OBJECTIVE: [ 177 Lu]Lu-PSMA radioligand therapy (PSMA-RLT) is a promising therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) and offers a survival benefit particularly to patients with only lymph node metastases. We therefore sought to evaluate the clinical outcome of this therapy in such a cohort. METHODS: Of all prostate cancer patients admitted to our department between September 2015 and March 2019 to receive 1-4 courses of PSMA-RLT (each course consisted of three cycles of highly standardized PSMA-RLT every 4 weeks), only 10 consecutive men were found to have nodal metastases only and were analyzed retrospectively. RESULTS: Nine out of 10 patients responded to their first PSMA-RLT course with a mean prostate-specific antigen (PSA) decline of 71.8 ± 25.2%, seven of them demonstrated a PSA decline of ≥50%. Collectively, seven of eight patients responded to further PSMA-RLT courses with a total PSA reduction of 59.8 ± 30.0%, five of which showed a PSA reduction of ≥50%. One patient experienced complete remission. Median progression-free survival was 85 weeks (range 14-255 weeks) and median overall survival was not reached during the median observation time of 209 weeks (30-298 weeks). Univariate Cox-regression identified initial PSA decline as the only predictive parameter for progression-free survival ( P = 0.047). CONCLUSION: mCRPC patients with only lymph node metastases showed favorable survival and excellent response to PSMA-RLT, leading to transient partial remission of the disease in most of them.

• MeSH
• dipeptidy terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické terapeutické užití   MeSH
• lidé MeSH
• lutecium terapeutické užití   MeSH
• lymfatické metastázy MeSH
• nádory prostaty rezistentní na kastraci * patologie   MeSH
• prostatický specifický antigen * MeSH
• radionuklidy MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. METHODS: Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. RESULTS: There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). CONCLUSION: Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.

• MeSH
• biologické markery metabolismus   MeSH
• idiopatické střevní záněty * diagnóza   metabolismus   patologie   MeSH
• kolorektální nádory * diagnóza   metabolismus   patologie   MeSH
• lidé MeSH
• metaloproteinasy secernované do matrix MeSH
• receptor pro konečné produkty pokročilé glykace metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. DESIGN: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. RESULTS: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. CONCLUSIONS: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.

• MeSH
• dospělí MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory slinných žláz genetika   MeSH
• onkogenní fúze genetika   MeSH
• protoonkogenní proteiny c-myb genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• sekreční karcinom mamárního typu genetika   MeSH
• senioři MeSH
• slinné proteiny a peptidy genetika   MeSH
• vimentin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• fúze genů MeSH
• lidé MeSH
• membránové proteiny MeSH
• nádory dělohy * MeSH
• nádory z pojivové a měkké tkáně * MeSH
• proteiny nervové tkáně MeSH
• proteiny vázající kalmodulin MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH

Adenine phosphoribosyltransferase (APRT) deficiency (OMIM #614723) is a rare autosomal recessive defect in the purine salvage pathway that causes excessive production of 2,8-dihydroxyadenine, leading to nephrolithiasis and chronic kidney disease (CKD). This case report describes the natural history of CKD in untreated APRT deficiency. We describe a novel APRT mutation (chr16:88877985 G / C; c.195 C>/G; p.His54Asp) presenting with CKD without nephrolithiasis. The patient initially required dialysis, but kidney function improved with allopurinol. We reviewed APRT deficiency reported in the literature to determine the loss of kidney function in individuals with untreated APRT deficiency and its relationship to nephrolithiasis. We identified 95 individuals in whom kidney function was assessed prior to treatment. There was a bimodal distribution of kidney failure. AKI occurred frequently in childhood due to obstructing nephrolithiasis or crystalline nephropathy and was usually reversible. CKD developed after age 20 in all patients irrespective of nephrolithiasis history, with 36/42 patients > 40 years of age having at least stage 3 CKD, and 24/42 having an eGFR > 10 mL/min/1.73m2 or being on dialysis. There were 13 adults without nephrolithiasis and 50 adults with nephrolithiasis. The mean age of end-stage renal diesease (ESRD) was 50.52 +/- 13.9 for those without nephrolithiasis and 43.4 +/- 15.8 years for those with nephrolithiasis (p = 0.24). APRT deficiency is associated with slowly progressive CKD that occurs independently of nephrolithiasis. Diagnosis should be considered in all individuals with chronic tubulointerstitial kidney disease, with or without the presence of nephrolithiasis. In our patient, allopurinol 300 mg/day resulted in improvement of kidney function..

