these markers in clinical practice., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC)., Methods: Merkel cell carcinoma cases diagnosed in 1978-2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes., Results: Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03-1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09-1.80) and diabetic conditions (OR 1.51, 95% CI 1.03-2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05)., Conclusions: Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID.

Rationale: Comparisons of home mechanical ventilation services have demonstrated considerable regional variation in patient populations managed with this therapy. The respiratory care practices used to support individuals receiving assisted ventilation also appear to vary, but they are not well described. It is uncertain whether differences in the approach to care could influence health outcomes for individuals receiving assisted ventilation., Objectives: We sought to identify and describe the respiratory care practices of home ventilation providers in two different regions and determine whether care practice differences influence health-related quality of life., Methods: We conducted a cross-national survey of individuals receiving assisted ventilation managed by two statewide home mechanical ventilation providers, one in Victoria, Australia, and the other in British Columbia, Canada. The survey was used to evaluate care practices, functional and physical measures, socioeconomic attributes, and health-related quality of life., Measurements and Main Results: Overall, 495 individuals receiving assisted ventilation (57.2%) responded to the survey. Responders had clinical attributes similar to those of nonresponders. The Canadian population had a greater proportion of individuals with neuromuscular disorders and lesser percentages with obesity hypoventilation syndrome and chronic obstructive pulmonary disease. We also found marked differences in the reported care practices in Canada that were not fully explained by population differences. Subjects in the Canadian sample were more likely than their Australian counterparts to use invasive mechanical ventilation (24.2% vs. 2.5%; P < 0.001), to use routine airway clearance techniques (28.9% vs. 14.8%; P < 0.001), and to have had home implementation of noninvasive ventilation (39.9% vs. 3.6%; P < 0.001). Subjects in the Australian population were more likely than those in Canada to have undergone polysomnography to evaluate their ventilatory support (93.9% vs. 37.4%; P < 0.001). There was no difference in summary measures of health-related quality of life between the two sites. In a multivariable regression model, age, ability to perform activities of daily living, physical function, employment, and household income were all independently associated with health-related quality of life, but neither geographic location (Canada vs. Australia) nor underlying diagnosis were significant factors in the model., Conclusions: In two cohorts of individuals receiving assisted ventilation, one in Australia and the other in Canada, we found marked differences in both the care practices employed and the populations served. Despite these regional differences, measures of health-related quality of life were not different. Further research is required to examine costly or burdensome interventions that are currently used routinely in the management of individuals receiving assisted ventilation.

Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression.

The objective of this study was to assess the reciprocal association between non-Hodgkin lymphoma (NHL) and Merkel cell carcinoma (MCC) using the data of four Nordic Cancer Registries. Data for this study were drawn from the Danish, Finnish, Norwegian, and Swedish cancer registries. Standardized incidence ratios (SIRs) for MCC among NHL patients, and for NHL among MCC patients, were calculated. There were 109 838 individuals with NHL and 1411 individuals with MCC, of which 28 had joint occurrence of NHL and MCC. In 18 cases, NHL was diagnosed first, and in 10 cases, MCC was diagnosed first. The SIR for MCC after NHL was 4.34 (95% confidence interval 2.57-6.85). The SIR for NHL after MCC was 3.13 (1.50-5.77). Although the absolute frequency of joint occurrence of MCC and NHL is low, individuals suffering from one of the cancer forms have an increased risk of the other.

