BACKGROUND AND OBJECTIVE: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is a rare variant of malignant pancreatic tumor. There is still no standardized treatment for this uncommon subtype, as surgical resection with lymphadenectomy is the only potentially curative treatment so far. In this paper, we describe the current knowledge of this very rare specific subtype of pancreatic cancer (PC) as a narrative review. METHODS: For this review, we did not specify the time range of studies referred to due to limited data availability. Our inclusion criteria comprised previous studies, which specifically focused on the rare UCOGC subtype of PC as a confirmed histopathology, either pure or present together with other subtypes. We disregarded the studies involving any other PC subtype but not UCOGC, including undifferentiated and anaplastic carcinomas without osteoclast-like giant cell components. KEY CONTENT AND FINDINGS: The limited available data precludes a definitive assessment of the efficacy of both neoadjuvant and adjuvant chemotherapy in the treatment of UCOGC. Monoclonal antibody pembrolizumab has been proven to be effective in metastatic cases. Multiple cases demonstrate a better overall survival rate for patients with UCOGC only versus those having UCOGC as a component with a pancreatic ductal adenocarcinoma (PDAC) histopathological subtype. The same conclusion can be also drawn comparing the survival rate of patients having pure UCOGC versus UCOGC with associated PDAC. Programmed cell death ligand-1 expression has been shown to be an important determinant, which shortens the survival period of patients diagnosed with UCOGC. CONCLUSIONS: The rarity of UCOGC limits data for clinical courses and treatment plans. We need more data to better understand the relationship between pathogenic mutations, histological subtypes, and prognosis in PC, including UCOGC. Understanding UCOGC's molecular, clinical, radiological, and pathological characteristics can lead to earlier, more accurate diagnoses and better management.

• Publication type
• Journal Article MeSH
• Review 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
• Humans MeSH
• Melanoma * genetics   pathology   mortality   MeSH
• Mutation MeSH
• Skin Neoplasms genetics   pathology   mortality   MeSH
• Promoter Regions, Genetic * genetics   MeSH
• Cross-Sectional Studies MeSH
• Retrospective Studies MeSH
• Telomerase * genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

AIMS: Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. METHODS AND RESULTS: Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. CONCLUSION: EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

• MeSH
• Child MeSH
• DNA-Binding Proteins genetics   MeSH
• Adult MeSH
• Gene Fusion MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• RNA-Binding Protein EWS genetics   MeSH
• RNA-Binding Proteins genetics   MeSH
• Retrospective Studies MeSH
• Rhabdomyosarcoma * genetics   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcription Factors * genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Middle Aged MeSH
• Humans MeSH
• Melanoma * epidemiology   etiology   diagnosis   MeSH
• Skin Neoplasms * etiology   complications   MeSH
• Vitamin D Deficiency * complications   epidemiology   MeSH
• Retrospective Studies MeSH
• Neoplasms, Second Primary * epidemiology   etiology   MeSH
• Vitamin D adverse effects   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH

Poznatky o molekulárních subtypech karcinomu endometria (EC) vedly v posledních několika letech k velkým změnám v klasifikačním systému, v prognostických skupinách a ve svém důsledku v terapeutických postupech u pacientek s pokročilým, metastatic­kým a recidivujícím karcinomem endometria. Nejvýznamnějším posunem v obtížně léčitelné kohortě pacientek s pokročilým, metastatickým a recidivujícím EC od dob konvenční chemoterapie je jednoznačně kombinace checkpoint inhibitoru pembrolizumabu s antiangiogenním preparátem lenvatinibem, nezávislá na přítomnosti mikrosatelitové nestability (MSI) nádorových buněk. Ve skupině MSI-high karcinomů se jako velmi úspěšné jeví podání dostarlimabu v monoterapii. iPARP byly vyšetřovány v mnoha terapeutických designech a je evidentní, že jejich léčebné využití bude u pacientek s EC s deficitem v homologní rekombinaci, bez ohledu na BRCA status. Mechanizmus účinku iPARP je u pacientek s EC založený na frekventní přítomnosti PTEN mutace a mutace TP53, jež souvisí právě s deficitem v homologní rekombinaci. iPARP mají jednak vlastní cytotoxický účinek a jednak senzitizují buňky EC k účinkům checkpoint inhibitorů. Ve sdělení je sumarizována současná evidence o preklinickém výzkumu a klinickém využití iPARP u pacientek s pokročilým, metastatickým a rekurentním EC. Nově je v České republice olaparib schválen k podávání v udržovací léčbě v kombinaci s durvalumabem u pacientek s primárně pokročilým nebo rekurentním EC (mismatch repair proficientním - pMMR), které neprogredovaly na I. linii systémové terapie v kombinaci paclitaxel, karboplatina a durvalumab.

