Malignant myoepithelioma of the external auditory canal - a rare case report with literature review and clinical importance of foramen of Huschke.

BACKGROUND: A malignant myoepithelioma is a rare tumor, mostly arising from the salivary glands. Myoepitheliomas of the ear have rarely been reported. The manuscript reports myoepithelial carcinoma of the external auditory canal (EAC) spreading to the infratemporal fossa. A clinician must be aware of anatomical variation of the bony EAC wall, such as the foramen of Huschke. This rare defect may be a pathway for spreading pathologies between these two anatomical regions. CASE REPORT: We present a case of osteoma-like stenosis of the EAC, which turned out to be an extremely rare malignant tumor. The preoperative MRI and PET/CT revealed that two parts of the tumor communicated through a defect in the antero-inferior portion of the bony ear canal. No distant metastases were detected. Subsequently, the tumor was resected from the ear canal and the infratemporal fossa en bloc. Perioperatively the defect in the EAC wall was suspected of the foramen of Huschke. After the surgery, the older scans of the patient from the past showed no presence of a congenital EAC wall defect. Therefore, the authors concluded that the tumor aggressively grew through the bone due to its biological nature. CONCLUSION: Malignant myoepithelioma of the external auditory canal is an extremely rare condition and could be misdiagnosed as other benign lesions. In cases of suspicious lesions, it is advisable to do a probatory biopsy from the EAC. Surgery is the treatment of choice in malignant myoepitheliomas, and regular follow-ups are essential to monitor for recurrence or metastatic disease. Any mass located at the antero-inferior portion of the EAC wall warrants close evaluation due to its potential for expansion from the EAC.

SMARCB1-deficient sinonasal adenocarcinoma: a rare variant of SWI/SNF-deficient malignancy often misclassified as high-grade non-intestinal-type sinonasal adenocarcinoma or myoepithelial carcinoma.

SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.

Microbiota Diversity in Non-Small Cell Lung Cancer Gut and Mouth Cavity Microbiota Diversity in Non-Small Cell Lung Cancer Patients.

Lung malignancies have a substantial impact on cancer incidence and mortality worldwide. Even though many factors involved in the development of the disease are known, many questions remain unanswered. Previous studies suggest that the intestinal microbiota may have a role in developing malignant diseases. According to some findings, the microbiota has proven to be a key modulator of carcinogenic processes and the immune response against cancer cells, potentially influencing the effectiveness of immunotherapy. In our study, we characterized culturable microorganisms associated with non-small cell lung cancer (NSCLC) that can be recovered from rectal swabs and mouthwash. In addition, we also explored differences in the culturable microbiota with two main types of NSCLC - adenocarcinoma (ADC) and squamous cell carcinoma (SCC). With 141 patients included in the study (86 ADC and 55 SCC cases), a significant difference was observed between the two types in seven bacterial species (Collinsella, Corynebacterium, Klebsiella, Lactobacillus, Neisseria, Rothia, and Streptococcus), including the site of origin. The relationship between microbial dysbiosis and lung cancer is poorly understood; future research could shed light on the links between gut microbiota and lung cancer development.

Importance of evaluation of bone invasion type in squamous cell carcinomas of the oral cavity and oropharynx.

AIMS: The objective of this study was to compare bone invasion type with histopathological, clinical and immunohistochemical prognostic factors. METHODS: The study included 49 patients who were treated for oral squamous cell carcinoma. Of which, 30 patients, with presence of bone invasion on histopathology, were divided according to the type of bone invasion (erosive, infiltrative, mixed). Each invasion type was compared to microvascular density using the CD34 marker. RESULTS: The bone invasion was observed in 30 out of 49 patients (61.22%). On McNemar's test, statistically significant association was observed between bone invasion types and histopathological grade. In contrast, no significant correlation was observed between bone invasion type, and tumour volume or nodal metastases. In tumours with bone invasion of the infiltrative type, higher frequency of locoregional relapses was observed. The 5-year survival, since diagnosis, was approximately 60% in the erosive group, 40% in the mixed group, and merely 15% in the infiltrative group. CONCLUSION: Peritumoural microvascular density was not significantly related to bone invasion types. Whereas, a significantly higher intratumoural microvascular density was observed in infiltrative type of the bone invasion, when compared to the erosive and mixed type.

