Autoimmune response to cutaneous basement membrane components superimposed on a genetic skin fragility disease, hereditary epidermolysis bullosa (EB), has been described, but its effects on disease ...course remain unclear. We report a 69-year-old individual with congenital skin fragility and acral trauma-induced blistering that had suddenly worsened with the onset of severe itch and diffuse spontaneous inflammatory blisters. Next-generation sequencing identified compound heterozygous null and missense
COL7A1
mutations, allowing the diagnosis of recessive dystrophic EB. However, the patient’s clinical history prompted us to investigate whether he might have developed a pathological autoimmune response against basement membrane components. Tissue-bound and circulating IgG antibodies to the major bullous pemphigoid (BP) antigen, BP180, were detected in the patient’s skin and serum, respectively, consistent with a diagnosis of BP. Corticosteroid therapy was initiated resulting in remission of BP manifestations. EB patients presenting rapid disease worsening should be investigated for the development of a concomitant autoimmune blistering disease.
ObjectivesKidney cancer has been identified as a disease for which screening might provide significant benefit for patients. The aim of this study was to understand in detail the facilitators and ...barriers towards uptake of a future kidney cancer screening programme, and to compare these across four proposed screening modalities.DesignAn online survey including free-text responses.SettingUKParticipants668 adultsPrimary and secondary outcome measuresThe survey assessed participants’ self-reported intention to take-up kidney cancer screening with four different test methods (urine test, blood test, ultrasound scan and low-dose CT). We conducted thematic analysis of 2559 free-text comments made within the survey using an inductive approach.ResultsWe identified five overarching themes that influenced screening intention: ‘personal health beliefs’, ‘practicalities’, ‘opinions of the test’, ‘attitudes towards screening’ and ‘cancer apprehension’. Overall, participants considered the tests presented as simple to complete and the benefits of early detection to outweigh any drawbacks to screening. Dominant facilitators and barriers varied with patterns of intention to take up screening across the four tests. Most intended to take up screening by all four tests, and for these participants, screening was seen as a positive health behaviour. A significant minority were driven by practicalities and the risks of the tests offered. A smaller proportion intended to reject all forms of screening offered, often due to fear or worry about results and unnecessary medical intervention or a general negative view of screening.ConclusionsMost individuals would accept kidney cancer screening by any of the four test options presented because of strong positive attitudes towards screening in general and the perceived simplicity of the tests. Providing information about the rationale for screening in general and the potential benefits of early detection will be important to optimise uptake among uncertain individuals.
Small-cell lung cancer is an extremely chemo-sensitive disease; the addition of immunotherapy to chemotherapy has demonstrated a slight clinical benefit in pivotal trials, even with a statistically ...significant difference in terms of survival outcomes when compared to chemotherapy alone. In this scenario, the role of radiotherapy as a consolidation treatment in thoracic disease or as a prophylactic therapy in the brain should be clarified. In addition, due to the frailty and the poor prognostic characteristics of these patients, the need for predictive biomarkers that could support the use of immunotherapy is crucial. PD-L1 and TMB are not actually considered definitive biomarkers due to the heterogeneity of results in the literature. A new molecular classification of small-cell lung cancer based on the expression of key transcription factors seems to clarify the disease behavior, but the knowledge of this molecular subtype is still insufficient and the application in clinical practice far from reality; this classification could lead to a better understanding of SCLC disease and could provide the right direction for more personalized treatment. The aim of this review is to investigate the current knowledge in this field, evaluating whether there are predictive biomarkers and clinical patient characteristics that could help us to identify those patients who are more likely to respond to immunotherapy.
The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), ...characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the "CNS tumor with EP300:BCOR(L1) fusion" methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD.
Timely diagnosis of bladder and kidney cancer is key to improving clinical outcomes. Given the challenges of early diagnosis, models incorporating clinical symptoms and signs may be helpful to ...primary care clinicians when triaging at-risk patients.
To identify and compare published models that use clinical signs and symptoms to predict the risk of undiagnosed prevalent bladder or kidney cancer.
Systematic review.
A search identified primary research reporting or validating models predicting the risk of bladder or kidney cancer in MEDLINE and EMBASE. After screening identified studies for inclusion, data were extracted onto a standardised form. The risk models were classified using TRIPOD guidelines and evaluated using the PROBAST assessment tool.
The search identified 20 661 articles. Twenty studies (29 models) were identified through screening. All the models included haematuria (visible, non-visible, or unspecified), and seven included additional signs and symptoms (such as abdominal pain). The models combined clinical features with other factors (including demographic factors and urinary biomarkers) to predict the risk of undiagnosed prevalent cancer. Several models (
= 13) with good discrimination (area under the receiver operating curve >0.8) were identified; however, only eight had been externally validated. All of the studies had either high or unclear risk of bias.
Models were identified that could be used in primary care to guide referrals, with potential to identify lower-risk patients with visible haematuria and to stratify individuals who present with non-visible haematuria. However, before application in general practice, external validations in appropriate populations are required.
Brain tumors are the leading cause of cancer‐related death in children. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of pediatric brain cancers are ...limited and hard to establish. We present a protocol that enables efficient generation, expansion, and biobanking of pediatric brain cancer organoids. Utilizing our protocol, we have established patient‐derived organoids (PDOs) from ependymomas, medulloblastomas, low‐grade glial tumors, and patient‐derived xenograft organoids (PDXOs) from medulloblastoma xenografts. PDOs and PDXOs recapitulate histological features, DNA methylation profiles, and intratumor heterogeneity of the tumors from which they were derived. We also showed that PDOs can be xenografted. Most interestingly, when subjected to the same routinely applied therapeutic regimens, PDOs respond similarly to the patients. Taken together, our study highlights the potential of PDOs and PDXOs for research and translational applications for personalized medicine.
