BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.
- MeSH
- antigeny CD278 metabolismus MeSH
- antigeny CD279 antagonisté a inhibitory MeSH
- antigeny CD28 MeSH
- CD8-pozitivní T-lymfocyty imunologie účinky léků metabolismus MeSH
- dospělí MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * farmakoterapie imunologie krev patologie MeSH
- nádory plic * farmakoterapie imunologie krev patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie imunologie krev patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.
- MeSH
- lidé MeSH
- melanom * genetika patologie mortalita MeSH
- mutace MeSH
- nádory kůže genetika patologie mortalita MeSH
- promotorové oblasti (genetika) * genetika MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- telomerasa * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Vitamin D deficiency associates with the risk of developing many diseases, including cancer. At the molecular level, vitamin D appears to have an antineoplastic effect. However, the role of vitamin D deficiency in cancer pathogenesis remains unelucidated and numerous studies have resulted in discordant results. This study aimed to determine whether vitamin D deficiency during melanoma diagnosis increases the risk of developing non-cutaneous second primary cancers (SPC). MATERIALS AND METHODS: A retrospective study on 663 patients diagnosed with melanoma between 1 January 2011 and 31 October 2022. The effect of each variable on the development of a subsequent non-cutaneous cancer was performed using Kaplan-Meier curves and differences were assessed by log-rank tests. Cox proportional hazard univariate and multivariate models were used to quantify the effect of each variable in the time to develop a non-cutaneous neoplasia. RESULTS: Out of 663 patients, 34 developed a non-cutaneous SPC. There was no statistically significant association between vitamin D levels and non-cutaneous SPC development (log-rank, p=0.761). Age>60 years, stage III/IV, and nodular melanoma subtype were significantly associated with the development of a SPC. After multivariate analysis, only age>60 years (HR 3.4; HR CI 95%: 1.5-7.6) and nodular melanoma subtype (HR 2.2; HR CI 95%: 1.0-4.8) were included in the final model. CONCLUSIONS: Our results suggest that vitamin D deficiency is not associated with an increased risk of developing non-cutaneous SPC in melanoma patients. However, age over 60 years and nodular melanoma subtype increase the risk for non-cutaneous SPC development.
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * epidemiologie etiologie diagnóza MeSH
- nádory kůže * etiologie komplikace MeSH
- nedostatek vitaminu D * komplikace epidemiologie MeSH
- retrospektivní studie MeSH
- sekundární malignity * epidemiologie etiologie MeSH
- vitamin D škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
Complex injuries to the posterior trunk can still pose a significant challenge to the reconstructive surgeon. Due to the lack of skin laxity, dependent anatomical location and the importance of the deeper structures, a systematic approach tailored to the individual defect should be considered for these types of reconstructions. In our case report, we present a reconstructive solution of a chronic defect of the back caused by resection of an ulceration. What was previously considered to be a relapse of a malignant melanoma turned out to be a chronic osteomyelitis of the spinous processes of the thoracic vertebrae. The defect after the resection of the ulceration and infected spinous processes of the thoracic vertebrae with exposed dorsal lamina was covered with pedicled myocutaneous flap. Reconstruction yielded well-vascularized tissue that provided sufficient volume and tissue quality. Even in the light of modern perforator flaps, local or locoregional muscle and myocutaneous flaps remain the first choice for the treatment of deep back defects. Considering all the factors in the given case, plastic surgeons are able to tailor the reconstructive technique to every individual case to match the desired reconstruction goal.
- MeSH
- chirurgické laloky * chirurgie MeSH
- dermatochirurgické výkony metody MeSH
- hrudní obratle chirurgie patologie MeSH
- lidé MeSH
- maligní melanom kůže komplikace MeSH
- osteomyelitida * chirurgie MeSH
- pooperační péče metody MeSH
- senioři MeSH
- stafylokokové infekce komplikace MeSH
- vřed chirurgie komplikace patologie MeSH
- záda chirurgie patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
Ambulantní chirurg se denně potýká s pacienty, kteří přichází pro různé pigmentové kožní léze. Řada pacientů přijde na doporučení dermatologa, ale u velké části pacientů je primární návštěva rovnou v chirurgické ambulanci. Důvodem k odstranění pigmentové léze může být nevyhovující kosmetický vzhled či častá iritace při nevhodném umístění léze, ale i strach z rozvoje malignity. Pigmentové léze kůže jsou velice heterogenní skupinou zastoupenou od benigních névů až po maligní melanom. Vyskytují se ve všech věkových skupinách. V raném věku se nejčastěji řeší kongenitální névy a hemangiomy, s narůstajícím věkem se pak zvyšuje incidence kožních malignit. Ambulantní chirurg často stojí před rozhodnutím, zda a jak radikálně pigmentovou lézi odstranit. Kožní projevy, jako je lentigo solaris, není nutné řešit chirurgicky. Jiné léze, jako např. bazocelulární karcinom, vyžadují radikální excizi a následnou odbornou dispenzarizaci. Léčba melanomu je však komplexní, je vedena specialisty v dermatoonkologických centrech, a proto je nezbytný multioborový přístup. Každý ambulantní chirurg by měl být dostatečně erudovaný a zkušený, aby byl schopen o nutnosti odstranění pigmentové léze rozhodnout a v případě nejistoty odkázat pacienta ke kožnímu specialistovi. Tento článek přináší stručný přehled a specifika základních kožních pigmentových projevů a kritéria pro jejich chirurgické odstranění.
