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Background: Numerous studies showed that methylation analysis represents a newly developed urinary marker based on DNA methylation changes in a panel of genomic biomarkers and it could represent a valid tool in terms of the diagnosis and prediction of high-grade urothelial carcinoma recurrences. One of the limits of the use of this new molecular method during a follow-up is represented by the number of invalid tests in routine practice. Method: A total of 782 patients with a diagnosis of non-muscle-invasive high-grade carcinoma (NMIBC) was studied. The Bladder EpiCheck test (BE) was performed together with cytology in all cases within 1 year after the end of treatment. In 402 patients, the urinary samples were voided urine (UV), while, in 380 cases, the samples were collected after bladder washing (IU). For all the patients with invalid BE results, a second BE test was performed following the instructions for use that indicated the test should be repeated with a new urinary sample in the case of an invalid result. Results: Analyzing the two different groups (UV and IU), we found the invalid BE results seemed to be not related to urinary samples (p = 0.13 Fisher’s exact test), suggesting that the collection method was not relevant in order to reduce the number of invalid tests. Conclusions: In the follow-up for NMIBC, for patients for whom a BE test is planned, a combined approach of cytology and a methylation test is recommended in order to repeat the BE test with an invalid result only in those cases with a cytological diagnosis of atypical urothelial cells (AUC) suspicious for high-grade urothelial carcinoma (SHGUC) and high-grade urothelial carcinoma (HGUC).

Abstract Background Platelets play an important role in the development of cardiovascular disease (CVD). Mean platelet volume (MPV) is considered as biological marker of platelets activity and function. The aim of the present study was to evaluate MPV values and its possible correlation with arterial stiffness and subclinical myocardial damage, in normal glucose tolerance patients (NGT), in newly diagnosed type 2 diabetic (T2DM) patients and in individuals with pre-diabetes. Methods We enrolled 400 newly diagnosed hypertensive patients. All patients underwent an Oral Glucose Tolerance test (OGTT). Arterial stiffness (AS) was evaluated with the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). Echocardiographic recordings were performed using an E-95 Pro ultrasound system. Results Among groups there was an increase in fasting plasma glucose (FPG) (p

Autophagy is a cellular process crucial for maintaining homeostasis by degrading damaged proteins and organelles. It is stimulated in response to stress, recycling nutrients and generating energy for cell survival. In normal endometrium, it suppresses tumorigenesis by preventing toxic accumulation and maintaining cellular homeostasis. It is involved in the cyclic remodelling of the endometrium during the menstrual cycle and contributes to decidualisation for successful pregnancy. Such a process is regulated by various signalling pathways, including PI3K/AKT/mTOR, AMPK/mTOR, and p53. Dysregulation of autophagy has been associated with benign conditions like endometriosis and endometrial hyperplasia but also with malignant neoplasms such as endometrial carcinoma. In fact, it has emerged as a crucial player in endometrial carcinoma biology, exhibiting a dual role in both tumour suppression and tumour promotion, providing nutrients during metabolic stress and allowing cancer cell survival. It also regulates cancer stem cells, metastasis and therapy resistance. Targeting autophagy is therefore a promising therapeutic strategy in endometrial carcinoma and potential for overcoming resistance to standard treatments. The aim of this review is to delve into the intricate details of autophagy's role in endometrial pathology, exploring its mechanisms, signalling pathways and potential therapeutic implications.

Introduction: To evaluate the detection rate for prostate cancer (PCa) performing multiparametric magnetic resonance imaging (mpMRI) fusion targeted biopsy (TPBx) combined only with ipsilateral systematic prostate biopsy (SPBx)., Materials and Methods: From January 2023 to December 2023, 495 men with clinical suspicion of PCa underwent transperineal SPBx plus TPBx in the presence of PI-RADS score lesions ≥ 3., Results: In 250/495 men (50.5%) a PCa was found, while 36/250 (14.4%) men had negative mpMRI. In comparison to TPBx, SPBx diagnosed a higher number of indolent PCa, 38.5 vs. 5.8%, respectively; conversely, SPBx demonstrated a higher detection rate for clinically significant PCa (97.3 vs. 85.4%) in the presence of ISUP Grade Group 2 (GG2). In details, rates were higher in the presence of GG2 (100 vs. 76%), GG3 (85.7 vs. 75.8%) and GG4 (100 vs. 86.4%) tumors. However, in GG5, both SPBx and TPBx diagnosed 100% of csPCa. Furthermore, 89.4% of the cases showed csPCa on the negative mpMRI side., Conclusions: SPBx combined with TPBx maximized csPCa diagnosis; the use of reduced biopsy scheme limited to ipsilateral side of mpMRI lesion plus TPBx missed 11.6% csPCa. Only in the presence of PI-RADS score 5 SPBx and TPBx diagnosed both 100% of csPCa.

