Hypocretin-1/orexin-A, sleep and excessive daytime sleepiness in patients with nonconvulsive status epilepticus: A cross-sectional cohort study.

BACKGROUND AND OBJECTIVES: Nonconvulsive status epilepticus (NCSE) manifests as a change in mental status without a coma (NCSE proper) or comatose NCSE. Hypocretin-1/orexin-A (H/O) is involved in alertness and sleep maintenance. Sleep impairment and excessive daytime sleepiness (EDS) have a negative impact on cognitive functions and activities of daily living (ADL). METHODS: Patients meeting the NCSE criteria underwent cerebrospinal fluid and brain magnetic resonance imaging examinations, polysomnographies (PSG), multiple latency sleep tests (MSLT), and completed Epworth Sleepiness Scale (ESS). Montreal Cognitive Assessment was used to evaluate cognitive functions, and the Barthel Index was used to assess ADL in the acute phase (V1) and three months follow-up (V2). RESULTS: From May 2020 to May 2023, we enrolled 15 patients, eight (53.3 %) women, with a median age of 69 (14) years. The median H/O CSF concentration was 250 (63.6) pg/ml; however, only three CSF samples (20 %) decreased below the borderline concentration of 200 pg/ml. Fourteen out of 15 patients (93.3 %) completed the PSG study. The median of wakefulness after sleep onset was 167 (173.5) min, sleep efficiency (SE) was 62.9 (63) %, sleep latency (SL) was 6 (32) min, REM sleep was 2.85 (7.2) %, and REM first episode latency was 210.5 (196.5) minutes. The medians of the stages N1 NREM were 4.65 (15) %, N2 NREM 68.4 (29.9) %, and N3 NREM 21.8 (35.5) %. MSLT mean latency was 7.7 (12.6) minutes. A significant negative correlation exists between H/O CSF concentrations and the stage N1 NREM (rs = -0.612, p = 0.02), and the proportion of cumulative sleep time with oxygen saturation below 90 % in total sleep time (TST) t90 (rs = -0.57, p = 0.03). MSLT had significant negative correlation with TST (rs = -0.5369, p = 0.0478), with SE (rs = -0.5897, p = 0.0265), with apnea-hypopnea index (rs = -0.7631, p = 0.0002) and with deoxygenation index (rs = -0.8009, p = 0.0006). A positive correlation exists between MSLT and SL (rs = 0.6284, p = 0.0161) and between ESS and t90 (rs = 0.9014, p = 0.0004). The correlation between H/O CSF concentrations and EDS, cognitive performance, and ADL was not proved. CONCLUSIONS: Patients after NCSE exhibited sleep impairment and excessive daytime sleepiness. Hypocretin-1/orexin-A concentrations decreased only in 20 % of these cases.

The Impact of Switching to a Second Antifibrotic in Patients With Idiopathic Pulmonary Fibrosis: A Retrospective Multicentre Study From the EMPIRE Registry.

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE). METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT). RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001). CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

The effect of nintedanib on lung functions and survival in idiopathic pulmonary fibrosis: real-life analysis of the Czech EMPIRE registry.

INTRODUCTION: The antifibrotic drug nintedanib is used for the treatment of idiopathic pulmonary fibrosis (IPF). We analysed the effect of nintedanib on antifibrotic treatment outcome in real-world cohorts of Czech EMPIRE registry. PATIENTS/METHODS: Data of 611 Czech IPF subjects, 430 (70%) treated with nintedanib (NIN group), 181 (30%) with no-antifibrotic treatment (NAF group) were analysed. The influence of nintedanib on overall survival (OS), pulmonary function parameters as forced vital capacity (FVC) and diffusing lung capacity for carbon monoxide (DLCO), as well as GAP score (gender, age, physiology) and and CPI (composite physiological index) were investigated. RESULTS: During 2 year follow-up we observed that nintedanib treated patients had longer OS, compared to those treated with no-antifibrotic drugs (p < 0.00001). Nintedanib reduces risk of mortality over no-antifibrotic treatment by 55% (p < 0.001). We have observed no significant difference in the rate of FVC and DLCO decline between the NIN and NAF group. Changes within 24 months from baseline in CPI were not significant between the groups (NAF and NIN). CONCLUSION: Our real-practice study showed the benefit of nintedanib treatment on survival. There were no significant differences between NIN and NAF groups in changes from baseline in FVC %, DLCO % predicted and CPI.

DSP rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study.