The ambulatory surgeon deals daily with patients who come for various pigmented skin lesions. A number of patients come on the recommendation of a dermatologist, but for the majority of patients, the primary visit is directly to the surgical clinic. The reason for removing a pigmented lesion may be an unsatisfactory cosmetic appearance or frequent irritation due to inappropriate location of the lesion, but also the fear of the development of malignancy. Pigmented lesions of the skin are a very heterogeneous group represented from benign nevi to malignant melanoma. They occur in all age groups. Congenital nevi and hemangiomas are most often treated at an early age, and the incidence of skin malignancies increases in older patients. The ambulatory surgeon is often faced with the decision whether and how radically the pigmented lesion needs to be removed. Skin lesions such as lentigo solaris do not need to be treated surgically. Other lesions, such as basal cell carcinoma, require radical excision and subsequent professional dispensary. However, the treatment of melanoma is complex, it is led by specialists in dermato-oncology centers and therefore interdisciplinary approach is necessary. Every ambulatory surgeon should be knowledgeable and experienced enough to be able to decide on the need for removal of pigmented lesions and, in case of uncertainty, refer the patient to a skin specialist. This article provides a brief overview and specifics of basic skin pigment manifestations and criteria for their surgical removal.
Breast cancer is the most frequently diagnosed cancer in women worldwide. Although dramatically increased survival rates of early diagnosed cases have been observed, late diagnosed patients and metastatic cancer may still be considered fatal. The present study's main focus was on cancer‐associated fibroblasts (CAFs) which is an active component of the tumor microenvironment (TME) regulating the breast cancer ecosystem. Transcriptomic profiling and analysis of CAFs isolated from breast cancer skin metastasis, cutaneous basal cell carcinoma, and squamous cell carcinoma unravelled major gene candidates such as IL6, VEGFA and MFGE8 that induced co‐expression of keratins‐8/‐14 in the EM‐G3 cell line derived from infiltrating ductal breast carcinoma. Western blot analysis of selected keratins (keratin‐8, ‐14, ‐18, ‐19) and epithelial‐mesenchymal transition‐associated markers (SLUG, SNAIL, ZEB1, E‐/N‐cadherin, vimentin) revealed specific responses pointing to certain heterogeneity of the studied CAF populations. Experimental in vitro treatment using neutralizing antibodies against IL-6, VEGF‐A and MFGE8 attenuated the modulatory effect of CAFs on EM‐G3 cells. The present study provided novel data in characterizing and understanding the interactions between CAFs and EM‐G3 cells in vitro. CAFs of different origins support the pro‐inflammatory microenvironment and influence the biology of breast cancer cells. This observation potentially holds significant interest for the development of novel, clinically relevant approaches targeting the TME in breast cancer. Furthermore, its implications extend beyond breast cancer and have the potential to impact a wide range of other cancer types.
- MeSH
- antigeny povrchové MeSH
- fibroblasty asociované s nádorem * metabolismus MeSH
- fibroblasty metabolismus MeSH
- keratiny genetika metabolismus MeSH
- lidé MeSH
- maligní melanom kůže MeSH
- MFC-7 buňky MeSH
- mléčné bílkoviny genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí genetika MeSH
- nádory prsu * farmakoterapie genetika metabolismus MeSH
- prognóza MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Cíl: Prezentovat vzácný případ leiomyomu řasnatého tělesa naší pacientky. Kazuistika: 72letá pacientka přichází na preventivní vyšetření do naší ambulance, kde nalézáme v periferii sítnice kopulovitý šedo-hnědavý útvar. Po doplnění gonioskopického a ultrazvukového vyšetření posíláme pacientku na pracoviště vyššího typu. Pro nález suspektního maligního melanomu doplňujeme vyšetření magnetické rezonance a doporučujeme enukleaci bulbu. Histopatologické vyšetření prokazuje leiomyom řasnatého tělesa. Závěr: Cílem kazuistiky je demonstrovat obtížnost diagnostiky nitroočního leiomyomu. Až imunohistochemické vyšetření odlišilo tumor od maligního melanomu a ukázalo na diagnózu leiomyomu řasnatého tělesa. Možná i pro extrémní vzácnost tohoto typu nádoru na diagnózu leiomyomu málo pomýšlíme.