Rare syringoid eccrine carcinoma of the upper lip and nasal base treated with resection and subsequent innovative reconstruction using an Abbé flap, turbinate flaps and three-stage forehead flap: a case report.

BACKGROUND: Although syringoma is a common benign tumour of the sudoriferous gland, there is also an extremely rare malignant form known as syringoid eccrine carcinoma (SEC). SEC usually exhibits slow growth with deep invasion and a frequent tendency to relapse. The treatment of choice is radical wide resection, which poses a difficult reconstructive problem, especially when the tumour is located in the centre of the face. CASE PRESENTATION: In this case, a 70-year-old man was diagnosed with an SEC at the same location as a benign syringoma of the upper lip and nasal base that had undergone primary excision 7 years prior. Primary radical resection was performed with immediate Abbé flap reconstruction. Nevertheless, histology revealed positive margins, and 3 additional re-excisions were needed to achieve clear margins. Four months after the initial resection, the patient had undergone an innovative reconstruction technique including not only the Abbé flap but also a turbinate flap harvested with functional endonasal surgery and a three-stage forehead flap. CONCLUSION: To the best of our knowledge, this is the first case report of a suspect malignant transformation of a benign syringoma after 7 years. In addition, from oncoplastic and reconstructive points of view, the bilateral use of the turbinate flap for reconstructing the intranasal lining of the alar base is unusual, and the use of functional endonasal surgery in nasal reconstruction for reducing the risk of damaging the vascular supply of the flap is innovative.

Epithelioid Soft Tissue Neoplasm of the Soft Palate with a PTCH1-GLI1 Fusion: A Case Report and Review of the Literature.

GLI1 fusions involving ACTB, MALAT1, PTCH1 and FOXO4 genes have been reported in a subset of malignant mesenchymal tumors with a characteristic nested epithelioid morphology and frequent S100 positivity. Typically, these multilobulated tumors consist of uniform epithelioid cells with bland nuclei and are organized into distinct nests and cords with conspicuously rich vasculature. We herein expand earlier findings by reporting a case of a 34-year-old female with an epithelioid mesenchymal tumor of the palate. The neoplastic cells stained positive for S100 protein and D2-40, whereas multiple other markers were negative. Genetic alterations were investigated by targeted RNA sequencing, and a PTCH1-GLI1 fusion was detected. Epithelioid mesenchymal tumors harboring a PTCH1-GLI1 fusion are vanishingly rare with only three cases reported so far. Due to the unique location in the mucosa of the soft palate adjacent to minor salivary glands, multilobulated growth, nested epithelioid morphology, focal clearing of the cytoplasm, and immunopositivity for S100 protein and D2-40, the differential diagnoses include primary salivary gland epithelial tumors, in particular myoepithelioma and myoepithelial carcinoma. Another differential diagnostic possibility is the ectomesenchymal chondromyxoid tumor. Useful diagnostic clues for tumors with a GLI1 rearrangement include a rich vascular network between the nests of neoplastic cells, tumor tissue bulging into vascular spaces, and absence of SOX10, GFAP and cytokeratin immunopositivity. Identifying areas with features of GLI1-rearranged tumors should trigger subsequent molecular confirmation. This is important for appropriate treatment measures as PTCH1-GLI1 positive mesenchymal epithelioid neoplasms have a propensity for locoregional lymph node and distant lung metastases.

Bone invasion by oral squamous cell carcinoma.

BACKGROUND: With regards to the anatomical relationships in the mouth, oral squamous cell carcinoma can invade the maxilla or the mandible. According to the TNM system, tumours that invade through cortical bone are classified as T4a, stage IVA. Bone invasion by oral squamous cell carcinoma most often occurs in tumours close to the bone or in larger and more advanced tumours. It is considered an adverse prognostic factor and it is often a diagnostic and therapeutic problem. Destruction of the bone tissue is mediated by activated osteoclasts rather than directly by carcinoma. Tumor necrosis factors - receptor activator of NF-kB (RANK), receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) - play an important role in osteoclastogenesis. According to histological point of view, there are three patterns of bone invasion - erosive, mixed and infiltrative. The most commonly used imaging techniques when evaluating bone invasion by oral squamous cell carcinoma include CT and MRI. PURPOSE: This review is focused on the cellular and molecular mechanisms, histological patterns and detection methods of bone invasion caused by oral squamous cell carcinoma.

Thymoma - diagnostics options.