BACKGROUND: The antifibrotic drugs nintedanib and pirfenidone are used for the treatment of idiopathic pulmonary fibrosis (IPF). We analysed the association of common profibrotic polymorphisms in MUC5B (mucin 5B, rs35705950) and DSP (desmoplakin, rs2076295) on antifibrotic treatment outcomes in IPF. METHODS: MUC5B rs35705950 and DSP rs2076295 were assessed in IPF patients (n = 210, 139 men/71 women) from the Czech EMPIRE registry and age- or sex-matched healthy individuals (n = 205, 125 men/80 women). Genetic data were collated with overall survival (OS), acute exacerbation episodes, worsening lung function and antifibrotic treatment. RESULTS: We confirmed overexpression of the MUC5B rs35705950*T allele (55.2% versus 20.9%, p < 0.001) and the DSP rs2076295*G allele (80.4% versus 68.3%, p < 0.001) in IPF compared with controls. On antifibrotic drugs, lower mortability was observed in IPF patients with DSP G* allele (p = 0.016) and MUC5B T* allele (p = 0.079). Carriers of the DSP rs2076295*G allele benefitted from nintedanib treatment compared with TT genotype by a longer OS [hazard ratio (HR) = 7.99; 95% confidence interval (CI) = 1.56-40.90; p = 0.013] and a slower decline in lung function (HR = 8.51; 95% CI = 1.68-43.14; p = 0.010). Patients with a TT genotype (rs2076295) benefitted from treatment with pirfenidone by prolonged OS (p = 0.040; HR = 0.35; 95% CI = 0.13-0.95) compared with nintedanib treatment. Both associations were confirmed by cross-validation analysis. After stratifying by MUC5B rs35705950*T allele carriage, no difference in treatment outcome was observed for nintedanib or pirfenidone (p = 0.784). In the multivariate model, smoking, age, forced vital capacity (FVC) and DLCO (diffuse lung capacity) at the IPF diagnosis were associated with survival. CONCLUSION: Our real-world study showed that IPF patients with MUC5B T* allele or DSP G* allele profit from antifibrotic treatment by lower mortability. Moreover, carriers of the DSP rs2076295*G allele benefit from treatment with nintedanib, and TT genotype from treatment with pirfenidone. MUC5B rs35705950 did not impact the outcome of treatment with either nintedanib or pirfenidone. Our single-registry pilot study should be confirmed with an independent patient cohort.

Expression of p16 Protein in Cutaneous Basal Cell Carcinoma: Still far from Being Clearly Understood.

Dear Editor, p16INK4a protein (p16) is an important tumor suppressor protein involved in the carcinogenesis of many human malignancies. I have read with interest an article by Donati et al. (1) in this journal, who investigated an expression of p16 and proliferation marker Ki-67 in cutaneous tumors. Among them, there were 27 cases of non-melanoma skin cancer (NMSC), 23 of which comprised basal cell carcinoma (BCC), and 4 squamous cell carcinoma (SCC) lesions. The authors stated "in NMSC, they found a high prevalence (69.6%) of lesions with p16 expression between 34-66%, while the remaining specimens showed p16 expression 34%". Although they did not specify the exact proportions of BCC and SCC, one may speculate that the majority of BCCs (and maybe all) were at least partly immunoreactive for p16. As the literature gives very contradictory data on this topic, herein I will present my personal observations in this field. I performed immunohistochemical analysis of p16 in a set of 24 cutaneous BCCs obtained from 23 patients. They were categorized into non-aggressive (4 superficial and 10 nodular subtypes) and aggressive (7 nodular-infiltrative and 3 infiltrative subtypes) subgroups. In all cases, monoclonal mouse antibody against p16 (clone G175-405, Zeta Corp., dilution 1:75) was used for staining. Overall, I found 7 cases (29.1%) of BCCs manifesting a certain degree of p16-immunoreactivity in the tumor tissue. These lesions arose on the head in four cases (4/17 23.5%) and on the back and limbs in three cases (3/7 42.8%). Histologically, they comprised four cases (4/14 28.6%) of non-aggressive and three cases (3/10 30%) of aggressive histologic subtypes, respectively. As regards to the extent of p16-positivity, it was only focal and involved merely 5-20% of total cancer tissue. Notably, p16-positive areas occurred only at the edges and at the invasive margins of tumor aggregates (Figure 1), except for the case of pure infiltrative BCC subtype in which they were haphazardly distributed within the tumor mass (Figure 2). p16-reactivity was not observed at the center of solid tumor nests. Immunohistochemical expression of p16 in cutaneous BCC is very variable and reported values vary greatly between publications. Some authors (2-6) demonstrated it in the vast majority (79.2-100%) of BCCs. Conscience et al. (7) and Zheng et al. (8) observed it only in 50% and 14.9% of the cases, respectively. Finally, Villada et al. (9) did not report any p16-positive BCC in their recent study. Based on the literature review (1-9), I speculate that such striking discrepancies could be attributed to the following reasons: a) different processing technique and methods used; b) heterogeneity of the biopsy sample size; c) case selection bias in terms of the prevalence of certain histological BCC subtypes; and d) different cut-off values defining the p16-positivity of tumors. Biologic and prognostic impact of p16 production in cutaneous BCC remains unclear. In principle, it would be valuable to know whether BCCs with at least focal p16 immunostaining behave differently from their p16-negative counterparts. Several studies have reported conflicting data regarding a potential effect of p16 to invasive properties. Svensson et al. (5) showed that p16 expression was associated with invasive BCCs with an infiltrative growth pattern. In superficial, nodular, and infiltrative histologic subtypes, they found p16-positivity in 75.0%, 88.8%, and 100.0% of the cases, respectively. Other authors (2,3) did not find a clear relationship between the aggressive growth phenotype of BCC and immunoreactivity for p16. The data presented herein support the results of the latter group, but the present sample of p16-positive BCCs was too small to provide a reliable conclusion. Nevertheless, evidence of p16-immunoreactivity at the edges of tumor nodules and in the infiltrative growth pattern was similar with the findings published by Svensson et al. (5). Another useful question is whether p16 protein production in neoplastic cells depends on the topographic distribution of lesions and if it may thus be influenced by solar exposure. Some authors (1,3,7) found that p16 overexpression was associated with NMSC arising on sun-exposed areas, suggesting a possible induction of p16 protein production by permanent ultraviolet radiation. On the other hand, Italian researchers (4) did not find such an association, as among the five BCCs arising on the head and neck region only one displayed a high p16 immunoreactivity. Furthermore, in the study conducted by Villada et al. (9), all ten p16-negative BCCs were situated on the head and neck. Taken together, the biologic and clinical aspects of p16 production in cutaneous BCC are still far from being clearly understood. I assume that a simple quantification of p16 expression in BCC by immunohistochemistry is not sufficient for a reliable assessment of the clinicopathologic significances. Further studies must be more focused on spatial distribution and intensity of p16-positive areas in tumor tissue.