Background/aim: This study aimed to evaluate the diagnostic accuracy of prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) in pelvic nodal staging, using postoperative histopathology data as the reference standard., Patients and Methods: From January 2020 to June 2024, 78 patients with clinically significant prostate cancer (PCa) (ISUP Grade Group 2) underwent radical prostatectomy plus extended pelvic lymph node dissection (ePLND): 60 (77%) vs. 18 (23%) men had an intermediate vs. high risk PCa. All the patients underwent PSMA PET/TC before surgery for clinical staging and nodes focal uptake (standardized uptake value "SUVmax) was evaluated to rule out the presence of metastases., Results: PSMA PET/CT was suspicious for nodes metastases in 16/78 (20.5%) men (median SUVmax 26.2), conversely, histology demonstrated nodes metastases in 18/78 (23.1%). PSMA PET/CT was negative for nodal involvement in all Grade Group 2 (GG2) PCa, positive in 4/4 (100%) GG3 PCa, and in 10/14 (71.4%) GG5 PCa. In detail, PSMA PET/CT was false negative in 2/4 PCa, characterized by GG5 plus ductal adenocarcinoma. Overall, PSMA PET/CT sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy in diagnosing nodal metastases were equal to 87.5, 96.8, 87.5 96.7, and 92.3%, respectively., Conclusion: PSMA PET/CT demonstrated an overall diagnostic accuracy of 92.3% in nodal staging (100% in GG2 PCa), which decreased to 63.6% in GG5 PCa. In high-risk patients or in case of ductal adenocarcinoma, a negative PSMA PET/CT does not rule out the need for ePLND., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Autophagy is a biological process that facilitates the degradation and removal of damaged structures and macromolecules. In neoplasms, autophagy has been proposed to play a dual role, functioning either as a tumor promoter or a tumor suppressor. To date, no comprehensive analysis of autophagy, primarily through immunohistochemical investigation of autophagy-related proteins (ATGs), has been conducted in chordomas (CHs), which are rare bone tumors that arise from remnants of the notochord. The present study aimed to investigate the immunoexpression of several ATGs, including microtubule-associated protein 1 light chain 3 (LC3A/B), Sequestosome-1 (p62) and autophagy and Beclin 1 regulator 1 (AMBRA-1) in a series of sporadic adult conventional clival CHs collected from a single neuropathological center in southern Italy. Immunohistochemical analysis revealed that LC3A/B, p62 and AMBRA-1 were exclusively found in neoplastic cells, with no expression detected in the surrounding stromal cells. Both LC3A/B and p62 were expressed in the cytoplasm and nucleus of neoplastic cells, while AMBRA-1 was predominantly localized in the cytoplasm. In all cases of CHs, p62 was consistently and highly expressed, whereas a similarly high expression of LC3A/B was observed in five cases, four of which were characterized by neoplastic recurrence and partial resection. Low immunoreactivity was noted in seven out of 10 cases (70%), while three recurrent cases exhibited high levels of AMBRA-1 immunostaining. Statistical analysis using Fisher's exact test revealed significant P-values for LC3A/B (P=0.048), AMBRA-1 (P=0.033), Ki-67 (P=0.048) and surgical treatment (P=0.048). Consequently, a negative prognostic role for these two ATGs may be hypothesized in the development of CHs., Competing Interests: No competing interests have been declared., (Copyright © 2024, Spandidos Publications.)

Thyroid nodules are a common, benign condition with a higher prevalence in women, individuals with iodine deficiency, and radiation exposure. Treatment options for benign thyroid nodules include pharmaceutical therapy, thyroidectomy, and thermal ablation (TA). TA, including laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA), is a procedure that uses heat to cause tissue necrosis. It is commonly used for large, firm, benign, non-functioning thyroid nodules that cause severe symptoms or pain when surgery is not recommended or desired. When thyroid nodules do not respond to TA, they undergo surgery to resolve the symptoms and clarify the diagnosis. This study aims to analyze the histological alterations found in surgically excised TA-treated thyroid nodules and to evaluate the morphological criteria of differential diagnosis between benign and malignant nodules, establishing whether the alterations observed on the histological sample are a consequence of TA or indicative of neoplastic disease. For this purpose, the adoption of ancillary methods, such as immunohistochemistry, is fundamental to distinguish the artifacts induced by TA from the typical morphological characteristics of malignant neoplasms.