Various types of tumors (either benign or malignant) can be found in mediastinum. Early diagnosis and treatment may help to improve survival and quality if life in these patients. Compared to direct mediastinoscopy, used for obtaining a specimen for histological analysis in previous decades, modern imaging methods, specifically the CT navigated biopsy, represent an effective and less invasive approach to the diagnosis. In our publication, we present a patient with thymoma, rather rare type of anterior mediastinum tumor.

Prognostic and predictive markers for perineural and bone invasion of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a growing problem worldwide. Several biological and molecular criteria have been established for making a prognosis of OSCC. One of the most important factors affecting the risk of tumor recurrence and overall prognosis is perineural invasion and bone invasion. Perineural invasion is defined as a tumor spreading and the ability of tumor cells to penetrate around or through the nerve tissue. Perineural invasion can cause the tumor to spread to distant areas from the primary tumor location. One possible explanation for this is the formation of microenvironment in the perineural space which may contain cellular factors that act on both nerve tissue and some types of tumor tissues. Bone invasion by OSCC has major implications for tumor staging, choice of treatment, outcome and quality of life. Oral SCCs invade the mandibular or maxillary bone through an erosive, infiltrative or mixed pattern that correlates with clinical behavior. Bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. Some cytokines (e.g. TNFα and PTHrP) lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression in oral SCC cells and in cancer stromal cells to induce osteoclastogenesis. Oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. A more molecular-based clinical staging and tailor-made therapy would benefit patients with bone invasion by OSCC.

Elevated DNA methylation in malignant tumors of the sinonasal tract and its association with patient survival.

BACKGROUND: Epigenetic modifications have been recognized as an important mechanism underlying carcinoma progression. DNA methylation plays an important role in cancer biology and represents potentially heritable changes in gene expression that do not involve DNA sequence. The aim of this study was to investigate promoter methylation of selected genes in sinonasal carcinoma by comparison with noncancerous sinonasal tissue. METHODS: To search for epigenetic events (methylation in 25 tumor suppressor genes) we used MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification) to compare methylation status of 59 formalin fixed, paraffin embedded tissue samples of sinonasal carcinomas with 18 control samples. The most important changes in methylation were confirmed using MSP (Methylation specific PCR). Detected alterations in methylation were compared with clinicopathological characteristics. RESULTS: Using a 20% cut-off for methylation (MS-MLPA), we found significantly higher methylation in GATA5 (P=0.0005), THSB1 (P=0.0002) and PAX5 (P=0.03) genes in the sinonasal cancer group compared to the control group. Methylation in five or more genes was associated with impaired overall survival (P=0.017). CONCLUSION: These findings provide evidence that alterations in methylation profile may be one of the major mechanisms in sinonasal carcinogenesis. In addition, changes in methylation could potentially be used as prognostic factors of sinonasal carcinoma and may have implications for future individualized therapy based on epigenetic changes.

Deregulation of selected microRNAs in sinonasal carcinoma: Value of miR-21 as prognostic biomarker in sinonasal squamous cell carcinoma.

BACKGROUND: Tumors occurring in the sinonasal area are characterized by unfavorable outcome due to difficult diagnosis, treatment, and prognosis of the disease corresponding with the anatomic complexity of the area. METHODS: We used quantitative real-time polymerase chain reaction (PCR) to compare relative expression of miR-21, miR-141, and miR-200c in 70 formalin-fixed, paraffin-embedded samples of sinonasal carcinoma tissue (majority of squamous cell carcinoma [SCC] samples) with 17 control samples of sinonasal tissue. RESULTS: Our data showed significant upregulation of miR-21 in sinonasal cancer tissue. Expression levels of miR-141 and miR-200c were below detectable levels in both sinonasal cancer samples and healthy tissue. Kaplan-Meier analysis with log-rank survival showed that patients with SCC with high expression of miR-21 (highest quartile) had impaired survival close to reaching statistical significance (P = .0630). CONCLUSION: Our results suggest that miR-21 upregulation is involved in tumorigenesis of sinonasal carcinoma and that it is associated with poor prognosis. Thus, miR-21 could be used as a valuable prognostic biomarker.

SMARCB1/INI1-deficient sinonasal carcinoma shows methylation of RASSF1 gene: A clinicopathological, immunohistochemical and molecular genetic study of a recently described entity.