Serum periostin levels in asthma patients in relation to omalizumab therapy and presence of chronic rhinosinusitis with nasal polyps.

INTRODUCTION: The serum periostin level is a promising biomarker of type 2- high inflammation pattern of bronchial asthma. It has been proven that serum periostin levels decrease in response to systemic and inhaled corticosteroid (ICS) therapy. However, we have only limited knowledge about changes in serum periostin levels reflecting omalizumab (OMA) treatment and other variables, such as chronic rhinosinusitis with nasal polyps (CRSwNP). AIM: To critically appraise clinically relevant parameters influencing periostin levels in asthma patients. MATERIAL AND METHODS: A pilot, cross-sectional, observational study to assess serum periostin levels of 48 asthma patients (38 treated by conventional therapy comprising ICS and 10 treated by ICS and OMA as an add-on therapy) with respect to asthma clinical traits, comorbidities and to other biomarkers of type 2-high asthma phenotype (total IgE, absolute and relative eosinophil count, eosinophilic cationic protein (ECP) and a fraction of exhaled NO (FeNO)). RESULTS: Serum periostin correlates with total IgE levels (Spearman rho = 0.364, p = 0.025) in a subgroup of conventionally treated patients, and with eosinophil count (Spearman rho = 0.401, p = 0.021) in a subgroup of patients with concurrent CRSwNP. Serum periostin levels were decreased in omalizumab-treated patients in comparison to conventionally treated patients (p = 0.025). This effect was remarkably apparent only if CRSwNP was not present (p = 0.005). Conversely, we measured elevated periostin levels in OMA-treated patients with concurrent CRSwNP (p = 0.017). CONCLUSIONS: Serum periostin production is significantly associated with treatment modality (omalizumab vs. conventional) and presence of CRSwNP. These variables need to be taken into account to interpret periostin levels accurately.

Actinomycotic Endomyometritis Associated with a Long-Term Use of Intrauterine Device Lasting for 42 Years.

In women, pelvic actinomycosis is closely associated with prolonged use of the intrauterine devices (IUD). A 70-year old female presented with intermittent blood-stained vaginal discharge. An analysis of her history revealed, she was inserted with an IUD 42 years ago, but it has remained in situ untill now. Curettage of the uterus was done, but an IUD was firmly attached inside the cavity and there was not able to remove it. A biopsy material consisted of the large round and oval granules of filamentous and mycelium-like microorganisms. They showed strong positivity with Periodic acid-Schiff stain and Gömöri methenamine silver stain. Histopathology was consisted with uterine actinomycosis. A total abdominal hysterectomy with bilateral adnexectomy was performed. The uterus contained a retained plastic IUD. Microscopic investigation revealed a diffuse chronic active endomyometritis with sporadic Actinomycetes colonies. Wearing an IUD continuously for very long periods of time can lead to actinomycotic infection, which may manifest for many years after its application. All IUD users have to keep in mind regular gynecological check-ups to avoid the complications of a retained and "forgotten" IUD.

Effect of pirfenidone on lung function decline and survival: 5-yr experience from a real-life IPF cohort from the Czech EMPIRE registry.