• MeSH
• adeninfosforibosyltransferasa * nedostatek   MeSH
• alopurinol terapeutické užití   MeSH
• antimetabolity terapeutické užití   MeSH
• chronická renální insuficience * etiologie   MeSH
• hodnoty glomerulární filtrace MeSH
• intersticiální nefritida etiologie   komplikace   MeSH
• ledvinové kameny * etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• urolitiáza * komplikace   MeSH
• vrozené poruchy metabolismu * komplikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH

The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of this disease is unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298-768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405-either alone or in combination with rs74395342-affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically.

• MeSH
• alely MeSH
• dospělí MeSH
• exom genetika   MeSH
• Fanconiho syndrom genetika   patologie   MeSH
• genetická predispozice k nemoci MeSH
• heterozygot MeSH
• homozygot MeSH
• ledviny metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mapování chromozomů MeSH
• mitochondriální nemoci genetika   metabolismus   patologie   MeSH
• mitochondriální proteiny genetika   MeSH
• mitochondrie metabolismus   patologie   MeSH
• mutace MeSH
• plíce metabolismus   patologie   MeSH
• respirační komplex I genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Kanada MeSH

UNLABELLED: Ovarian carcinoids are very rare, and only their insular form is associated with carcinoid syndrome. We herein describe a case report of an elderly woman who presented with typical carcinoid syndrome, which is routinely characterized by right-sided heart failure, diarrhoea, flushes, and other common manifestations. Further examination and biochemical testing of the patient confirmed suspected carcinoid tumor. However, the tumor was surprisingly localized in the left ovary. The presence of the patient's severe combined tricuspid valve disease would create impossible surgical management conditions, so we decided to first perform cardio-surgery with tricuspid valve replacement. After tumor removal, levels of hydroxyindolacetic acid did not normalize and although the patient was asymptomatic, a small lesion was detected by tectrotyd scan paravertebrally. Treatment with lanreotide led to complete remission with negative biochemical and imaging signs of tumor. Thus, to summarize, carcinoid tumor even in an atypical localization (ovary) should be considered in elderly female patients with severe combined tricuspid valve disease due to carcinoid syndrome. KEY WORDS: Carcinoid syndrome; Ovarian carcinoid; Tricuspid valve.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Severe Acinetobacter baumannii infections in immunocompetent patients are uncommon, and the virulence mechanisms of this organism are not fully understood. METHODS: Following an outbreak of fatal A. baumannii infections in a cohort of relatively immunocompetent patients (low comorbidity and illness severity scores), isolates were investigated with comparative genomics and in animal models. RESULTS: Two unrelated A. baumannii clades were associated with the outbreak. The clone associated with the majority of patient deaths, clade B, is evolutionarily distinct from the 3 international clonal complexes, belongs to multilocus sequence type (MLST) 10, and is most closely related to strains isolated from the Czech Republic, California, and Germany in 1994, 1997, and 2003, respectively. In 2 different murine models, clade B isolates were more virulent than comparator strains, including the highly virulent reference strain AB5075. The most virulent clade B derivative, MRSN 16897, was isolated from the patient with the lowest combined comorbidity/illness severity score. Clade B isolates possess a unique combination of putative virulence genes involved in iron metabolism, protein secretion, and glycosylation, which was leveraged to develop a rapid and specific clinical assay to detect this clade that cannot be distinguished by MLST. CONCLUSIONS: Clade B warrants continued surveillance and investigation.

• MeSH
• Acinetobacter baumannii klasifikace   genetika   izolace a purifikace   patogenita   MeSH
• centra terciární péče statistika a číselné údaje   MeSH
• dospělí MeSH
• epidemický výskyt choroby * MeSH
• fylogeneze MeSH
• genomika MeSH
• imunokompetence MeSH
• infekce bakteriemi rodu Acinetobacter epidemiologie   genetika   mikrobiologie   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetná bakteriální léková rezistence * genetika   MeSH
• modely nemocí na zvířatech MeSH
• multilokusová sekvenční typizace MeSH
• myši MeSH
• senioři nad 80 let MeSH
• virulence genetika   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Geografické názvy
• Česká republika MeSH
• Kalifornie MeSH
• Německo MeSH
• Spojené státy americké MeSH

Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P<0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.

• MeSH
• Crohnova nemoc genetika   imunologie   MeSH
• dítě MeSH
• epigeneze genetická MeSH
• exprese genu MeSH
• kolon imunologie   MeSH
• lidé MeSH
• metylace DNA imunologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• slizniční imunita MeSH
• střevní sliznice imunologie   MeSH
• studie případů a kontrol MeSH
• ulcerózní kolitida genetika   imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Publikační typ
• abstrakt z konference MeSH