The aim of the study was detailed clinicopathological investigation of SMARCB1/INI1-deficient sinonasal carcinomas, including molecular genetic analysis of mutational status and DNA methylation of selected protooncogenes and tumor suppressor genes by means of next generation sequencing (NGS) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). A total of 4/56 (7%) cases of SMARCB1/INI1-deficient carcinomas were detected among 56 sinonasal carcinomas diagnosed over a 19year period using immunohistochemical screening. The series comprised 3 males and 1 female, aged 27-76 years (median 64 years). All tumors arose in the nasal cavity. Three neoplasms were diagnosed in advanced stage pT4. During the follow-up period (range 14-111 months (median 72 months)), three tumors recurred locally, but none of the patients developed regional or distant metastases. Ultimately, two patients died due to the tumor. Microscopically, all tumors consisted of infiltrating nests of polygonal basaloid cells with a variable component of rhabdoid cells with eosinophilic cytoplasm. Immunohistochemically, there was almost diffuse expression of cytokeratins (CK), p16, p40 and p63 in all cases, while expression of CK5/6, CK7 and vimentin was only focal or absent. The detection of NUT gave negative results. In three cases, the absence of SMARCB1/INI1 expression was due to deletion of SMARCB1/INI1 gene. Methylation of SMARCB1/INI1 gene was not found. One tumor harbored HPV18 E6/E7 mRNA. All 12 genes (BRAF, BRCA1, BRCA2, KIT, EGFR, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, RET, and ROS1) tested for mutations using NGS were wild-type. Regarding DNA methylation, all four SMARCB1/INI1-deficient tumors showed methylation of RASSF1 gene by means of MS-MLPA. There was a statistically significant difference in RASSF1 gene methylation between SMARCB1/INI1-deficient and SMARCB1/INI1-positive tumors (p=0.0095). All other examined genes (ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDKN1B, CDKN2A, CDKN2B, CHFR, DAPK1, ESR1, FHIT, GSTP1, HIC1, KLLN, MLH1a, MLH1b, RARB, and VLH) were unmethylated. In summary, we described four cases of SMARCB1/INI1-deficient sinonasal carcinoma with detailed clinicopathological data indicating that these tumors can be regarded as a distinct entity with aggressive behaviour. For the first time, we performed analysis of DNA methylation in SMARCB1/INI1-deficient sinonasal carcinomas, reporting on significantly higher methylation of RASSF1 gene in this neoplasm.

Oncolysate-loaded Escherichia coli bacterial ghosts enhance the stimulatory capacity of human dendritic cells.

The natural adjuvant properties of bacterial ghosts (BGs) lie within the presence of intact pathogen-associated molecular patterns on their surface. BGs can improve the direct delivery, natural processing and presentation of target antigens within dendritic cells (DCs). Moreover, sensitization of human DCs by cancer cell lysate (oncolysate)-loaded BGs in the presence of IFN-α and GM-CSF enhanced DC maturation as indicated by an increased expression of maturation markers and co-stimulatory molecules, higher production of IL-12p70 and stimulation of significantly increased proliferation of both autologous CD4+ and CD8+ T cells compared to DCs matured in the presence of purified lipopolysaccharide. The induced T cells efficiently recognized oncolysate-derived tumor-associated antigens expressed by cancer cells used for the production of oncolysate. Our optimized one-step simultaneous antigen delivery and DC maturation-inducing method emerges as a promising tool for the development and implementation of next-generation cellular cancer immunotherapies.

High-grade urothelial bladder cancer in children: A case report and critical analysis of the literature.

BACKGROUND: Bladder cancer is relatively common in adults. In children, it is extremely rare and in the majority of cases, low grade, low stage urothelial cancers are found. CASE REPORT: We describe the diagnostic, therapeutic, and follow-up management of bladder cancer in a 3-year-old boy examined for painless hematuria. Transurethral resection of the tumor was performed and T1 high grade urothelial cancer with osseous metaplasia was found in definitive specimens. During the 2-year follow-up, there has been no recurrence. Typical characteristics of the most prevalent bladder tumors are presented. CONCLUSION: Despite its low incidence and low prevalence bladder cancer in children is a very serious condition which must not be missed in the differential diagnosis of hematuria or urinary tract infection. It is vital to differentiate urothelial cancer from hamartoma and nephrogenic adenoma and, particularly in osseous metaplasia, from sarcomatoid carcinoma. Especially in high-grade cancers, precise TUR of the tumor with a careful follow-up is essential to detect cancer recurrence and reduce progression.