INTRODUCTION: Pirfenidone, an antifibrotic drug, slows-down the disease progression in idiopathic pulmonary fibrosis (IPF) over 12 months, however limited data on the decline of lung function and overall survival (OS) in real-world cohorts on longer follow-up exists. PATIENTS/METHODS: Of the enrolled Czech IPF patients (n = 841) from an EMPIRE registry, 383 (45.5%) received pirfenidone, 218 (25.9%) no-antifibrotic treatment and 240 (28.5%) were excluded (missing data, nintedanib treatment). The 2- and 5-yrs OS and forced vital capacity (FVC) and diffusing lung capacity for carbon monoxide (DLCO) were investigated at treatment initiation and 6, 12, 18 and 24 months' follow-up. RESULTS: During a 2-yr follow-up, less than a quarter of the patients progressed on pirfenidone as assessed by the decline of ≥10% FVC (17.0%) and ≥ 15% DLCO (14.3%). On pirfenidone, the DLCO (≥10%) declines at 6, 12, 18 and 24 months' and DLCO (≥15%) declines at 6, 18 and 24 months' follow-up were associated with increased mortality. The DLCO decline showed higher predictive value for mortality than FVC decline. In patients with no-antifibrotics, FVC and DLCO declines were not predictive for mortality. Pirfenidone increased 5-yrs OS over no-antifibrotic treatment (55.9% vs 31.5% alive, P = 0.002). CONCLUSION: Our study observed the 2-yrs sustained effect of pirfenidone on the decline of lung function and survival in the real-world patient's IPF cohort. DLCO decline of ≥10% shows a potential as a mortality predictor in IPF patients on pirfenidone, and should be routinely evaluated during follow-up examinations.

Metachronous Bilateral Acinic Cell Carcinoma of the Parotid Gland in a Young Woman.

Bilateral involvement of major salivary glands by carcinoma of an identical histologic subtype is uncommon. In this study, a 26-year old female patient was diagnosed to have a low-grade acinic cell carcinoma (ACC) in the left parotid gland. After superficial parotidectomy, she was referred to the oncological dispensary care without further oncological therapeutic intervention. During 11 years of follow-up, she had no evidence of locoregional recurrence or metastasis. However, at the age of 37, she was recognized to have another tumor mass in the contralateral parotid gland. Right superficial parotidectomy was done, and histology confirmed an ACC showing the same picture as it was found previously. A year after the operation, no sign of tumor relapse was seen. Although metachronous bilateral ACC of the parotid gland is very rare, it is occasionally encountered in medical practice. Such an event may occur many years after a diagnosis of the initial tumor. Every patient once treated for parotid ACC warrants periodical clinical examinations and long-term follow-up (more than 10 years), even with attention to the contralateral non-affected parotid gland.

Development of Multiple-Lesion Basal Cell Carcinoma of the Skin: A Comprehensive Review.

An interesting clinical feature of basal cell carcinoma (BCC) of the skin is a marked variation in tumor number, sites, and accrual. Some individuals develop only a single BCC lesion with no impact on health status, while a significant proportion is affected repeatedly with new primary tumors at various body sites. Approximately 29% of patients with a first BCC will develop at least 1 more lesion during their lifetime. The candidate predictors for multiple BCC development include younger age and a superficial BCC subtype at the time of the first diagnosis, red hair phenotype, initial or frequent tumor location on the trunk or on the upper limbs, and male gender. The pathogenesis of multiple BCC development does not seem to be related to greater UVR exposure. Individual genetic susceptibility may have a greater impact than extrinsic factors. In clinical practice, it is meaningful to estimate the probability of new BCC development in patients who have an initial lesion. A reliable prediction model for individualized risk stratification remains a subject of continued research; however, a focus on the risk factor profile is beneficial for clinical screening and may help clinicians to determine the individuals who should be followed up more closely.

Desmoplastic Trichoepithelioma: An Uncommon but Diagnostically Problematic Benign Adnexal Tumor.