Background/Objectives: Bladder cancer is a prevalent urinary system malignancy and urinary cytology is widely used for its screening and follow-up. A novel diagnostic tool called Bladder Epicheck ® (BE) is increasingly being used for monitoring the recurrence of non-muscle-invasive bladder cancer (NMIBC). The simultaneous use of BE and urinary cytology can increase the diagnostic performances in the follow-up of bladder neoplasms. Methods: In this multicenter study, we retrospectively evaluated the data of 322 patients in follow-up for a high-grade bladder carcinoma over a six-year period (from January 2018 to March 2024). The diagnostic performances of both cytology and BE and their combination were calculated using histology as gold standard. Results: Recurrences were diagnosed as high-grade urothelial carcinoma NMIBC in 18 cases, low-grade papillary NMIBC in 8 cases, and carcinoma in situ (CIS) in 4 cases. Cytological analysis correctly identified 26 out of 30 carcinomas, while 286 were correctly diagnosed as negative results. BE correctly identified 25 out of 30 carcinomas, 285 were correctly diagnosed as negative results. The combination of BE and urinary cytology correctly identified 29 out of 30 carcinomas, while 289 were correctly diagnosed as negative results. Conclusions: The combination of BE and cytology could be the most effective approach for follow-up diagnosis in patients with high-grade NMIBC, reducing unnecessary invasive procedures.

Among autophagic-related proteins, p62/SQSTM1/Sequestosome-1 represents a relevant actor in cellular proliferation and neoplastic growth. Although, recently, p62 expression has been analyzed in different neurodegenerative and glial neoplastic diseases, no available information have been reported in meningiomas, which have an high epidemiological relevance being the second most common category of intracranial tumors after gliomas. Generally meningiomas have a benign behavior, but their recurrence is not uncommon mainly when atypical or anaplastic varieties occur. However, intranuclear vacuoles have been ultrastructurally observed in meningiomas, and they were labelled by p62 antibodies. Therefore, in the present study, we have investigated p62 immunohistochemical pattern in a cohort of 133 cases representative of low- and high-grade meningiomas, to verify if p62 expression may be related to clinicopathological data, thus achieving a potential prognostic role. The p62 immunoexpression was frequently found in the nucleus and cytoplasm of neoplastic elements, and utilizing an intensity-distribution score, 55 (41.3%) cases were considered as high expressors while 78 (58.7%) cases were instead recorded as low expressors. Fifteen cases exhibited recurrences of the disease, 14 of which were codified as high expressors. Moreover, a direct relationship between p62 and Mib-1 immunoexpression as well as between p62 and neoplastic grade have been documented. Finally, we suggest that impaired autophagic flux with an increase in p62 expression may be involved in the activation of NRF2 also contributing in the development of recurrence in meningioma patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Antonio Ieni et al.)

The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette-Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.

Background: Nasal polyps (NPs) represent the end-stage manifestation of chronic rhinosinusitis (CRS), a relatively common pathological condition encountered in all ages of life., Methodology: The aim of our study was to evaluate the histological features and inflammatory cellular components of NPs in a retrospective cohort (143 cases) of pediatric, adult and elderly populations in order to discuss the possible morphological age-related differences statistically documented., Results: In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident, frequently with a perivascular distribution or with the formation of subepithelial lymphoid nodules. In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. Nearly all morphological findings exhibited statistically significant values among differently aged subgroups., Conclusions: Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. The future role of biological therapies, mainly in cases refractory to already available standard medical and surgical treatments, may be analyzed by a prospective study using a larger cohort with a long-term evaluation also in relation to a possible relapse.

Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several protein post-translational modifications and it is also implicated in signal transduction thanks to its GTP binding/hydrolyzing activity. In the nervous system, TG2 regulates multiple physiological processes, such as development, neuronal cell death and differentiation, and synaptic plasticity. Given its different enzymatic activities, aberrant expression or activity of TG2 can contribute to tumorigenesis, including in peripheral and central nervous system tumors. Indeed, TG2 dysregulation has been reported in meningiomas, medulloblastomas, neuroblastomas, glioblastomas, and other adult-type diffuse gliomas. The aim of this review is to provide an overview of the biological and functional relevance of TG2 in the pathogenesis of nervous system tumors, highlighting its involvement in survival, tumor inflammation, differentiation, and in the resistance to standard therapies.

Among low-grade gliomas, representing 10-20% of all primary brain tumours, the paradigmatic entity is constituted by pilocytic astrocytoma (PA), considered a grade 1 tumour by the World Health Organization. Generally, this tumour requires surgical treatment with an infrequent progression towards malignant gliomas. The present review focuses on clinicopathological characteristics, and reports imaging, neurosurgical and molecular features using a multidisciplinary approach. Macroscopically, PA is a slow-growing soft grey tissue, characteristically presenting in association with a cyst and forming a small mural nodule, typically located in the cerebellum, but sometimes occurring in the spinal cord, basal ganglia or cerebral hemisphere. Microscopically, it may appear as densely fibrillated areas composed of elongated pilocytic cells with bipolar 'hairlike' processes or densely fibrillated areas composed of elongated pilocytic cells with Rosenthal fibres alternating with loosely fibrillated areas with a varied degree of myxoid component. A wide range of molecular alterations have been encountered in PA, mostly affecting the MAPK signalling pathway. In detail, the most frequent alteration is a rearrangement of the BRAF gene, although other alterations include neurofibromatosis type-1 mutations, BRAFV600E mutations, KRAS mutations, fibroblast growth factor receptor-1 mutations of fusions, neurotrophic receptor tyrosine kinase family receptor tyrosine kinase fusions and RAF1 gene fusions. The gold standard of PA treatment is surgical excision with complete margin resection, achieving minimal neurological damage. Conventional radiotherapy is not required; the more appropriate treatment appears to be serial follow-up. Chemotherapy should only be applied in younger children to avoid the risk of long-term growth and developmental issues associated with radiation. Finally, if PA recurs, a new surgical approach should be performed. At present, novel therapy involving agents targeting MAPK signalling pathway dysregulation is in development, defining BRAF and MEK inhibitors as target therapeutical agents., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Pizzimenti et al.)

Background: About 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and β4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models., Methods: H19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects., Results: H19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and β4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs., Conclusions: Our findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy., (© 2024. The Author(s).)

Cutaneous melanoma (CM) is traditionally considered one of the most "immunogenic" tumors, eliciting a high immune response. However, despite the presence of tumor-infiltrating lymphocytes (TILs), melanoma cells use strategies to suppress antitumor immunity and avoid being eliminated by immune surveillance. The PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis is a well-known immune escape system adopted by neoplastic cells. Therefore, immunotherapy with PD-1 and PD-L1 inhibitors is quickly becoming the main treatment approach for metastatic melanoma patients. However, the clinical utility of PD-L1 expression assessment in CM is controversial, and the interpretation of PD-L1 scores in clinical practice is still a matter of debate. Nonetheless, the recent literature data show that by adopting specific PD-L1 assessment methods in melanoma samples, a correlation between the expression of such a biomarker and a positive response to PD-1-based immunotherapy can be seen. Our review aims to describe the state-of-the-art knowledge regarding the prognostic and predictive role of PD-L1 expression in CM while also referring to possible biological explanations for the variability in its expressions and related treatment responses.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.

Primary central nervous system (CNS) extranodal marginal zone B-cell lymphoma (MZBL) is a rare low-grade non-Hodgkin lymphoma, characterised predominantly by small B cells, plasma cells, monocytoid cells and scattered large immunoblasts. Primary CNS MZBL is a slow-growing tumour that remains localised and is characterised by an excellent clinical prognosis. The present study describes the case of a 48-year-old HIV-negative female patient with a history of head trauma 1 year prior, who presented with worsening neurological symptoms and a magnetic resonance imaging finding of a ~3-cm extra-axial mass within the left lateral ventricle. From histopathology and immunohistochemistry, the lesion was diagnosed as a CNS MZBL; as no other primary lesions were found, the base of the choroid plexuses of the left lateral ventricle was considered the primary site. To the best of our knowledge, the current case is the first study to report on primary CNS MZBL arising in this anatomical site and paves the way for further studies on the role of chronic inflammation (in the present case resulting from trauma) in the pathogenesis not only of primary CNS MZBL but also of lymphoma in general. Additionally, this report could serve as a starting point for studies analysing the role of meningothelial cells in the pathogenesis of primary CNS MZBL., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Fiorentino et al.)