Aim: To demonstrate a rare case of ciliary body leiomyoma in our patient Case report: A 72-year-old female reported to our clinic for a preventive examination, upon which we found a dome-shaped grey-brownish mass on the retinal periphery. After completing gonioscopic and ultrasound examinations, we referred the patient to a specialist facility. Due to a finding of suspicious malignant melanoma, we completed the MRI scan and recommended enucleation of the eyeball. A histopathological examination showed a leiomyoma of the ciliary body. Conclusion: The aim of this case report is to demonstrate the difficulty of intraocular leiomyoma diagnosis. Only immunohistochemical examination differentiated the tumor from malignant melanoma and determined the diagnosis of ciliary body leiomyoma. Perhaps because of the extreme rarity of this type of tumor, we often neglect to consider a diagnosis of leiomyoma.
- MeSH
- corpus ciliare * diagnostické zobrazování patologie MeSH
- diferenciální diagnóza MeSH
- enukleace oka klasifikace metody MeSH
- leiomyom * diagnostické zobrazování diagnóza klasifikace MeSH
- lidé MeSH
- melanom diagnóza patologie MeSH
- nádory oka diagnostické zobrazování diagnóza klasifikace patologie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
We report a very unusual case of melanocytic neoplasm appearing clinically as a 0.5-cm dome-shaped pigmented papule on the chest of a 63-year-old man. Microscopically, it was an asymmetric, entirely dermally based neoplasm characterized by a multinodular, vaguely plexiform architecture composed of moderately pleomorphic spindled melanocytes with ample, dusty pigmented cytoplasm and scattered multinucleated cells. The tumor cells were strongly positive for Melan-A, HMB45, S100, and PRAME, whereas p16 showed diffuse nuclear loss. β-catenin presented a strong and diffuse cytoplasmic staining, while nuclei were negative. Despite an increased cellularity, mitotic count was low (1/mm 2 ). Fluorescence in situ hybridization revealed no copy number alteration in melanoma-related genes ( CDKN2A, MYB, MYC, CCND1 and RREB1 ). DNA and RNA sequencing identified KIT c.2458G>T and APC c.6709C>T mutations. No further genetic alteration was detected including TERT-promoter (TERT-p ) hot-spot mutation. A re-excision was performed. A sentinel lymph node biopsy was negative. Clinical investigations revealed no extracutaneous involvement. The patient is disease-free after a follow-up period of 8 months. Given the peculiar morphologic and molecular findings, we hypothesize the lesion may represent a novel subtype of an intermediate grade melanocytic tumor (melanocytoma).
- MeSH
- antigeny nádorové MeSH
- biopsie sentinelové lymfatické uzliny MeSH
- hybridizace in situ fluorescenční MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanocyty patologie MeSH
- melanom * patologie MeSH
- mutace MeSH
- nádory kůže * patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- MeSH
- doxorubicin farmakologie terapeutické užití MeSH
- inhibitory kontrolních bodů klasifikace terapeutické užití MeSH
- ipilimumab farmakologie terapeutické užití MeSH
- leiomyosarkom farmakoterapie MeSH
- melanom diagnóza farmakoterapie MeSH
- nádory žaludku farmakoterapie MeSH
- nivolumab farmakologie terapeutické užití MeSH
- protokoly protinádorové léčby MeSH
- trabektedin farmakologie terapeutické užití MeSH
- Publikační typ
- souhrny MeSH
The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
- MeSH
- eukaryotický iniciační faktor 4F * metabolismus genetika MeSH
- extracelulárním signálem regulované MAP kinasy metabolismus MeSH
- fosfatasa 6 s dvojí specificitou metabolismus genetika MeSH
- GTP-fosfohydrolasy * metabolismus genetika MeSH
- lidé MeSH
- MAP kinasový signální systém * genetika MeSH
- melanom * genetika metabolismus patologie MeSH
- membránové proteiny * metabolismus genetika MeSH
- mutace * MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protoonkogenní proteiny B-Raf * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