Sequestration of the tumor suppressor retinoblastoma protein (RB) by the Merkel cell polyomavirus (MCV) is a crucial step in the pathogenesis of Merkel cell carcinoma (MCC). RB expression is frequently lost, particularly in MCV-negative MCC tumors, through yet unknown mechanisms. We compared the genomic copy number changes of 13 MCV-positive and 13 -negative MCC tumors by array comparative genomic hybridization. The analysis revealed increased genomic instability, amplification of 1p34.3-1p34.2, and losses of 11p in the absence of MCV infection. Deletions of the RB1 locus were also detected at high rates in MCV-negative tumors. None of the tumors with heterozygous RB1 losses expressed RB in immunohistochemistry. RB1 promoter hypermethylation was studied with a methylation-specific multiplex ligation-dependent probe amplification technique. The RB1 promoter was methylated in all tumor specimens at CpG islands located close to the ATG start codon, albeit at low levels. The pattern of hypermethylation was similar in all MCC samples, despite RB expression, survival or MCV status. In conclusion, the frequent heterozygous losses of the RB1 locus could partly explain the decreased RB expression in MCV-negative MCC tumors, although the effects of RB1 mutations, coinciding promoter hypermethylation and, for example, miRNA regulation, cannot be excluded., (© 2014 APMIS. Published by John Wiley & Sons Ltd.)

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. The recently found Merkel cell polyomavirus (MCV) integrates clonally in the tumour genome, which suggests an important role in the pathogenesis of the disease. Previous small-scale studies have detected anti-apoptotic protein bcl-2 in 80 % of MCC tumours, but its correlation to the prognosis of MCC remains controversial. Our aim was to clarify the correlation of immunohistochemical expression of bcl-2 to MCV presence and MCC prognosis. We analyzed 116 primary MCC specimens with corresponding clinical data by immunohistochemistry for bcl-2. The presence of MCV DNA had been analyzed by quantitative PCR for 108 tumours. The correlations were analyzed statistically. Of the primary MCC samples, 85 % were bcl-2 positive. No significant differences in MCV DNA occurred between the bcl-2-positive and bcl-2-negative tumours. Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33 %) than in patients with bcl-2-positive tumours (12 %; p = 0.04) at the time of diagnosis. The mean overall survival was higher in patients with bcl-2-positive tumours than of those with negative tumours (mean survival 1,814 days (5.0 years) vs. 769 days (2.1 years), p = 0.01). Bcl-2 positivity indicates better clinical stage at the time of diagnosis and a longer survival in MCC.

Background: Statins (HMG-CoA-reductase inhibitors) are suggested to act as a predisposing factor for autoimmune diseases, have immunomodulatory effects, and possibly prevent some cancer types - the sum of these effects is unknown in cancers of viral aetiology, such as Merkel cell carcinoma (MCC). Aim of our study was to find out whether statin users in Finland have an increased incidence of MCC., Patients and Methods: A cohort of 224715 male and 230220 female statin users during 1994-2007 was identified from the Prescription Register of the National Social Insurance Institution. This cohort was followed up through the Finnish Cancer Registry for MCC up to 2009., Results: There were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93-1.65). The standardized incidence ratio (SIR) for MCC in ages <60 years was 3.16 (95% CI 0.65-9.23), in ages 60-74 years 1.94 (95% CI 1.23-2.90) and in ages ≥75 years 0.89 (95% CI 0.57-1.31). The relative risk of MCC decreased significantly, 0.79 fold (95% CI 0.67-0.92), at each 5 year step when moving towards older age groups. There was no significant variation in SIR related to years since starting the statin use, or between the genders., Conclusions: MCC is the first neuroendocrine cancer linked to statin use. The association is statistically significant and biologically plausible through immunomodulatory effects of statins. The excess of MCCs was observed in atypically young patients, a similar phenomenon as noted earlier in patients with immunocompromising states., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: The objective of our study was to evaluate chest computed tomography (CT) findings in 3 lung transplant recipients infected with Pseudallescheria boydii complex or its asexual anamorph, Scedosporium apiospermum, 2 after double-lung transplant and 1 after single-lung transplantation. Awareness and early diagnosis of this rare but potentially lethal infection are important, as it is largely refractory to treatment with the antifungal agents of choice used for the more common Aspergillus species. Computed tomography investigation focused on the location, quality, and appearance of the various pulmonary lesions as well as the presence of cavitation, mediastinal lymphadenopathy, and pleural effusions. A literature review of previous lung and other solid organ transplant recipients infected with pulmonary Pseudallescheria boydii was also conducted and compared with our findings., Conclusion: While the high-resolution CT findings of pulmonary P. boydii infection are nonspecific and markedly similar to the manifestations of the more common Aspergillus species, awareness of this rare opportunist is important, given the high mortality associated with disseminated infection and the relative success possible with timely and appropriate treatment. The most common CT abnormalities present in our 3 patients included hilar and paratracheal adenopathy, noncavitary tree-in-bud nodules surrounded by ground-glass opacities, and airway thickening.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition that has frequent morbidity and mortality, with associated costs of US $ 2.5 billion annually and nearly 14,000 deaths each year. In the most advanced stages it causes debilitating breathlessness which is not improved despite maximal medical therapy including smoking cessation, bronchodilators, steroids and supplemental oxygen. Limitations of medical therapy led to the development of several surgical techniques to improve quality of life. However, surgical techniques still carry substantial morbidity even if the mortality is low at centers with larger experience; hence investigators are vigorously pursuing research into innovative, alternative methods for achieving lung volume reduction (LVR), in recent years. Endoscopic techniques for LVR are proposed, based on two main approaches, either closing of anatomical airway passages into destroyed lobe/segment of the lung to affect a collapse and reduction in volume or opening extra-anatomical airway passages, aimed at improving expiratory collateral flow from hyper-inflated areas bypassing the flow limited segments of the emphysematous airways. This article reviews the available endoscopic devises and the evidence supporting their use in the treatment of COPD.

