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A 19-year-old patient presented for syncope with third-degree AV block (TDAVB) at ECG. A chest-CT showed a thymic mass that could be responsible for TDAVB due to extrinsic vagal nerve compression. Thymectomy led to complete AV block resolution. An extrinsic vagal compression mechanism should be considered among causes of complete atrioventricular block.

Background: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers (mTNBC). Atezolizumab was approved for patients with mTNBC whose tumours express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 Pathology Departments of the Lazio Region during a 6-months period.Methods: The survey comprised 12 questions regarding the availability of SP142 in the Pathology Departments, the percentage of positive tests, the difficulties of pathologists in case close to cut-off value and the tested samples.Results: The SP142 assay was available only in 8 Centers. In case of positive result, most Centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to Conclusion: Our results raise some important issues concerning the evaluation of PD-L1 in the “real-life” setting, providing strategies for its implementation.

Clinical evidences have shown good results using dermal/epidermal substitutes (DESs) to treat diabetic foot ulcers. Recent studies suggest that, in addition to their scaffold action, DESs may favor wound healing by influencing wound bed inflammatory cells. This study aims to investigate whether DES may influence the inflammatory infiltrate and macrophages polarization toward a reparative phenotype. Fifteen diabetic patients with chronic foot ulcers have been randomly enrolled: 5 treated only by standard of care, served as control group (CG), and 10 treated with DES composed of type 1 bovin collagen (Nevelia, SYMATESE) considered as test group (TG). A biopsy was taken at baseline (T0) and after 30 days (T1). From bioptic paraffin specimen histological, immunohistochemical, and immunofluorescence analysis was performed. Immunohistochemistry reactions evaluated the number of M1 macrophage (CD38+) and M2 macrophage (CD163+). TG patients displayed general macrophage activation and their greater polarization toward M2 subpopulation 30 days after DES implant, compared with CG. From T0 to T1 there was a significant decrease of CD38+ (230 ± 42 and 135 ± 48 mm2, respectively; P < .001) and significant increase of CD163+ (102 ± 21 positive cells/mm2 and 366 ± 42 positive cells/mm2, respectively; P < .001). Confocal microscopy confirmed an increase of M2 cells as expressed by the reduced CD68+/CD163+ ratio. After 6 months of observation 6 patients (60%) of the TG completely healed, while only 1 patient (20%) healed in the CG ( P < .01). The tested DES makes possible to treat diabetic foot ulcers inducing tissue reparative processes through macrophage activation and M2 reparative polarization.

Primary effusion lymphoma (PEL) is defined as a HHV-8-associated large B-cell lymphoma, which favors HIV-infected young adults, typically presenting as a serous (pleural, pericardial, or peritoneal) effusion with no identifiable tumor mass. Uncommon instances of lymphoid proliferations with the same morphology, immunophenotype, and molecular features as PEL, but occurring as a solid tumor mass without serous cavities involvement, have been termed extracavitary (or solid) variant of PEL. We hereby report the exceptional case of a HIV-associated extracavitary PEL primarily localized to the skin and exhibiting a panniculitis-like presentation. Primary cutaneous presentation of extracavitary PEL is exceedingly uncommon, with only 6 cases previously described in the literature. In light of its atypical immunophenotype, the differential diagnosis in case of skin involvement by extracavitary PEL is challenging: demonstration of HHV-8 infection in neoplastic cells is of pivotal importance. Our case is further atypical in that the lymphoid proliferation underwent complete and protracted regression solely by establishment of highly active antiretroviral therapy.