Treatment of metastatic renal cell carcinoma (mRCC) has radically changed, switching from interferon alfa (IFN-α) and high-dose interleukin-2 (HD IL-2) to new targeted therapies directed against tumoral neoangiogenesis, the mammalian target of the rapamycin (mTOR) pathway and immune checkpoints. Of note, the inhibition of immune checkpoints restores antitumor immune response, therefore promoting immune-mediated elimination of neoplastic cells. The best example of this targeted treatment is represented by PD-1/PD-L1 inhibition that has become the standard of care in mRCC treatment and has improved mRCC patients' prognoses after failure of other targeted therapies. In this manuscript, we review the main therapeutic protocols adopted for mRCC, based on the use of immune checkpoint inhibitors (ICIs) alone or combined with other drugs.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment ( p = 0.001), higher expression of the AXL gene ( p = 0.007), lower expression of NIS ( p = 0.045) and higher expression of PD-L1 ( p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL ( p = 0.0003), a lower level of NIS ( p = 0.0004) and a higher PD-L1 level ( p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression ( p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs ( p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

The present review focuses on the phenomenon of autophagy, a catabolic cellular process, which allows for the recycling of damaged organelles, macromolecules, and misfolded proteins. The different steps able to activate autophagy start with the formation of the autophagosome, mainly controlled by the action of several autophagy-related proteins. It is remarkable that autophagy may exert a double role as a tumour promoter and a tumour suppressor. Herein, we analyse the molecular mechanisms as well as the regulatory pathways of autophagy, mainly addressing their involvement in human astrocytic neoplasms. Moreover, the relationships between autophagy, the tumour immune microenvironment, and glioma stem cells are discussed. Finally, an excursus concerning autophagy-targeting agents is included in the present review in order to obtain additional information for the better treatment and management of therapy-resistant patients.

Background: Programmed death-ligand 1 (PD-L1) checkpoint inhibitors represent a mainstay of therapy in head and neck squamous cell cancer (HNSCC). However, little is known about the influence of combined therapy on PD-L1 expression. The study aims to gather evidence on this topic., Methods: A systematic search was carried out in electronic databases Pubmed-MEDLINE and Embase to retrieve studies on the comparison of PD-L1 expression before and after conventional therapy. Data were extracted and a quantitative analysis with pooled odds ratios (ORs) was performed when applicable., Results: Of 5688 items, 15 were finally included. Only a minority of studies assessed PD-L1 with the recommended combined positive score (CPS). The results are highly heterogeneous, with some studies reporting an increase in PD-L1 expression and others reporting a decrease. Three studies allowed for quantitative analysis and showed a pooled OR of 0.49 (CI 0.27-0.90)., Conclusions: From the present evidence, a clear conclusion towards an increase or decrease in PD-L1 expression after combined therapy cannot be drawn, but even with few studies available, a trend towards an increase in expression in tumor cells at a cutoff of 1% can be noted in patients undergoing platinum-based therapy. Future studies will provide more robust data on the effect of combined therapy on PD-L1 expression.