Dear Editor, I read an interesting recent article by Karimzadeh et al. (1) in an earlier issue of your journal, who provided a comprehensive review addressing a relatively rare benign tumor originating from the hair follicles - trichoepithelioma (TE). They rightly claimed that trichoepithelioma can be divided into the following 3 subgroups: a) multiple familiar TE, b) solitary non-hereditary TE, and c) desmoplastic trichoepithelioma (DTE). I would like to stress that the last category represents a distinct variant with some unique clinical and particularly histopathological characteristics. However, Karimzadeh et al. (1) did not provide any further information on DTE in their review. In my opinion, this variant of TE deserves special mention. The main reason is that it histomorphologically mimics infiltrative (morpheic) basal cell carcinoma (BCC) and can be challenging to differentiate for pathologists, particularly in small biopsies (2-5). Therefore, I report the case of young woman with two simultaneously growing DTEs with emphasis on the histopathology of this tumor. A 32-year old woman presented with two skin lesions arising on the left side of the forehead and on the right side of the neck. She claimed they had been present for one year. On gross examination, the lesion arising on the forehead was flat, whitish, and about 10 mm in diameter. The lesion on the neck was flat, light brownish, and 6 mm in diameter. A total surgical extirpation was performed. At a low magnification, both lesions histologically mimicked infiltrative (morpheic) BCC of the skin. However, more detailed inspection of individual microscopic features excluded this diagnosis. The tumors were composed of narrow lines and irregular strands of basaloid epithelial cells embedded in a dense stroma (Figure 1). Neoplastic aggregates grew within the dermis and were not attached to the surface epidermis. In the larger lesion, they extended into the subcutaneous fat. No ulceration was present. At high magnification, the tumor cells presented a bland appearance with prominent oval nuclei and scant cytoplasm (Figure 2). There were some signs that abortive follicular (hair bulb) differentiation occurred. Nuclear pleomorphism and mitotic figures as well as peripheral palisading and tumor-stroma retraction phenomenon were not present. Furthermore, sporadic keratinous cysts lined by stratified squamous epithelium were found. The stroma was densely collagenous, hypocellular, without solar elastosis, and without any inflammatory infiltration. Foreign body type granulomas with multinucleated giant cells were sometimes present, usually in relation to disrupted keratinous cysts. Calcifications were observed in both lesions, and ossification also occurred in the larger tumor. Immunohistochemically, the tumor was positive for high molecular weight cytokeratin (clone 34bE12) and epithelial antigen (clone BerEP4) (Figure 3). A few cells immunoreactive for cytokeratin 20 (CK20, clone Ks20.8) were observed within tumor aggregates. The Ki-67 proliferation index (clone MIB-1) did not exceed 10%. A spectrum of histomorphological findings of both lesions were consistent with DTE. Resection margins were intact and no local recurrence has been observed at the time of this writing. The differential diagnosis between DTE and infiltrative BCC is sometimes exceedingly difficult, even when assessed by a dermatopathology expert. However, establishing the correct diagnosis is crucial for clinicians, as the first entity represents a benign adnexal tumor with an excellent prognosis, while the latter is a high-risk variant of BCC that requires much more stringent clinical management. As we have already pointed out, both tumors share many histomorphological features. Firstly, they both consist of small strands and thin cords of basaloid epithelial cells in a densely sclerotic stroma. Several attempts have been made to provide reliable and reproducible criteria for their differentiation. An excellent description of various histopathological features that help to discriminate DTE from infiltrative BCC has been published by Costache et al. (3). They studied samples from 19 DTEs and 18 infiltrative BCCs. They revealed that the most reliable findings that favored a diagnosis of DTE rather than infiltrative BCC were as follows: architectural symmetry and well-circumscribed lesions, depression in the center of the tumor, connection of tumor aggregation to infundibula, at least one sign of follicular, infundibular, or sebaceous differentiation, granulomatous giant cell reaction due to rupture of keratinous cysts, foci of calcification and ossification, no tumor-stroma clefting, absence of solar elastosis, and association with melanocytic nevus. Another set of criteria also thought to provide significant diagnostic evidence for DTE was the lack of connection of neoplastic nests to the surface epidermis, the clefts between the peritumorous stroma and the surrounding dermis, and the presence of cut artefacts (knife marks) in histologic sections. In challenging cases, immunohistochemical stains for CK20 and androgen receptors can be helpful in discriminating between DTE and BCC. While TEs usually contain at least a few CK20-positive Merkel cells and are negative for androgen receptors, BCCs are mostly negative for Merkel cells and positive for androgen receptors (2,3). However, the diagnostic limitation of these markers should be kept in mind. For example, an expression of androgen receptors is often focal and sometimes completely absent in BCCs (2). On the other hand, many TEs have very low density of colonizing Merkel cells, which may require serial sections for reliable detection (2). Along with histopathology, clinical aspects have also to be taken into consideration when deciding on the final diagnosis. DTE occurs mainly in young and middle-aged women and has a predilection for the face, principally for the cheeks (4,5). In contrast, an age of the onset is much higher and a prevalence of women much lower in cutaneous BCCs (6). Overall, DTE is an uncommon adnexal tumor and its aggressive histological features can cause diagnostic uncertainty and confusion with infiltrative BCC. Distinguishing of these two structurally similar but biologically completely different tumor entities often requires a comprehensive diagnostic approach that includes the complexity of histopathological, immunohistochemical, and clinical findings.

Malignant Melanomas of the Skin Arising on the Feet.