Background: Male breast-cancer (MBC) is often diagnosed late. Our purpose was to evaluate fine-needle aspiration cytology (FNAC) versus Tru-Cut biopsy (TCNB) in MBC diagnosis. Patients and Methods: Men with suspicious breast lesions were prospectively enrolled; 54 met the inclusion criteria and underwent FNAC and TCNB. FNAC, TCNB and gold-standard results were compared. Results: Unsatisfactory results were 11.1% after FNAC and none after TCNB (p=0.027). After gold-standard evaluation, the diagnosis of FNAC and TCNB was confirmed, respectively, in 63.0% and 98.1% and changed in 37.0% and 1.9% (p

Background/Aim: In 2016, in the United States, more than 50% of breast cancer (BC) cases were diagnosed in patients older than 60 years of age. Our study aimed to estimate the risk of locoregional recurrence (LR) in patients who underwent breast-conservative treatment (BCT), according to age. Patients and Methods: This retrospective monocentric study analyzed 613 cases of patients who underwent BCT between 2003 and 2014. Patients were divided into groups according to age: Under70 (under 70 years old) and Over70 (above 70 years old). Margins width, histology results, prognostic and predictive factors were compared. Subgroup analysis was performed for patients who experienced LR. Results: LR Incidence among Under70 and Over70 was 5.4% and 1.7%, respectively (p

Background: The aim of this study was to evaluate how the high sensitivity C-reactive protein (hs-CRP) values influence the risk of carotid plaque instability in association with other cardiovascular risk factors. Methods: One hundred and fifty-six carotid plaques from both symptomatic and asymptomatic patients requiring surgical carotid endarterectomy were retrospectively collected. According to the modified American Heart Association, atherosclerosis plaques have been histologically distinguished into unstable and stable. The following anamnestic and hematochemical data were also considered: age, gender, hypertension, diabetes mellitus, smoking habit, therapy, low-density lipoprotein (LDL)-C, kidney failure and hs-CRP. Results: The results of our study clearly show that high levels of hs-CRP significantly increase the carotid plaque instability in dyslipidemic patients. Specifically, a 67% increase of the risk of carotid plaque instability was observed in patients with high LDL-C. Therefore, the highest risk was observed in male dyslipidemic patients 2333 (95% CI 0.73–7.48) and in aged female patients 2713 (95% CI 0.14–53.27). Discussion: These data strongly suggest a biological relationship between the hs-CRP values and the alteration of lipidic metabolism mostly in male patients affected by carotid atherosclerosis. The measurement of hs-CRP might be useful as a potential screening tool in the prevention of atheroscletotic disease.

Background Metabolic syndrome certainly favors growth of carotid plaque; however, it is uncertain if it determines plaque destabilization. Furthermore, it is likely that only some components of metabolic syndrome are associated with increased risk of plaque destabilization. Therefore, we evaluated the effect of different elements of metabolic syndrome, individually and in association, on carotid plaques destabilization. Methods A total of 186 carotid endarterectomies from symptomatic and asymptomatic patients were histologically analysed and correlated with major cardiovascular risk factors. Results Metabolic syndrome, regardless of the cluster of its components, is not associated with a significant increase in risk of plaque destabilization, rather with the presence of stable plaques. The incidence of unstable plaques in patients with metabolic syndrome is quite low (43.9 %), when compared with that seen in the presence of some risk factors, but significantly increases in the subgroup of female patients with hypertriglyceridemia, showing an odds ratio of 3.01 (95% CI, 0.25–36.30). Conclusions Our data may help to identify patients with real increased risk of acute cerebrovascular diseases thus supporting the hypothesis that the control of hypertriglyceridemia should be a key point on prevention of carotid atherosclerotic plaque destabilization, especially in post-menopausal female patients.

Obesity and low-grade inflammation are associated with an increased risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The tissue inhibitor of metalloproteinase (TIMP) 3, an endogenous inhibitor of protease activity that represents a key mediator of inflammation, is reduced in inflammatory metabolic disorders and cancer. In contrast, Timp3-deficient mice (Timp3−/−) are highly resistant to developing HCC in response to a diethylnitrosamine (DEN); therefore, we aimed to elucidate the biological role of genetic loss of Timp3 in obesity-related hepatocarcinogenesis. Fourteen-day-old male wild-type (wt) and Timp3−/− mice were injected with 25 mg/kg DEN or an equal volume of saline. After 4 weeks, mice were randomized into two dietary groups and fed either normal or high-fat diet and allowed to grow until 32 weeks of age. Liver histological features were analyzed, and differentially expressed genes in the liver were quantified. In Timp3−/− mice fed with the obesogenic diet, despite the increase in liver steatosis and inflammation, both the number of tumors and the total tumor size are significantly reduced 30 weeks post-DEN injection, compared to control mice. Moreover, Timp3 deletion in hepatocarcinogenesis during obesity is associated with a reduction in FoxM1 transcriptional activity through H19/miR-675/p53 pathway. This study suggests that Timp3 ablation leads to cell cycle perturbation, at least in part by repressing FoxM1 transcriptional activity through H19/miR-675/p53 pathway.