Background: Hepatitis C virus (HCV) infects 4 million people in the USA, with a prevalence of 1.4%. The seropositivity rate among potential lung transplant candidates is 1.9%, yet little information is available regarding outcomes of lung transplantation in HCV-positive lung transplant recipients. Our study reports outcomes of lung transplantation in HCV-positive recipients and compares them to HCV-negative controls., Methods: A retrospective analysis of the Cleveland Clinic Foundation's lung transplant database (465 patients) identified six HCV-positive patients. Demographic data, etiology of HCV infection, HCV viral load pre- and post-transplant, pre-transplant hepatic pathology, serial transaminases, incidence of acute hepatitis, graft function data and patient survival data were obtained by chart extraction., Results: Five HCV-positive recipients had a pre-transplant liver biopsy, none of whom had evidence of cirrhosis pre-transplant. Although HCV RNA levels markedly increased post-transplant, no concomitant increase in transaminases was noted. There was no significant difference in the incidence of acute rejection at 1 year in our HCV-positive cohort compared with the HCV-negative lung transplant recipients from our institution. One patient developed bronchiolitis obliterans syndrome (BOS) during the follow-up period. Two patient deaths occurred, one at 8 months and the other at 2 years post-transplant. No evidence of hepatic dysfunction was noted in either deceased patient. The four surviving patients are alive at a median 3.2 years (range 1 to 6 years)., Conclusions: No significant difference in patient or graft survival was noted between the HCV-positive lung transplant recipients and the HCV-negative recipients.

Background: Scedosporium apiospermum, the asexual counterpart of the teleomorph Pseudallescheria boydii, is increasingly recognized as an important opportunistic pathogen in transplant recipients. Infection is associated with a high rate of dissemination and poor outcome overall., Methods: A retrospective analysis of The Cleveland Clinic lung transplant database identified 5 patients with S. apiospermum isolated from respiratory tract specimens. Demographic data and lung transplant outcomes were obtained by review of medical records., Results: S. apiospermum was isolated from respiratory culture in 5 lung transplant recipients. Disseminated disease developed in 3 patients, whereas 2 appeared only to be colonized., Conclusions: Our experience and review of the literature highlights the importance of early diagnosis and differentiation from Aspergillus, since Scedosporium is inherently resistant to amphotericin B. Effective therapeutic approaches being explored include combinations of anti-fungals, because even the newer triazoles have a 50% response rate in clinical studies. Surgical débridement and immune recovery are associated with improved prognosis, favoring the use of agents that expedite immune reconstitution in these patients. Close monitoring of clinical improvement and frequent reevaluation of treatment is essential.