The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis.

The aim of the study was to investigate prevalence of high-risk human papillomavirus (HR-HPV) infection in sinonasal carcinomas by immunohistochemistry, in situ hybridization, and polymerase chain reaction, detecting p16(INK4a) protein (p16) expression and presence of both HPV DNA and HPV E6/E7 messenger RNA (mRNA). The study comprised 47 males and 26 females, aged 23-83 years (median 62 years), mostly (67 %) with a squamous cell carcinoma (SCC). Of the tumors, 53 % arose in the nasal cavity, 42 % in the maxillary sinus, and 5 % in the ethmoid complex. The follow-up period ranged 1-241 months (median 19 months). HPV16, HPV18, or HPV35 were detected in 18/73 (25 %) tumors, 17 SCCs, and 1 small cell neuroendocrine carcinoma. There was a strong correlation between results of HPV detection methods and p16 expression (p < 0.005). HPV-positive SCCs occurred more frequently in smokers (p = 0.04) and were more frequently p16-positive (p < 0.0001) and nonkeratinizing (p = 0.02), the latter occurring more commonly in nasal cavity (p = 0.025). Median survival for HPV-positive SCC patients was 30 months, while for HPV-negative SCC patients was 14 months (p = 0.23). In summary, we confirm that HR-HPV is actively involved in the etiopathogenesis of a significant subset of sinonasal SCCs. p16 may be used as a reliable surrogate marker for determination of HPV status also in sinonasal SCCs. Although we observed a trend toward better overall survival in HPV-positive SCCs, the prognostic impact of HPV status in sinonasal carcinomas needs to be elucidated by further studies.

Mesenchymal stromal cell labeling by new uncoated superparamagnetic maghemite nanoparticles in comparison with commercial Resovist--an initial in vitro study.

OBJECTIVE: Cell therapies have emerged as a promising approach in medicine. The basis of each therapy is the injection of 1-100×10(6) cells with regenerative potential into some part of the body. Mesenchymal stromal cells (MSCs) are the most used cell type in the cell therapy nowadays, but no gold standard for the labeling of the MSCs for magnetic resonance imaging (MRI) is available yet. This work evaluates our newly synthesized uncoated superparamagnetic maghemite nanoparticles (surface-active maghemite nanoparticles - SAMNs) as an MRI contrast intracellular probe usable in a clinical 1.5 T MRI system. METHODS: MSCs from rat and human donors were isolated, and then incubated at different concentrations (10-200 µg/mL) of SAMN maghemite nanoparticles for 48 hours. Viability, proliferation, and nanoparticle uptake efficiency were tested (using fluorescence microscopy, xCELLigence analysis, atomic absorption spectroscopy, and advanced microscopy techniques). Migration capacity, cluster of differentiation markers, effect of nanoparticles on long-term viability, contrast properties in MRI, and cocultivation of labeled cells with myocytes were also studied. RESULTS: SAMNs do not affect MSC viability if the concentration does not exceed 100 µg ferumoxide/mL, and this concentration does not alter their cell phenotype and long-term proliferation profile. After 48 hours of incubation, MSCs labeled with SAMNs show more than double the amount of iron per cell compared to Resovist-labeled cells, which correlates well with the better contrast properties of the SAMN cell sample in T2-weighted MRI. SAMN-labeled MSCs display strong adherence and excellent elasticity in a beating myocyte culture for a minimum of 7 days. CONCLUSION: Detailed in vitro tests and phantom tests on ex vivo tissue show that the new SAMNs are efficient MRI contrast agent probes with exclusive intracellular uptake and high biological safety.

MicroRNA profiling of activated and tolerogenic human dendritic cells.

