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The introduction of deep learning caused a significant breakthrough in digital pathology. Thanks to its capability of mining hidden data patterns in digitised histological slides to resolve diagnostic tasks and extract prognostic and predictive information. However, the high performance achieved in classification tasks depends on the availability of large datasets, whose collection and preprocessing are still time-consuming processes. Therefore, strategies to make these steps more efficient are worth investigation. This work introduces SlideTiler, an open-source software with a user-friendly graphical interface. SlideTiler can manage several image preprocessing phases through an intuitive workflow that does not require specific coding skills. The software was designed to provide direct access to virtual slides, allowing custom tiling of specific regions of interest drawn by the user, tile labelling, quality assessment, and direct export to dataset directories. To illustrate the functions and the scalability of SlideTiler, a deep learning-based classifier was implemented to classify 4 different tumour histotypes available in the TCGA repository. The results demonstrate the effectiveness of SlideTiler in facilitating data preprocessing and promoting accessibility to digitised pathology images for research purposes. Considering the increasing interest in deep learning applications of digital pathology, SlideTiler has a positive impact on this field. Moreover, SlideTiler has been conceived as a dynamic tool in constant evolution, and more updated and efficient versions will be released in the future.

Summary: Background: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis. Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS). Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI. Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS. Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds—2016, Italian Ministry of Health; AIRC Grant [ID#28546].

Introducción: El aclaramiento dental se usa hoy en día como un método para devolver la estética dental, teniendo dos agentes aclaradores como el peróxido de carbamida y peróxido de hidrógeno. Objetivo: Establecer las diferencias significativas entre el aclaramiento dental casero y aclaramiento dental en consultorio. Metodología: Es un estudio de enfoque cualitativo de tipo retrospectivo con un diseño correlacional.Se seleccionaron artículos en español e inglés publicados desde el año 2000 hasta la actualidad; la búsqueda se realizó en PubMed, Google académico, Scielo, Science Direct, Embase, Cochrane. Se revisaron 152 artículos y se seleccionaron 40 donde se incluyen revisiones sistemáticas, ensayos clínicos, revisión de la literatura, ensayos clínicos aleatorios, estudio clínico, excluyendo estudios in vitro y en animales. Resultados: En la modalidad casero se analizó que el mayor cambio de color y su efectividad según su duración en el tiempo se da no solo por la concentración del producto sino también por las sesiones y días aplicados, mientras en la modalidad de consultorio esos resultados se dan al usar altas concentraciones y pocas sesiones. En lo que respecta a efectos secundarios y sensibilidad, se encuentran que a mayor concentración y aplicaciones en ambas modalidades existirán más efectos adversos. Conclusión: En la modalidad casero (PC) la concentración de 10% con prolongadas sesiones a varios días dan menos efectos adversos y buen rango de efectividad. En la modalidad consultorio (PH) la concentración de 35% tiene gran efectividad y presenta menos efectos adversos aplicada a sesiones de tiempo corto.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.

Carbapenem resistance is a serious public health threat, causing numerous deaths annually primarily due to healthcare-associated infections. To face this menace, surveillance programs in high-risk patients are becoming a widespread practice. Here we report the performance of the combined use of a recently approved commercial multiplex real-time PCR assay (REALQUALITY Carba-Screen kit) with conventional phenotypic screening. In this three-month study, 479 rectal swabs from 309 patients across high-risk units were evaluated by combining the two approaches. Although the molecular assay showed a higher positivity rate than phenotypic screening (7.1% vs. 5%), it should be noted that the molecular method alone would have missed eight carbapenem-resistant isolates, while using only phenotypic screening would not have detected sixteen isolates. This demonstrates the complementary strengths of each method. Our study confirms the need for a combined approach to maximize the possible clinical impact of this kind of screening, ensuring a more comprehensive detection of resistant strains.

Abstract Background The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high‐risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG‐STS 1001). Patients and Methods Patients with available pre‐treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype‐tailored (HT) chemotherapy, were scored according to CINSARC (low‐risk, C1; high‐risk, C2). The 10‐year overall survival probability (pr‐OS) according to SARCULATOR was calculated, and patients were classified accordingly (low‐risk, Sarc‐LR, 10‐year pr‐OS>60%; high‐risk, Sarc‐HR, 10‐year pr‐OS

Abstract Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals which could be associated with cancer development, such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma and thyroid tumor. Available scientific literature offers no information on the role of PFAS in melanoma development/progression. Since 1965, a massive environmental contamination by PFAS has occurred in northeastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n = 194) and unexposed (n = 488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998–2014. Patients were categorized in exposed or unexposed groups according to their home address and the geographical classification of municipalities affected by PFAS contamination as provided by Veneto Government in 2018. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p = 0.005). Median follow-up was 90 months (IQR 59–136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (overall survival: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; disease-specific survival: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; disease-free survival: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62). Although the magnitude of PFAS exposure was not quantifiable, our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, but this did not translate into a survival difference. Further studies are required to investigate this relationship and all effects of PFAS on prognosis.

Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management.