Background: The aim of this study was to investigate the persistence of SARS-CoV-2 in post-mortem swabs of subjects who died from SARS-CoV-2 infection. Methods: The presence of the virus was evaluated post-mortem from airways of 27 SARS-CoV-2 positive patients at three different time points (T1 2 hours; T2 12 hours – T3 24 hours) by real-time PCR. Detection of antibodies to SARS-CoV-2 was performed by Maglumi 2019-nCoV IgM/IgG chemiluminescence assay. Results: SARS-CoV-2 viral RNA was still detectable in 70,3% of cases within 2 hours after death and in 66,6% of cases up to 24 hours after death. Our data showed an increase of the viral load in 78,6% of positive individuals 24 hours post-mortem (T3) in comparison to that evaluated 2 hours after death (T1). Noteworthy, we detected a positive T3 post-mortem swab (24 hours after death) from 4 subjects who were negative at T1 (2 hours after death). Conclusion: The results of our study may have an important value in the management of deceased subjects not only with a suspected or confirmed diagnosis of SARS-CoV-2, but also for unspecified causes and in the absence of clinical documentation or medical assistance.

Breast cancer (BC) is the second leading cause of cancer death in women worldwide, and settings of specific prognostic factors and efficacious therapies are made difficult by phenotypic heterogeneity of BC subtypes. Therefore, there is a current urgent need to define novel predictive genetic predictors that may be useful for stratifying patients with distinct prognostic outcomes. Here, we looked for novel molecular signatures for triple negative breast cancers (TNBCs). By a bioinformatic approach, we identified a panel of genes, whose expression was positively correlated with disease-free survival in TNBC patients, namely IL18R1, CD53, TRIM, Jaw1, LTB, and PTPRCAP, showing specific immune expression profiles linked to survival prediction; most of these genes are indeed expressed in immune cells and are required for productive lymphocyte activation. According to our hypothesis, these genes were not, or poorly, expressed in different TNBC cell lines, derived from either primary breast tumours or metastatic pleural effusions. This conclusion was further supported in vivo, as immuno-histochemical analysis on biopsies of TNBC invasive ductal carcinomas highlighted differential expression of these six genes in cancer cells, as well as in intra- and peri-tumoral infiltrating lymphocytes. Our data open to the possibility that inter-tumour heterogeneity of immune markers might have predictive value; further investigations are recommended in order to establish the real power of cancer-related immune profiles as prognostic factors. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-021-00401-0.

Breast reconstruction plays a fundamental role in the therapeutic process of breast cancer treatment and breast implants represents the leading breast reconstruction strategy. Breast Implant Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL), locoregional recurrence in the skin flap, and skin flap necrosis are well-known complications following mastectomy and immediate breast reconstruction (IBR). We report a case of locoregional cancer recurrence in the mastectomy flap mimicking BIA-ALCL, in a patient who underwent 6 breast procedures in four facilities across 15 years including immediate breast reconstruction with macrotextured breast implants. Despite the rate and onset of the disease, clinicians should be aware of BIA-ALCL. Due to the risk of false negative results of fine needle aspiration, clinical suspicion of BIA-ALCL should drive clinicians' choices, aside from cytological results. In the present case, surgical capsulectomy of the abnormal periprosthesic tissue revealed locoregional recurrence.