Knowledge of molecular subtypes of endometrial cancer (EC) has led to major changes in the classification system, prognostic groups and, as a result, in therapeutic procedures in patients with advanced, metastatic and recurrent endometrial cancer (EC) in the last few years. The most significant shift in the difficult-to-treat cohort of patients with advanced, metastatic and recurrent EC since conventional chemotherapy is clearly the combination of the checkpoint inhibitor pembrolizumab with the antiangiogenic agent lenvatinib, independent of the presence of microsatellite instability (MSI) of tumor cells. In the MSI-high group of carcinomas, the administration of dostarlimab monotherapy appears to be very successful. iPARPs have been investigated in many therapeutic designs and it is evident that their therapeutic use will be in EC patients with homologous recombination deficiency, regardless of BRCA status. The mechanism of action of iPARP in EC patients is based on the frequent presence of PTEN mutation and TP53 mutation, which is related to the deficit in homologous recombination. iPARPs have both their own cytotoxic effect and sensitize EC cells to the effects of checkpoint inhibitors. The article summarizes the current evidence on preclinical research and clinical use of iPARP in patients with advanced, metastatic and recurrent EC. In the Czech Republic, olaparib is newly approved for administration in maintenance therapy in combination with durvalumab in patients with primarily advanced or recurrent EC (mismatch repair proficient - pMMR) who have not progressed on first-line systemic therapy in combination with paclitaxel, carboplatin and durvalumab.

• MeSH
• Molecular Targeted Therapy MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   therapeutic use   MeSH
• Immune Checkpoint Inhibitors therapeutic use   MeSH
• Humans MeSH
• Endometrial Neoplasms * diagnosis   drug therapy   genetics   pathology   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors administration & dosage   pharmacology   therapeutic use   MeSH
• Antineoplastic Agents, Immunological administration & dosage   therapeutic use   MeSH
• Antineoplastic Protocols MeSH
• Genes, Tumor Suppressor MeSH
• Check Tag
• Humans MeSH

Circulating endometrial cells (CECs) have emerged as a new biomarker of advanced disease in women with endometriosis. The identification of several subtypes of CECs (e.g., stem cell-like, epithelial, glandular, stromal) has opened the way for characterization of endometriosis-associated CECs. This study focused on the isolation and characterization of CECs and disseminated endometrial cells (DECs) in patients with spontaneous pneumothorax (SP). The primary objective was to differentiate between cancer and non-cancer cells in patients with no previous cancer diagnosis. The MetaCell® size-based separation protocol was used to enrich CECs/DECs. Evaluation of the captured cells by 3D microscopy was performed using a NANOLIVETM microscope using a holographic approach. Based on gene expression analysis (GEA), we can conclude that mitochondria are much more active in primary tumors compared to endometriosis tissue (e.g. MT-ND1, MT-ATP6 genes). The culture of DECs is made of stromal, stem and immune cells. In vitro culture of DECs is characterized by an increase in the epithelial marker KRT18. Similarly, NFE2L2, a proerythroid factor, is also elevated. Further, a significant decrease in the amount of stem and immune cells was observed in the cell culture of DECs. The data presented here show how morphologically plastic the changes in the mitochondrial network can be and how cells can reflect them at the level of gene expression. The markers identified could help in the accompanying diagnostic process of the spontaneous pneumothorax in women of reproductive age.