BACKGROUND: Cutaneous melanoma frequently develops on the lower limbs, but rarely on the feet, in people with light skin. By contrast, the feet are one of the most frequently affected sites in people with dark skin. This study assessed the prevalence and clinico-pathological findings of biopsy-proven skin melanomas that were diagnosed over 11 years. MATERIALS AND METHODS: The study group comprised 217 primary melanomas from 210 patients. RESULTS: Eight (3.7%) melanomas were located on the feet. These were all invasive and obtained from 8 patients (5 females and 3 males) aged 56-85 years (mean age 72 years). In general, the lesions were large (mean diameter 3.5cm) and had a high Breslow index (mean thickness 5.6mm). They were all ulcerated, and some invaded deep into the subcutaneous tissue. Histologic analyses demonstrated that three tumors exhibited features of acral lentiginous melanoma, two were nodular melanomas, and one was a superficial spreading melanoma. Two cases could not be histologically classified. CONCLUSION: Although skin melanomas arising on the feet are relatively rare in our ethnicity, they are usually bioptically diagnosed at an advanced stage. Such melanomas may initially imitate other pathologic entities. Therefore, this location should not be overlooked during the medical workup, and melanoma should be suspected when patients present with non-healing defects or local pigmented changes on the soles of the feet or toes. Key words: malignant melanoma - anatomic distribution - foot The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 9. 2. 2018 Accepted: 16. 5. 2018.

Tumor-to-Tumor Metastasis - a Unique Case of Clear Cell Renal Cell Carcinoma Harboring Metastasis of Adenocarcinoma of Unknown Origin.

BACKGROUND: The tumor-to-tumor metastasis is exclusively rare finding, in which one malignant neoplasia metastasizes to another tumor of different origin. CASE: The author describes an 68-year-old woman, who was found to have a solitary tumor in the right kidney, as well as multiple tumor nodules in the liver. She underwent a radical nephrectomy. A histology of lesion in the kidney revealed a conventional clear cell renal cell carcinoma (RCC) harboring multiple metastatic foci of another adenocarcinoma. At that time, there was not possible to reliably specify a primary source. Subsequently, a probatory excision of tumor lesion in the liver was also done. A microscopy confirmed an adenocarcinoma with a similar appearance as found in RCC. Due to unfavourable health condition, a paliative chemotherapy could not be realized and the patient died shortly thereafter. A primary origin of adenocarcinoma remained unclear. CONCLUSION: A unique case of metastatic adenocarcinoma is described, that was initially diagnosed as an incidental finding within a clear cell RCC of the kidney. Such unexpected feature may represent a great diagnostic challenge for both, pathologist and clinician. From a prognostic point of view, an evidence of intratumoral cancer metastasis within a primary RCC is usually an indicator of disseminated oncologic disease with a poor outcome. Key words: tumor-to-tumor metastasis - donor - recipient - renal cell carcinoma.

Giant Uterine Leiomyoma in a Young Woman as an Incidental Finding After a Car Accident: a Case Report.

Leiomyomas are the most common benign tumor of the uterus. Occasionally, they may reach an extreme dimension. The authors present a case of a 44-year old woman, who suffered a car accident as a driver of personal motor vehicle. At the hospital, a huge tumor mass filling the entire abdominopelvic cavity was incidentally detected. The patient admitted a progressive abdominal enlargement for the last 5 years. An urgent laparotomy was performed, during which a giant, well-demarcated tumor arising from the uterine body had been disclosed. It was completely surgically removed and sent for histopathology. Grossly, the tumor measured 30 × 30 × 20 cm in the largest diameters and weighed 8.1 kg. The tissue was markedly edematous with foci of massive hemorrhages and contained confluent pseudocystic formations of various sizes, filled with a fluid and fresh blood. Solid foci of rubber consistency were also visible. Microscopic examination revealed a conventional subserous uterine leiomyoma with marked regressive and degenerative changes. Giant uterine leiomyomas occur extremely rare, but because of the often unexpected finding and atypical presentation, they may represent a great diagnostic challenge for both, pathologists and clinicians. At the biopsy examination, a multiple-section sampling is very important to avoid the possibility of underlying malignancy.

Cutaneous and Subcutaneous Metastases of Adenocarcinoma as a Dominant Clinical Manifestation of Malignancy of Unknown Origin - a Case Report.

BACKGROUND: Cutaneous metastases occur in 0.6-10.4% of all patients with underlying malignancy. Among them, the site of origin remains unknown in 4.4-14.5% of all cases. CASE: The authors describe a 68-year-old man with widespread skin and soft tissue metastases appearing as the first and dominant clinical manifestation of oncologic disease. Physical examination and CT scans revealed multiple cutaneous and subcutaneous tumor nodules arising in the neck, chest, abdomen, lumbar region and right forearm, as well as in the gluteal and iliacus muscles and in the proximal part of the left thigh. Light microscopy confirmed a metastasis of adenocarcinoma exhibiting a tubuloglandular pattern and a slight mucin production. It was immunoreactive for cytokeratin 7 and carcinoembryonic antigen and negative for cytokeratin 20, CDX-2, TTF-1 and prostatic specific antigen. Based upon the histomorphology and immunophenotype, the pathologist suggested a primary tumor in the stomach or biliopancreatic tract. However, further clinical workup did not clearly identify a primary lesion. CONCLUSION: Determining the origin of cutaneous metastases might be a challenging issue for both clinicians and pathologists. The case we describe is uncommon because widespread skin and subcutaneous metastases appeared as the first and dominant clinical sign of adenocarcinoma, the origin of which has not been established. This unusual tumor behavior may suggest that a spreading and colonization of metastatic cancer cells in the skin and soft tissue may be a specific biologic process.Key words: skin metastases - malignancy of unknown origin - adenocarcinoma.