The detection of psammoma bodies (PBs) in the thyroid gland is commonly associated to classic papillary thyroid carcinoma (PTC) and are frequently encountered in differnt subtypes of PTCs. Nonetheless, the evidence of PBs without a PTC may represent a diagnostic challenge. The general statement is that PBs represent a metastatic finding of PTC either when encountered inside the thyroid parenchyma or in the perithyroidal lymph nodes. The majority of authors assess that in presence of PBs, a search for an occult PTC is strongly encouraged and mandatory, especially if a lobectomy had been performed. In fact, it is not uncommon that a contralateral or ipsilateral tumor, mostly PTC, is found leading to the suggestion that the best recommendation is to submit the entire thyroid tissue. Nonetheless, when a cancer has not been found, the possibility of the rare evenience that PBs are likely to be associated with benign conditions should be considered among the differential diagnosis. Herein a short commentary and review of the literature on PBs detection and its diagnosis, based on our recent experience., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Purpose: The purpose of this study was to prospectively evaluate the capability of diffusion tensor imaging (DTI) of the lumbosacral plexus to identify parametrial invasion by uterine cervical cancer., Materials and Methods: Twenty-seven women with biopsy-proven cervical cancer were prospectively enrolled and underwent DTI at 1.5 TMRI. Fractional anisotropy (FA) values were calculated at the level of right and left L5 and S1 roots. The two sides of each patient were considered independently in two groups, according to the presence or absence of parametrial invasion. Differences between FA values of invaded parametria and those of non-invaded parametria were searched using Student t-test. Receiver operating characteristic (ROC) analysis was performed to identify the cut-off value of FA that yielded best sensitivity, specificity and accuracy for the diagnosis of parametrial invasion., Results: A total of 54 parametria in 27 participants (mean age, 52.9 ± 12 years; age range, 30-81 years) were analyzed. Invasion was present in 37/54 (68%) parametria and absent in 17/54 (31%) parametria. FA was greater in parametrial invasion (mean, 0.321 ± 0.036; range: 0.285-0.357) than in the absence of parametrial invasion (0.292 ± 0.02; range: 0.272-0.312) (P = 0.01). At ROC analysis, best cut-off value of FA for the diagnosis of parametrial invasion was >0.3099 (AUC, 0.681; 95% CI: 0.583- 0.768), yielding 62% sensitivity (95% CI: 50.3-73.64), 73% specificity (95% CI: 50.6-85.27) and 66% accuracy (95% CI: 54.62-73.91)., Conclusion: Using >0.3099 as cut off-value for FA of L5-S1 roots, DTI has an accuracy of 73% in the diagnosis of parametrial invasion by uterine cervical cancer., (Copyright © 2022 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

The correct N-staging in breast cancer is crucial to tailor treatment and stratify the prognosis. N-staging is based on the number and the localization of suspicious regional nodes on physical examination and/or imaging. Since clinical examination of the axillary cavity is associated with a high false negative rate, imaging modalities play a central role. In the presence of a T1 or T2 tumor and 0-2 suspicious nodes, on imaging at the axillary level I or II, a patient should undergo sentinel lymph node biopsy (SLNB), whereas in the presence of three or more suspicious nodes at the axillary level I or II confirmed by biopsy, they should undergo axillary lymph node dissection (ALND) or neoadjuvant chemotherapy according to a multidisciplinary approach, as well as in the case of internal mammary, supraclavicular, or level III axillary involved lymph nodes. In this scenario, radiological assessment of lymph nodes at the time of diagnosis must be accurate. False positives may preclude a sentinel lymph node in an otherwise eligible woman; in contrast, false negatives may lead to an unnecessary SLNB and the need for a second surgical procedure. In this review, we aim to describe the anatomy of the axilla and breast regional lymph node, and their diagnostic features to discriminate between normal and pathological nodes at Ultrasound (US) and Magnetic Resonance Imaging (MRI). Moreover, the technical aspects, the advantage and limitations of MRI versus US, and the possible future perspectives are also analyzed, through the analysis of the recent literature.

DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43-0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) represent a group of hematological disorders that are traditionally considered as indistinct slow progressing conditions; still, a subset of cases shows a rapid evolution towards myelofibrotic bone marrow failure. Specific abnormalities in the megakaryocyte lineage seem to play a central role in this evolution, especially in the bone marrow fibrosis but also in the induction of myeloproliferation. In this review, we analyze the current knowledge of prognostic factors of MPNs related to their evolution to myelofibrotic bone marrow failure. Moreover, we focused the role of the megakaryocytic lineage in the various stages of MPNs, with updated examples of MPNs in vitro and in vivo models and new therapeutic implications.