Dendritic cells (DCs) belong to the immune system and are particularly studied for their potential to direct either an activated or tolerogenic immune response. The roles of microRNAs (miRNAs) in posttranscriptional gene expression regulation are being increasingly investigated. This study's aim is to evaluate the miRNAs' expression changes in prepared human immature (iDCs), activated (aDCs), and tolerogenic dendritic cells (tDCs). The dendritic cells were prepared using GM-CSF and IL-4 (iDC) and subsequently maturated by adding LPS and IFN-γ (aDC) or IL-10 and TGF-ß (tDC). Surface markers, cytokine profiles, and miRNA profiles were evaluated in iDC, tDC, and aDC at 6 h and 24 h of maturation. We identified 4 miRNAs (miR-7, miR-9, miR-155 and miR-182), which were consistently overexpressed in aDC after 6 h and 24 h of maturation and 3 miRNAs (miR-17, miR-133b, and miR-203) and miR-23b cluster solely expressed in tDC. We found 5 miRNAs (miR-10a, miR-203, miR-210, miR-30a, and miR-449b) upregulated and 3 miRNAs downregulated (miR-134, miR-145, and miR-149) in both tDC and aDC. These results indicate that miRNAs are specifically modulated in human DC types. This work may contribute to identifying specific modulating miRNAs for aDC and tDC, which could in the future serve as therapeutic targets in the treatment of cancer and autoimmune diseases.

[Dynamics of interleukin 6 levels in the patients with cardiogenic and septic shock and in a control group of patients with uncomplicated AMI]. / Dynamika hladiny interleukinu 6 u pacientu v septickém a kardiogenním soku a u pacientu s akutním infarktem myokardu s elevacemi ST.

INTRODUCTION: Cardiogenic shock (CS) is the leading cause of mortality in patients with acute myocardial infarction (AMI). Inflammatory response seems to be common response in patients with AMI, especially those with CS. We have therefore conducted a study to determine diagnostic and prognostic utility of interleukin 6 (IL6) levels in the cohort of patients with cardiogenic and septic shock (SS) and in a control group of patients with uncomplicated AMI. METHODS: In this prospective study 71 patients fulfilled the inclusion criteria: 30 patients with cardiogenic shock, 21 patients with septic shock and 20 patients with ST elevation myocardial infarction (STEMI). Plasma levels of IL6 were measured at 8 time points. The main endpoint was 3 month mortality. RESULTS: We have shown that the highest IL6 levels during the first week were recorded in patients with septic shock with peak value at admission. The maximum level of IL6 was detected between 12 to 24 hours after the onset of MI among patients with cardiogenic shock. According to Receiver operating characteristic (ROC) statistics levels of IL6 > 357 pg/ml at admission (AUC 0.730, p = 0.031) were typical for patients with CS in comparison with control group of STEMI patients. Values of IL6 > 1 237 pg/ml at admission and > 1 071 pg/ml at 24 hours (after admission?) were typical for thouse in septic shock in comparison with CS patients. We found only a non-significant trend of IL6 for the prediction of mortality in the cohort of CS patients for levels 1 854 pg/ml (AUC 0.769, p = 0.066) sampled 12 hours after admission. There was no association of plasma levels of IL6 with mortality in septic shock patients. CONCLUSIONS: Patients with cardiogenic shock demonstrated more pronounced cytokine response as evidenced by increased levels of IL6 compared to patients with uncomplicated STEMI. Levels of IL6 peaked in SS patients at admission, in CS patients 12-24 hours after admission. In daily clinical practice routine measurement of IL6 levels for prediction of prognosis both in cardiogenic and septic shock are of little value mainly due to significant interindividual variability of IL6 values.

Immune adjuvants as critical guides directing immunity triggered by therapeutic cancer vaccines.

Tumor growth is controlled by natural antitumor immune responses alone or by augmented immune reactivity resulting from different forms of immunotherapy, which has demonstrated clinical benefit in numerous studies, although the overall percentage of patients with durable clinical responses remains limited. This is attributed to the heterogeneity of the disease, the inclusion of late-stage patients with no other treatment options and advanced tumor-associated immunosuppression, which may be consolidated by certain types of chemotherapy. Despite variable responsiveness to distinct types of immunotherapy, therapeutic cancer vaccination has shown meaningful efficacy for a variety of cancers. A key step during cancer vaccination involves the appropriate modeling of the functional state of dendritic cells (DCs) capable of co-delivering four critical signals for proper instruction of tumor antigen-specific T cells. However, the education of DCs, either directly in situ, or ex vivo by various complex procedures, lacks standardization. Also, it is questioned whether ex vivo-prepared DC vaccines are superior to in situ-administered adjuvant-guided vaccines, although both approaches have shown success. Evaluation of these variables is further complicated by a lack of consensus in evaluating vaccination clinical study end points. We discuss the role of signals needed for the preparation of classic in situ and modern ex vivo DC vaccines capable of proper reprogramming of antitumor immune responses in patients with cancer.