EMPIRE Registry, Czech Part: Impact of demographics, pulmonary function and HRCT on survival and clinical course in idiopathic pulmonary fibrosis.

INTRODUCTION: Prognostic factors of idiopathic pulmonary fibrosis (IPF) currently recognized include changes in vital capacity and radiologic findings. However, most of the prognostic studies in IPF are based on clinical studies with preselected IPF populations. Therefore, we decided to analyze the factors influencing IPF prognosis based on the real-practice data from our IPF registry. METHODS: Data of 514 subjects consecutively entered since 2012 into Czech EMPIRE IPF registry were analyzed. RESULTS: Median age of our patient cohort was 67 years (50-82). Median overall survival (OS) of the cohort was 63.1 months. The clinical course of IPF according to FVC (forced vital capacity) changes was stabilized in 32.8% of patients (29.7% according to DLCO [diffuse lung capacity] changes), slowly progressive in 39.5% (45%), rapidly progressive in 23.5% (20.7%); and 1.7% patients had at least one acute exacerbation during follow-up. Deterioration in FVC of ≥10% at month 12 and in DLCO of ≥15% at months 12, 18, and 24 influenced the OS significantly. The fast progressors defined by the DLCO decline rate had higher risk of death compared to those defined by the FVC change over time. In multivariate analysis, age ≥70 years, interstitial HRCT scores ≥3, and change in DLCO of ≥15% at month 12 were confirmed as factors negatively influencing OS. CONCLUSIONS: DLCO changes over time were shown as a better predictor of mortality compared with FVC changes in our study. In our opinion it is necessary to implement the DLCO analysis into clinical trials and routine practice.

Investigation of P120catenin Expression in Human Basal Cell Carcinoma of the Skin.

BACKGROUND: P120(ctn) is a specific membranous adhesion protein, that maintains the stability of intercellular junctions. An altered expression of p120(ctn), either reduced in the cell membrane or increase in the cytoplasm, plays a crucial role in carcinogenesis. No research has analysed the expression of p120(ctn) in basal cell carcinoma (BCC) of the skin so far. Therefore, we immunohistochemically studied p120(ctn) in a set of cutaneous BCCs in order to determine, whether there is difference in the expression pattern related to the histologic subtypes and tumor growth characteristics. MATERIAL AND METHODS: The study group consisted of 38 BCCs cathegorized into low-risk (non-infiltrative) subroup (8 superficial and 12 nodular subtypes) and high-risk (infiltrative) subgroup (10 nodular-infiltrative and 8 infiltrative subtypes). Specific monoclonal antibody against p120(ctn) was used for staining. RESULTS: Overall, there were 12 cases (31.6%) with normal preserved and 26 cases (68.4%) with abnormal p120(ctn) expression. In superficial, nodular, nodular-infiltrative and infiltrative subtypes, abnormal p120(ctn) immunoreactivity was found in 37.5% (3/8), 41.7% (5/12), 100% (10/10) and 100% (8/8), respectively. We have confirmed a strong correlation between the expression of p120(ctn) and both given, non-infiltrative and infiltrative BCC growth phenotypes. In the latter subgroup, almost all lesions showed diffusely reduced membranous staining, of which five also manifested an aberrant immunoreactivity in the cytoplasm. This cytoplasmic positivity occurred solely at the invasive front of the infiltrative tumor formations. CONCLUSION: Our results showed that decreased membranous expression of p120(ctn) was a frequent event in human cutaneous BCC and it was associated with infiltrative growth phenotype. Considering that nearly half of the BCCs with non-infiltrative growth pattern also exhibited reduced membranous expression, aberrant cytoplasmic immunoreactivity of p120(ctn), which was found exclusively in the high-risk BCC variants, can more reliably reflect and predict biological behaviour and malignant potential.

Non-melanoma Skin Cancer - a Clinicopathological Study of Patients with Basal Cell Carcinoma and Squamous Cell Carcinoma.

BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in Caucasians. It mainly includes two major keratinocyte tumors - basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The objective of the study was to analyze and compare the clinicopathological differences between patients with BCC and SCC of the skin. MATERIAL AND METHODS: A cohort of 541 patients with a total of 719 BCCs, and 126 patients with a total of 162 SCCs were retrospectively analyzed. RESULTS: While there was virtually the same proportion of men (49.91%) and women (50.09%) in BCC patients, SCCs occurred more frequently in men (68.2%) than in women (31.8%). The mean age of the individuals with BCC and SCC was 70.8 and 78.2 years, resp. The number of BCCs rises from 50 years of age and this increase showed a linear trend up to 80 years, subsequently followed by decline. SCC lesions occur more rapidly from 70 years of age followed by a sharp increase that exhibited an exponential relationship. BCCs and SCCs occurred predominantly on the head and neck region, comprising a total of 69.8% and 81.4% of the cases, resp. However, BCC lesions were seen more often on the face and SCC lesions were diagnosed more frequently on the extra-facial parts of the head. Further, BCCs occurred more frequently on the trunk, and particularly on the back, compared to SCCs. CONCLUSION: Although BCC and SCC are covered under common term NMSC, they manifest several clinicopathological differences. Despite sharing common etiologic determinants, at least from the onco-epidemiologic perspective, they should be considered separately.Key words: non-melanoma skin cancer - basal cell carcinoma - squamous cell carcinoma.

Basal cell carcinoma of the skin with mixed histomorphology: a comparative study.

Basal cell carcinoma (BCC) of the skin exhibits a very heterogeneous histomorphology, on the basis of which it is classified into several subtypes and variants. In many cases, however, a definite categorization remains difficult, because BCC may consist of more than one histopathological subtype. There are limited data exploring the characteristics of these mixed BCCs, since they have not been specifically analysed. The aim of this study was to estimate the prevalence of BCCs with mixed histomorphology observed in a set of primary BCCs and to compare their clinicopathological features with a single type BCC subgroup. A total of 911 histologically proven primary BCCs from 697 patients were investigated. Prevalence of single and mixed type BCCs was 64.9 % and 35.1 %, respectively. In mixed type BCC subgroup, a very heterogeneous histomorphology was found comprising a mixture of two to four different subtypes in various proportions. The most frequent combinations included nodular-infiltrative, superficial-nodular, nodular-trichoepithelial and nodular-micronodular subtype. Comparative analysis of the two given subgroups showed that mixed type BCCs were significantly more frequently localized on the extrafacial regions of the head (30.0 % vs. 20.0 %, p = 0.02) and less often on the face (37.2 % vs. 45.2 %, p = 0.03). There were not convincing differences in the occurrence of single vs mixed type BCCs in other parts of the body. Histologically, mixed type BCCs exhibited an aggressive-growth pattern more frequently (64.6 % vs. 13.0 %, p < 0.0001). Positive surgical margins were significantly more common in mixed type BCC subgroup (17.8 % vs. 12.6 %, p = 0.02). Cutaneous BCCs with mixed histomorphology represented about one third of the cases. It is a common finding in routine pathological practice, probably suggestive of evolution and phenotypic transformation of the cancer. Since mixed type BCCs are frequently composed of aggressive histological subtypes, regardless the personal habits in description or terminology among pathologists, the presence of aggressive-growth component in tumor tissue should always be mentioned in final biopsy report.

Assessment of Intrathecal Free Light Chain Synthesis: Comparison of Different Quantitative Methods with the Detection of Oligoclonal Free Light Chains by Isoelectric Focusing and Affinity-Mediated Immunoblotting.

OBJECTIVES: We aimed to compare various methods for free light chain (fLC) quantitation in cerebrospinal fluid (CSF) and serum and to determine whether quantitative CSF measurements could reliably predict intrathecal fLC synthesis. In addition, we wished to determine the relationship between free kappa and free lambda light chain concentrations in CSF and serum in various disease groups. METHODS: We analysed 166 paired CSF and serum samples by at least one of the following methods: turbidimetry (Freelite™, SPAPLUS), nephelometry (N Latex FLC™, BN ProSpec), and two different (commercially available and in-house developed) sandwich ELISAs. The results were compared with oligoclonal fLC detected by affinity-mediated immunoblotting after isoelectric focusing. RESULTS: Although the correlations between quantitative methods were good, both proportional and systematic differences were discerned. However, no major differences were observed in the prediction of positive oligoclonal fLC test. Surprisingly, CSF free kappa/free lambda light chain ratios were lower than those in serum in about 75% of samples with negative oligoclonal fLC test. In about a half of patients with multiple sclerosis and clinically isolated syndrome, profoundly increased free kappa/free lambda light chain ratios were found in the CSF. CONCLUSIONS: Our results show that using appropriate method-specific cut-offs, different methods of CSF fLC quantitation can be used for the prediction of intrathecal fLC synthesis. The reason for unexpectedly low free kappa/free lambda light chain ratios in normal CSFs remains to be elucidated. Whereas CSF free kappa light chain concentration is increased in most patients with multiple sclerosis and clinically isolated syndrome, CSF free lambda light chain values show large interindividual variability in these patients and should be investigated further for possible immunopathological and prognostic significance.