Primary lymphoma of the peripheral nerve is very rare and occurs most frequently in sciatic nerves. We describe the first patient reported in literature with a primary lymphoma in a pure sensory peripheral nerve of the upper limb. A woman in her 40s, with painful swelling and dysaesthesias in her left forearm in the past 3 months, was presented at our unit. Clinical MRI and ultrasound findings revealed a lesion that showed signs of a peripheral nerve sheath tumour. After complete excision, morpho-pathological evaluation revealed a primary B-cell lymphoma. The patient underwent radiotherapy and at the last follow-up there were no signs of residual pathology. Peripheral neuropathy may be caused by a lymphoma involving the nerve. Hand surgeons have to distinguish primary lymphoma of the peripheral nerves from schwannoma for their different clinical behaviour., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Philadelphia-negative chronic myeloproliferative neoplasms (MPN) have been traditionally considered as indistinctly slowly progressing conditions; recent evidence proves that a subset of cases have a rapid evolution, so that MPN prognosis needs to be personalized. We identified a new morphological parameter, defined as megakaryocytic activation (M-ACT) based on the coexistence of megakaryocytic emperipolesis, megakaryocytes (MK) cluster formation and evidence of arrangement of collagen fibers around the perimeter of MK. We retrospectively analyzed the bone marrow biopsy of two MPN cohorts of patients with polycythemia (PV) (n=64) and non-PV patients (including essential thrombocythemia, and early/prefibrotic primary myelofibrosis [PMF]) (n=222). M-ACT showed a significant correlation with splenomegaly, white blood cell count, and lactate dehydrogenase serum levels in both groups, with JAK2 V617F allele burden in PV patients, and with CALR mutations, and platelet count in non-PV patients. Progression-free survival, defined as PV-to-secondary MF progression and non-PV-to-overt PMF, was worse in both PV and early/prefibrotic PMF patients with M-ACT in comparison to those without M-ACT (P<0.0001). Interestingly, M-ACT was not found in the subgroup of essential thrombocythemia patients. In conclusion, M-ACT can be helpful in the differential diagnosis of MPN and can represent a new morphologic parameter with a predictive value for progression of MPN.

Thyroid nodules are common and typically detected by palpation and/or ultrasound (US). Guidelines have defined the management of large nodules, but controversy exists regarding nodules ≤ 1 cm. We evaluated a cohort of patients with subcentimeter nodules to determine their rate of malignancy (ROM). A total of 475 thyroid FNAs of lesions ≤ 1 cm with available follow-up were identified from January 2015-December 2019. For comparative analysis, we added a control series of 606 thyroid lesions larger than 1 cm from the same reference period. All aspirates were processed with liquid-based cytology and classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Subcentimeter nodules were stratified as 35 category I-non-diagnostic cases (ND; 7.3%), 144 category II-benign lesions (BL; 30.3%), 12 category III-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; 2.5%), 12 category IV-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN; 2.5%), 124 category V-suspicious for malignancy (SM; 26.1%), and 148 category VI-positive for malignancy (PM; 31.1%). A total of 307 cases (64.6%) underwent subsequent surgery. Only one ND and three BLs had a malignant outcome. ROM for indeterminate lesions (III + IV) was 3.2%; with 1.6% for category III and 3.2% for category IV. ROM for the malignant categories (V + VI) was 88.2%. The control cohort of lesions demonstrated a higher number of benign histological diagnoses (67.3%). We documented that 57.2% of suspected subcentimeter lesions were malignant, with a minor proportion that belonged in indeterminate categories. There were very few ND samples, suggesting that aspirates of subcentimeter lesions yield satisfactory results. Suspected US features in subcentimeter lesions should be evaluated and followed by an interdisciplinary team for appropriate patient management.

Endometrial carcinoma represents the most common gynecological cancer in Europe and the USA. Histopathological classification based on tumor morphology and tumor grade has played a crucial role in the management of endometrial carcinoma, allowing a prognostic stratification into distinct risk categories, and guiding surgical and adjuvant therapy. In 2013, The Cancer Genome Atlas (TCGA) Research Network reported a large scale molecular analysis of 373 endometrial carcinomas which demonstrated four categories with distinct clinical, pathologic, and molecular features: POLE/ultramutated (7% of cases) microsatellite instability (MSI)/hypermutated (28%), copy-number low/endometrioid (39%), and copy-number high/serous-like (26%). In the present article, we report a detailed histological and molecular review of all endometrial carcinoma histotypes in light of the current ESGO/ESTRO/ESP guidelines. In particular, we focus on the distribution and prognostic value of the TCGA groups in each histotype.

Colonization of breast carcinoma by non-neoplastic melanocytes of epidermal origin was first described by Azzopardi and Eusebi in 1977. We herein report two cases on the exceptional clinical and pathological features of this phenomenon in a 66-year-old and a 51-year-old patients. The pathogenesis is not fully understood, but a disrupted basement membrane and the role of tumoral growth factors are considered essential.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase ( HMBS ) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.