Synopsis
Patient‐derived organoids (PDOs) and patient‐derived xenograft organoids (PDXOs) have been established through direct in vitro culture of primary tumors and patient‐derived xenograft (PDX)‐derived tumors with the goal to better model pediatric tumors of the central nervous system.
PDOs recapitulate cellular heterogeneity, histological features, mutational profiles (number of variants, microsatellite instability, tumor mutational burden) of the corresponding parental tumor even after 1 year of in vitro culture
ZFTA‐RELA EPN‐ and G3 MB‐PDOs recapitulate patients' response to routinely applied therapeutic regimens
Several PDOs and PDXOs were derived from human tumors for which there are currently very limited in vivo and in vitro models available
PDOs and PDXOs are available to the research community, and can be subjected to genetic manipulations, to drug screening, and translational applications for personalized medicine
Patient‐derived organoids (PDOs) and patient‐derived xenograft organoids (PDXOs) have been established through direct in vitro culture of primary tumors and patient‐derived xenograft (PDX)‐derived tumors with the goal to better model pediatric tumors of the central nervous system.
Culuccia is a small peninsula of about 3 km
placed in north-western Sardinia (Italy) at the margin of the Maddalena Archipelago. The marine area surrounding this Peninsula is a Special Area of ...Conservation, included in the European Natura 2000 Ecological Network of protected areas, but until now, no information on biodiversity of this area is available. In 2021, a research project to study both terrestrial and marine biodiversity of Culuccia has started in order to fill this gap of knowledge.
This work provides the first inventory of the marine malacofauna of the coast of Culuccia. Fifteen sites were sampled seasonally for one-year by using different sampling methods and the present study shows the results from approximately 50 scientific SCUBA and free dive surveys, carried out in all main marine habitats of the studied area. In total, 259 species of molluscs were recorded along the coasts of the Culuccia Peninsula (0-25 m depth), belonging to the classes Bivalvia, Gastropoda, Polyplacophora and Scaphopoda. Amongst the four classes recorded, gastropods were the most represented (66.90%; 173 species), followed by bivalves (28.10%; 73 species), polyplacophorans (4.60%; 12 species) and scapophods (0.40%; 1 species). Notes about distribution, conservation status and ecology for some valuable species are provided, together with images of representative species, consisting mainly of
photographs. Additionally, the present investigation recorded the presence of four alien species, whose Mediterranean distribution was extended to north-western Sardinia.
Kidney cancer is often asymptomatic, leading to proposals for a screening programme. The views of the public towards introducing a new screening programme for kidney cancer are unknown. The aim of ...this study was to explore attitudes towards kidney cancer screening and factors influencing intention to attend a future screening programme.
We conducted an online population-based survey of 1021 adults aged 45-77 years. The main outcome measure was intention to attend four possible screening tests (urine, blood, ultrasound scan, low-dose CT) as well as extended low-dose CT scans within lung cancer screening programmes. We used multivariable regression to examine the association between intention and each screening test.
Most participants stated that they would be 'very likely' or 'likely' to undergo each of the screening tests urine test: n = 961 (94.1%); blood test: n = 922 (90.3%); ultrasound: n = 914 (89.5%); low-dose CT: n = 804 (78.8%); lung CT: n = 962 (95.2%). Greater intention to attend was associated with higher general cancer worry and less perceived burden/inconvenience about the screening tests. Less worry about the screening test was also associated with higher intention to attend, but only in those with low general cancer worry (cancer worry scale ≤ 5). Compared with intention to take up screening with a urine test, participants were half as likely to report that they intended to undergo blood OR 0.56 (0.43-0.73) or ultrasound OR 0.50 (0.38-0.67) testing, and half as likely again to report that they intended to take part in a screening programme featuring a low dose CT scan for kidney cancer screening alone OR 0.19 (0.14-0.27).
Participants in this study expressed high levels of intention to accept an invitation to screening for kidney cancer, both within a kidney cancer specific screening programme and in conjunction with lung cancer screening. The choice of screening test is likely to influence uptake. Together these findings support on-going research into kidney cancer screening tests and the potential for combining kidney cancer screening with existing or new screening programmes.
Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in
,
, or
genes encoding keratins of suprabasal epidermis. Characteristic clinical ...features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to
or
mutations (7 and 9 cases, respectively); (ii)
-mutated ichthyosis with confetti (2 cases); (iii)
-mutated superficial epidermolytic ichthyosis (5 cases); and (iv)
-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the
gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic
mutation.
Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults, with no effective treatment. These highly heterogeneous malignancies arise in different ...sites of the Central Nervous System (CNS), carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity). Moreover, deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity). Despite the recent advances made in the field, the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers. In order to fill the existing gap, we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity. This is one of the most advanced technologies of the "-omics" era that, using antibodies conjugated to heavy metals, allows the simultaneous measurement of more than 40 markers at single-cell level. To this end, we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups. By using a panel of 15 antibodies, directly conjugated to metals or specifically customized to detect important histone variants, significant differences were highlighted in the expression of the considered antigens. The single-cell multiparametric approach realized has deepened our understanding of PDHGG, confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups.
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