Background: Granulomatosis with polyangiitis (GPA) is characterised by granulomatous inflammation and small-to-medium vessel necrotising vasculitis, mainly affecting respiratory tract and kidneys. Renal involvement presenting as tumour-like lesions poses diagnostic and treatment challenges. Methods: Following the observation of a GPA patient presenting with multiple renal tumour-like lesions, we conducted a systematic literature review on MEDLINE/PubMed, EMBASE, and Cochrane databases. Data gathered from the literature were analysed to summarise the diagnostic approach, management, and outcome of renal GPA-related tumour-like lesions. Results: a 49-year-old female presented with persistent constitutional symptoms and multiple bilateral renal lesions. Renal biopsy showed chronic interstitial inflammation with necrotising granulomas. Laboratory tests disclosed positive anti-proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) leading to a final diagnosis of GPA. She was effectively treated with high-dose glucocorticoids and rituximab. Literature search yielded 41 articles, concerning 42 GPA patients with renal masses, presenting bilaterally in 23.8% of the cases. Positive PR3-ANCA was observed in 86.5% of the cases. Half of 42 patients showed kidney abnormalities. Treatment with glucocorticoids (83.3%) and immunosuppressive agents (80.9%) resulted in an overall good remission rate and favourable prognosis. Conclusions: GPA should be considered in the differential diagnoses of kidney tumour-like lesions. The diagnosis is challenging, and histological examination greatly contributes to the diagnostic work-up.

BackgroundSoft tissue sarcomas (STS) are rare malignancies which prognosis varies significantly by primary site, histological subtype, and tumor stage. Their low incidence, and the complexity of their clinico-pathological characteristics demand standardized, cancer-tailored diagnostics and therapies managed at high-volume, multidisciplinary care centers. This study evaluates the quality of STS management in north-east Italy (Veneto Region) through a list of ad hoc defined clinical indicators.MethodsThis population-based study concerns all incident cases of STS in 2018 (214 cases) recorded in the adult population censored by the Veneto’s regional Cancer Registry. Based on the international literature, a multidisciplinary working group of experts identified a set of indicators for monitoring the quality of diagnostic, therapeutic, and end-of-life clinical interventions. The quality of care was assessed by comparing the reference thresholds with the indicators’ values achieved in clinical practice.ResultsDiagnostic procedures showed poor adherence to the thresholds, with a low percentage of histological diagnoses validated by a second opinion. The indicators relating to the surgical treatment of superficial, small, low-grade STS, or of medium, high-grade STS of the head–neck, trunk, or limbs were consistent with the thresholds, while for intermediate, high-grade (large-sized, deep) and retroperitoneal STS they fell significantly below the thresholds.ConclusionA critical evaluation of the clinical indicators allowed to uncover the procedures needing corrective action. Monitoring clinical care indicators improves cancer care, confirms the importance of managing rare cancers at highly specialized, high-volume centers, and promotes the ethical sustainability of the healthcare system.

Objective Digital pathology (DP) is currently in the spotlight and is rapidly gaining ground, even though the history of this field spans decades. Despite great technological progress, the adoption of DP for routine clinical diagnostic use remains limited. Methods A systematic search was conducted in the electronic databases Pubmed-MEDLINE and Embase. Inclusion criteria were all published studies that encompassed any application of DP. Results Of 4888 articles retrieved, 4041 were included. Relevant articles were categorized as “diagnostic” (147/4041, 4%) where DP was utilized for routine diagnostic workflow and “non-diagnostic” (3894/4041, 96%) for all other applications. The “non-diagnostic” articles were further categorized according to DP application including “artificial intelligence” (33%), “education” (5%), “narrative” (17%) for reviews and editorials, and “technical” (45%) for pure research publications. Conclusion This manuscript provided temporal and geographical insight into the global adoption of DP by analyzing the published scientific literature.

Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK–) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK– ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK– ALCL.

Background/Objectives: Splenectomy leads to a high rate of remission in chronic primary immune thrombocytopenia (ITP), but its unpredictable long-term positive outcomes and that it is a irreversible surgical approach discourage clinicians and patients. The identification of predictors of response may redefine the timing of splenectomy. In this retrospective, multicentric study we aimed to investigate clinical–histological predictors of splenectomy response in ITP patients and provide an easy-to-use score to predict splenectomy response in ITP. Methods: We considered a discovery set (n = 17) and a validation set (n = 30) of adult ITP patients, who underwent splenectomy for refractory disease in three Italian referral centers for ITP. Results: We found that the presence of autoimmune comorbidities, daily steroid dose prior to splenectomy, age at diagnosis and age at splenectomy were significantly associated with the outcome. Variables singly associated with an adverse outcome were combined into a clinical and a clinical–pathological score, allowing us to define a "high-risk" group which accounted for about 80% of the disease relapses observed in this cohort. At the same time, a certain clinical–pathological score indicated a "high-risk" group characterized by significantly poorer outcomes. Results were confirmed in the validation cohort. Conclusions: An integrated set of clinical and histological parameters may predict the response to splenectomy in ITP patients. While these findings provide valuable insights, they were derived from a small cohort of patients and therefore require validation in larger, more diverse populations to ensure their generalizability and robustness. [ABSTRACT FROM AUTHOR]