Biopsy proven Gleason score is essential to decide treatment modalities for prostate cancer, either surgical (radical prostatectomy) or non-surgical (active surveillance, watchful waiting, radiation therapy and hormone therapy). Several studies indicated that biopsy proven Gleason score may underestimate Gleason score at radical prostatectomy, hence we aimed to calculate the minimum length of biopsy cores needed to have Gleason score agreement. We evaluated 115 prostate cancer patients who underwent multiparametric magnetic resonance/transperineal ultrasonography fusion biopsy and subsequently, radical prostatectomy. Biopsy proven Gleason score was consistent with Gleason score at subsequent radical prostatectomy in 82.6% of patients, while in 17.4% of patients, Gleason score was higher at radical prostatectomy. Gleason score agreement showed a strong direct association with a ratio > 0.05 between the total volume of biopsies performed in tumor area and the volume of the corresponding tumor at radical prostatectomy. A significant association was also found with a ratio ≥ 0.0034 between the tumor volume in the biopsy and the volume of the corresponding tumor at radical prostatectomy and with a ratio ≥ 0.086 between the tumor volume in the biopsy and the total volume of biopsies performed in the tumor area. These results could be exploited to calculate the minimum length of biopsy cores needed to have a correct Gleason score estimation and therefore be used in fusion targeted biopsies with volume adjustments.

Objective: We compared ultrastaging and one-step nucleic acid amplification (OSNA) examination of sentinel lymph nodes in two homogeneous patient populations diagnosed with early stage cervical cancer. The primary aim of our study was to evaluate the rate and type of sentinel lymph node metastases detected by ultrastaging and OSNA assay. Secondary aims were to define the sensitivity and the negative predictive value of sentinel lymph node biopsy assessed with OSNA and ultrastaging and to define the role of sentinel lymph node assessment in predicting non-sentinel lymph node status., Methods: Consecutive patients who underwent surgery (radical hysterectomy or trachelectomy or cervical conization) at our institution, between January 2018 and March 2020, were enrolled. All patients had a preoperative diagnosis of early-stage cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) 2018 stages IA-IIB) and underwent sentinel lymph node assessment with ultrastaging or OSNA. Patients with advanced FIGO stages and special histology subtypes (other than squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) or patients with sentinel lymph nodes analyzed only with hematoxylin and eosin were excluded. Clinical data were compared using the χ 2 test and Fisher's exact test. A κ coefficient was determined with respect to lymph node assessment. A p value <0.05 was considered statistically significant., Results: A total of 116 patients were included in this retrospective analysis (53 ultrastaging, 63 OSNA). Overall, 531 and 605 lymph nodes were removed in the ultrastaging and OSNA groups, respectively, and 140 and 129 sentinel lymph nodes were analyzed in the ultrastaging and OSNA groups, respectively. 22 patients had metastatic sentinel lymph nodes: 6 (11.3%) of 53 patients in the ultrastaging group and 16 (25.4%) of 63 patients in the OSNA group. The total amount of positive SLNs was 7 (5%) of 140 in the ultrastaging group and 21 (16.3%) of 129 in the OSNA group, respectively (p=0.0047). Pelvic lymphadenectomy was performed in 26 (49.1%) of 53 patients in the ultrastaging group and in 34 (54%) of 63 patients in the OSNA group due to comorbidities. Metastatic non-sentinel lymph nodes were found in 4 patients: 2 (7.7%) of 26 patients in the ultrastaging group and 2 (5.9%) of 34 patients in the OSNA group, respectively. The total amount of positive pelvic lymph nodes was 3 (0.6%) of 531 in the ultrastaging group and 4 (0.7%) of 605 in the OSNA group (p=0.61). In the OSNA group, only 2 patients with negative sentinel lymph nodes had metastatic disease in the pelvic lymph nodes. By contrast, no patients with OSNA-positive sentinel lymph nodes had metastases in the pelvic lymph nodes. In the ultrastaging group, all patients with negative sentinel lymph nodes did not have metastatic disease in other pelvic lymph nodes., Conclusions: OSNA assessment of sentinel lymph nodes was associated with a negative predictive value of 91% but poor reliability in detecting node metastases in non-sentinel pelvic lymph nodes. Of note, the ultrastaging protocol revealed higher sensitivity and more reliability in predicting pelvic non-sentinel lymph node status., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)