• MeSH
• Adult MeSH
• Endometriosis * pathology   diagnosis   genetics   MeSH
• Endometrium pathology   metabolism   MeSH
• Humans MeSH
• Mitochondria * metabolism   pathology   MeSH
• Pneumothorax * pathology   diagnosis   MeSH
• Gene Expression Profiling methods   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The interaction between the main psychotropic ingredient of Cannabis, Δ9- tetrahydrocannabinol (THC), with the endogenous cannabinoid system (ECS) is a critical and underrated issue that deserves utmost attention. The ECS, indeed, contributes to the formation and regulation of excitatory and inhibitory (E/I) neuronal networks that in the hippocampus underly spatial memory. This study explored sex-specific consequences of prenatal exposure to THC in hippocampus-dependent memory and the underlying cellular and molecular contributors of synaptic plasticity and E/I homeostasis. Sprague Dawley dams were exposed to THC (2 mg/kg) or vehicle, from gestational day 5-20. The adolescent progeny of both sexes was tested for: spatial memory retrieval and flexibility in the Barnes Maze; mRNA expression of relevant players of hippocampal synaptic plasticity; density of cholecystokinin-positive basket cells (CCK+BCs) - a major subtype of hippocampal inhibitory interneurons; mRNA expression of the excitatory and inhibitory synaptic proteins neuroligins (Nlgns), as a proxy of synaptic efficiency. Our results show a sex-specific disruption in spatial memory retrieval and flexibility, a male-specific decrease in CCK+BCs density and increase in the expression of markers of neuroplasticity, and consistent changes in the expression of Nlgn-1 and 3 isoforms. Despite a delay in memory retrieval, flexibility of memory was spared in prenatally-THC-exposed female offspring as well as most of the markers of neuroplasticity; a sex-specific increase in CCK+BCs density, and a consistent expression of Nlgn-3 was observed. The current results highlight a major vulnerability to prenatal exposure to THC on memory processing in the male progeny, and sex-specific alterations in the E/I balance and synaptic plasticity.

• MeSH
• Maze Learning drug effects   MeSH
• Cholecystokinin metabolism   MeSH
• Hippocampus * drug effects   metabolism   MeSH
• Rats MeSH
• Neuronal Plasticity * drug effects   MeSH
• Sex Characteristics * MeSH
• Rats, Sprague-Dawley * MeSH
• Spatial Memory * drug effects   MeSH
• Pregnancy MeSH
• Dronabinol * pharmacology   toxicity   MeSH
• Prenatal Exposure Delayed Effects * chemically induced   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

• MeSH
• Child MeSH
• Phenotype MeSH
• Glioma * genetics   pathology   diagnostic imaging   MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Adolescent MeSH
• Brain Neoplasms * genetics   pathology   diagnostic imaging   MeSH
• Neoplasms, Neuroepithelial * genetics   pathology   diagnostic imaging   MeSH
• Child, Preschool MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article 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
• Antigens, Neoplasm MeSH
• Sentinel Lymph Node Biopsy MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanocytes pathology   MeSH
• Melanoma * pathology   MeSH
• Mutation MeSH
• Skin Neoplasms * pathology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

BACKGROUND: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. METHODS: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. RESULTS: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. CONCLUSIONS: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.

• MeSH
• Lymphoma, Large-Cell, Anaplastic * genetics   pathology   drug therapy   MeSH
• Phenotype MeSH
• Cadherins * genetics   MeSH
• Humans MeSH
• Mutation * MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Prognosis MeSH
• Exome Sequencing MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH