Direct healthcare costs of oral cancer: A retrospective study from a tertiary care center.

The aim of this study was to retrospectively evaluate the direct costs of OSCC treatment and postsurgical surveillance in a tertiary hospital in northeast Italy. Sixty-three consecutive patients surgically treated for primitive OSCC at S. Orsola Hospital in Bologna (Italy) between January 2018 and January 2020 were analyzed. Billing records of the Emilia Romagna healthcare system and institutional costs were used to derive specific costs for the following clinical categories: operating theatre costs, intensive and ordinary hospitalization, radiotherapy, chemotherapy, postsurgical complications, visits, and examinations during the follow-up period. The study population comprised 17 OSCC patients classified at stage I, 14 at stage II, eight at stage III, and 24 at stage IV. The estimated mean total direct cost for OSCC treatment and postsurgical surveillance was €26 338.48 per patient (stage I: €10 733, stage II: €19 642.9, stage III: €30 361.4, stage IV: €39 957.2). An advanced diagnosis (stages III and IV), complex surgical procedure, and loco-regional recurrences resulted in variables that were significantly associated with a higher cost of OSCC treatment and postsurgical surveillance. Redirection of funds used for OSCC treatment to screening measures may be an effective strategy to improve overall health outcomes and optimize national health resources.

Second edition of the Milan System for Reporting Salivary Gland Cytopathology: Refining the role of salivary gland FNA.

The use of standardized reporting systems for nongynecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung, and more. In February 2018, the first edition Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of Non-Neoplastic, benign, and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarizing the use of salivary gland imaging, new advances in ancillary testing, and updates in nomenclature. CONCISE SENTENCE: The second edition of the Milan System for Reporting Salivary Gland Cytopathology, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarizing the use of salivary gland imaging, new advances in ancillary testing, updates in nomenclature, and a guide to the practical application of the latest ancillary markers for the diagnosis of selected salivary gland fine-needle aspiration cases.

Thirteen-gene DNA methylation analysis of oral brushing samples: A potential surveillance tool for periodic monitoring of treated patients with oral cancer.

BACKGROUND: We evaluated the prognostic role of 13-gene DNA methylation analysis by oral brushing repeatedly performed during the follow-up of patients surgically treated for oral cancer. METHODS: This is a nested case-control study including 61 patients for a total of 64 outcomes (2/61 patients experienced multiple relapses). Samples were collected at baseline (4-10 months after OSCC resection) and repeatedly every 4-10 months until relapse or death. DNA methylation scores were classified as persistently positive, persistently negative, or mixed. RESULTS: Twenty cases who had persistently positive scores and 30 cases with mixed scores had, respectively, an almost 42-fold (p < 0.001) and 32-fold (p = 0.006) higher likelihood of relapse, compared to 14 patients with persistently negative scores. The last score before reoccurrence was positive in 18/19 secondary events. CONCLUSIONS: The 13-gene DNA methylation analysis may be considered for the surveillance of patients treated for oral carcinoma.

Second edition of the Milan System for Reporting Salivary Gland Cytopathology: Refining the role of salivary gland FNA.

The use of standardized reporting systems for non-gynecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung, and more. In February 2018, the first edition Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of non-neoplastic, benign, and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarizing the use of salivary gland imaging, new advances in ancillary testing, and updates in nomenclature.

Second edition of the Milan System for Reporting Salivary Gland Cytopathology: Refining the role of salivary gland FNA.

The use of standardised reporting systems for non-gynaecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung and more. In February 2018, the first edition of the Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of non-neoplastic, benign and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published, confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarising the use of salivary gland imaging, new advances in ancillary testing and updates in nomenclature.

Pre-operative incisional biopsy of oral squamous cell carcinoma: high podoplanin expression is related to perineural invasion and may be a useful predictor of disease progression.

OBJECTIVE: Immunohistochemical analysis of podoplanin expression as a pre-operative molecular marker for perineural invasion (PNI) may represent an attractive strategy for surgical management of oral squamous cell cancer (OSCC). We evaluated the relationship between podoplanin expression and PNI in pre-operative incisional biopsies of OSCC. STUDY DESIGN: After performing pathological staging and histologic and immunohistochemical evaluation of 83 surgical specimens, we performed multivariable logistic regression analysis to examine the relationship between PNI and independent variables. To evaluate the utility of podoplanin immunopositivity for discrimination of PNI status pre-operatively, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value. We performed receiver operating characteristic curve analysis to evaluate the diagnostic accuracy of podoplanin immunopositivity for predicting PNI alone and in combination with age, T stage, N stage, and index site. RESULTS: We observed podoplanin expression in 42 (50.6%) of all the 83 pre-operative incisional biopsies and 29 of the pre-operative biopsies of the 31 (93.5%) postoperative specimens with PNI. The rate of podoplanin expression was significantly higher in patients with pT3 to pT4 stage and pN+ stage disease. Podoplanin positivity in the pre-operative biopsy showed high sensitivity in predicting PNI in the surgical specimen. CONCLUSION: Podoplanin expression appears to be an independent pre-operative variable significantly related to PNI and a possibly valuable prognostic marker for therapeutical planning and surgical treatment of OSCC.

Prognostic Markers of Microinvasive Breast Carcinoma: A Systematic Review and Meta-Analysis.

(1) Background: The prognostic factors of microinvasive (≤1 mm) breast carcinoma are not completely clear. The aim of this study was to perform a systematic review and meta-analysis to clarify these factors. (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. Two databases were interrogated, PubMed and Embase, and papers in English were included to address this question. The selected studies were those that reported on female patients affected by microinvasive carcinoma, and on prognostic factors with a hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS). (3) Results: In total, 618 records were identified. After removing duplicates (166), identification, and screening (336 by title and abstract alone, 116 by full text and eventual supplementary material), 5 papers were selected. Seven different meta-analyses were conducted in this study, all referring to DFS, analyzing the following prognostic factors: estrogen receptor, progesterone receptor, HER2 status, multifocality and grade of microinvasion, patient's age, and lymph node status. Only lymph node status was associated with prognosis and DFS (total number of cases: 1528; Z = 1.94; p = 0.05). The other factors examined did not significantly affect prognosis (p > 0.05). (4) Conclusions: Positive lymph node status significantly worsens prognosis in patients with microinvasive breast carcinoma.

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy.

IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with IRF2BPL-related disorders previously reported. Our three probands, aged 28-40 years, harbored de novo nonsense variants in IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the "coiled-coil" domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME.

ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

Carotid free-floating thrombus in COVID-19: a cerebrovascular disorder of cytokine storm-related immunothrombosis.

BACKGROUNDS: Several neurological manifestations, including stroke, have been reported in COVID-19 patients. The putative role of the COVID-19-related hyperinflammatory state in cerebrovascular disorders remains unclear. METHODS: From March 2020 to September 2021, we searched for patients who exhibited an ischemic stroke related to carotid free-floating thrombus (CFFT) to investigate its incidence and relationship with COVID-19. RESULTS: Of 853 ischemic strokes referred to our Stroke Centre during the study period, 5.7% (n = 49) were positive for SARS-CoV-2. Six had CFFT, of which two tested positive for SARS-CoV-2 (2/49 = 4.1%), and four did not (4/802 = 0.5%). The former were two middle-aged men suffering from COVID-19 pneumonia. Floating thrombi were promptly extracted by endarterectomy and endovascular thrombectomy, respectively, with no early and long-term complications. Notably, our COVID-19 patients exhibited little or no atherosclerosis burden on CT angiography, markedly elevated D-dimer levels, and extensive thrombus length. CONCLUSIONS: COVID-19-induced immunothrombosis possibly played a significant pathogenic role in CFFT.

Shared epigenetic alterations between oral cancer and periodontitis: A preliminary study.

INTRODUCTION: We recently developed a non-invasive sampling procedure for oral squamous cell carcinoma (OSCC) detection based on DNA methylation analysis of a panel of 13 genes. Oral cancer, as well as acute and chronic inflammatory diseases, may influence the methylation level of several genes in the oral cavity. In the present study, we evaluated the presence of periodontal disease (PD) and the methylation status using our 13-gene panel. METHODS: Oral brushing specimens were collected from three different patient groups: 23 gingival OSCC patients, 15 patients affected by PD, and 15 healthy volunteers lacking evidence of PD. DNA methylation analysis was performed and each sample was determined to be positive or negative based on a predefined cut-off value. RESULTS: Positive results were found for 23/23 OSCC patients, 3/15 PD patients, and 0/15 samples from healthy volunteers. The GP1BB and MIR193 genes in the PD group exhibited mean methylation levels similar to OSCC patients. ZAP70 showed different methylation levels among three groups. CONCLUSION: Preliminary data identified shared epigenetic alterations between PD and OSCC patients in two inflammatory genes (GP1BB and MIR193). This study may help to identify potential links between the two diseases and serve as a starting point for the future research focused on pathogenesis.

Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy.

Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.

COVID-19 and the Brain: The Neuropathological Italian Experience on 33 Adult Autopsies.

Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February-April 2020) and the second/third (November 2020-April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.

Endometrioid Cancer Associated With Endometriosis: From the Seed and Soil Theory to Clinical Practice.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. It is still debated whether endometriosis is a disease that can predispose to the pathogenesis of endometrial cancer outside the uterus. Deficiencies in mismatch repair (MMR) genes are a known risk factor for developing endometrioid cancer. Starting from two cases of patients with abnormal MMR endometrioid carcinoma of the uterus and synchronous endometrioid carcinoma in non-ovarian and ovarian endometriosis, we performed a somatic mutation profile and phylogenetic analysis of the lesions in order to identify if they were metastasis or primary de novo tumors. In the first case, we identified de novo activating mutations in PIK3CA and KRAS in endometrioid cancer lesions but not in endometriosis. Although the acquisition of a de novo mutation in ESR1 and a decrease in mutant allele fraction (MAF) from the endometrial tumor to the localizations in the endometriosis lesions, the clonal relationship was confirmed by the limited number of heteroplasmic mutations in D-loop mitochondrial DNA region. In the other case, the clonal behavior was demonstrated by the overlap of MAF at each site. Our data support the hypothesis of a retrograde dissemination of tumor cells, moving from the primary carcinoma in the endometrium to ectopic sites of endometriosis where localizations of tumor arise.

Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze-thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.

Role and evaluation of pathologic response in early breast cancer specimens after neoadjuvant therapy: consensus statement.

Pathologic evaluation of early breast cancer after neoadjuvant therapy is essential to provide prognostic information based on tumor response to treatment (pathologic complete response [pCR] or non-pCR) and to inform therapy decisions after surgery. To harmonize the pathologist's handling of surgical specimens after neoadjuvant therapy, a panel of experts in breast cancer convened to developed a consensus on six main topics: (1) definition of pCR, (2) required clinical information, (3) gross examination and sampling, (4) microscopic examination, (5) evaluation of lymph node status, and (6) staging of residual breast tumor. The resulting consensus statements reported in this document highlight the role of an accurate evaluation of tumor response and define the minimum requirements to standardize the assessment of breast cancer specimens after neoadjuvant therapy.

Diagnostic challenges of an incidental finding: case report of definitely-congenital glioblastoma multiforme in a very preterm infant.

BACKGROUND: Congenital brain tumors are extremely rare in the neonatal population, and often associated with a poor prognosis. The diagnostic suspicion is often aroused at antenatal scans or postnatally, if clinical signs and symptoms of increased intracranial pressure become evident. We present a case of definitely congenital glioblastoma multiforme incidentally diagnosed in a preterm infant, aiming to raise clinical awareness on this condition and to highlight the challenges of the related diagnostic work-up. CASE PRESENTATION: This female infant was born at 31 weeks' gestation after an uneventful pregnancy. No abnormalities were detected at antenatal ultrasound scans and genetic tests. Head circumference at birth was on the 25th centile. A routine brain ultrasound scan performed on day 1 revealed a large, inhomogeneous lesion in the right cerebral hemisphere, with contralateral midline shift, which was confirmed by brain magnetic resonance imaging (MRI). Eye fundus and routine blood exams, including platelets count, coagulation screening and C-reactive protein, were normal. Given the high risk of complications, surgical biopsy of the lesion was temporarily hold and a daily sonographic follow-up was undertaken. Although head circumference growth was steady on the 25th centile, progressive changes of the lesion were detected by cranial ultrasound. The repeat MRI scans showed a significant enlargement of the mass, with contralateral midline shift and signs of intralesional and intraventricular bleeding. In view of this worsening, surgical resection was performed. The histological examination of the lesion biopsy documented a GFAP+ highly cellular neoplasm, with no mutation on SMARCB1 gene. At the molecular analysis, mutations on IDH and H3F3A genes were absent, whereas MGMT promoter was unmethylated. The diagnosis was grade IV glioblastoma IDH wild-type. CONCLUSIONS: Congenital glioblastoma multiforme is an extremely rare but highly aggressive neoplasm. Since intralesional biopsy is not often feasible in affected neonates, knowledge of the associated clinical and neuroradiological features is particularly important, as they can also add useful information on the neoplasm behavior. Specimens from open surgical resection allow to perform a definite histological analysis and an extended molecular characterization, with relevant prognostic implications.

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis.

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.

Intra-Tumour Heterogeneity Is One of the Main Sources of Inter-Observer Variation in Scoring Stromal Tumour Infiltrating Lymphocytes in Triple Negative Breast Cancer.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539-0.735, p < 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727-0.864, p < 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561-0.756, p < 0.001) and 40% (ICC 0.644, 95% CI 0.546-0.745, p < 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.