Background: Metabolic syndrome certainly favors growth of carotid plaque; however, it is uncertain if it determines plaque destabilization. Furthermore, it is likely that only some components of metabolic syndrome are associated with increased risk of plaque destabilization. Therefore, we evaluated the effect of different elements of metabolic syndrome, individually and in association, on carotid plaques destabilization. Methods: A total of 186 carotid endarterectomies from symptomatic and asymptomatic patients were histologically analysed and correlated with major cardiovascular risk factors. Results: Metabolic syndrome, regardless of the cluster of its components, is not associated with a significant increase in risk of plaque destabilization, rather with the presence of stable plaques. The incidence of unstable plaques in patients with metabolic syndrome is quite low (43.9%), when compared with that seen in the presence of some risk factors, but significantly increases in the subgroup of female patients with hypertriglyceridemia, showing an odds ratio of 3.01 (CI 95% 0.25 - 36.30). Conclusions: Our data may help to identify patients with real increased risk of acute cerebrovascular diseases and may support the hypothesis that the control of hypertriglyceridemia should be a key point on prevention of carotid atherosclerotic plaque destabilization, especially in post-menopausal female patients. Keywords: Metabolic syndrome, carotid, histology, hypertriglyceridemia , post-menopause.

Summary In this study, the authors report on the activity of Juan Rosai, one of the pathologists most engaged in the definition of cells, diseases and tumors occurring in the thymus and in the mediastinum during the last 60 years. With his morphological skills and tireless interest in clarification of disease patterns, he contributed extraordinarily to expand our knowledge of the mediastinal diseases and to improve our diagnostic approach. He determined extraordinary advances also in trasmission electron microscopy and in immunohistochemistry as powerful diagnostic tools. Moreover, he proposed and promoted, together with an international panel of Pathologists, the World Health Classification of Thymic tumors as a definite progress in our comprehension and diagnostics of thymic epithelial tumors (TET). Our purpose is to review J. Rosai’s achievements in thymic normal structure, in TET and particularly in the entity now definied as “thymoma”, in distinction from the thymic carcinoma. To do this, our narrative will also be based on personal memories, longstanding collaborations and/or friendship with J. Rosai.

Patient: Female, 59-year-old Final Diagnosis: Invasive breast carcinomas of no special type (NST) Symptoms: Recurrent hemorrhagic cystic lesion Medication: — Clinical Procedure: — Specialty: Surgery Objective: Challenging differential diagnosis Background: Breast trauma can always have diagnostic pitfalls. In the presence of a recurrent hemorrhagic cysts, cancer should always be suspected. Case Report: A 59-year-old woman noted a palpable mass after breast trauma from falling at home. Radiological exams showed a breast cyst with well-defined margins, with corpuscular and dense fluid components. First, a conservative approach was implemented. One week later, a fine-needle aspiration cytology (FNAC) of the mass showed bloody fluid without atypical cells. Three weeks later, the patient was emergently evaluated due to increased size of the lesion and anemia. To avoid further blood loss and due to suspected malignancy, an urgent surgical excision biopsy was planned. Histopathology revealed a poorly-differentiated carcinoma and the patient was treated with left modified radical mastectomy with axillary dissection. Adjuvant chemotherapy was administered. At 6-month follow-up, the patient was free from recurrences. Conclusions: Recurrent hemorrhagic cysts should always be investigated and considered as a possible cancer lesion. Sonography and cytological exam are the first steps in case of suspicious cysts, but false-negative results are common. In such cases, resection of the cyst should be considered. Immediate resection is valid in cases of diagnostic uncertainty or inability to assess the cyst with imaging or biopsy.

BACKGROUND AND AIMS Several studies demonstrated a role of active chronic inflammatory infiltrate in carotid plaques progression suggesting a possible link between cardiovascular risk factors and inflammation-related plaque instability. The aim of this study is therefore to evaluate the possible effects of cardiovascular risk factors on in situ expression of proinflammatory markers associated with carotid plaque instability. METHODS AND RESULTS A tissue microarray containing carotid plaques from 36 symptomatic (major stroke or transient ischemic attack) and 37 asymptomatic patients was built. Serial sections were employed to evaluate the expression of some inflammatory markers by immunohistochemistry [CD3, CD4a, CD8, CD20, CD86, CD163, interleukin (IL)-2, IL-6, IL-17]. Immunohistochemical data were analyzed to study the possible associations between in situ expression of inflammatory biomarker and the main cardiovascular risk factors. Our data demonstrated that plaque instability is associated with the high in situ expression of some cytokines, such as IL-2, IL-6, IL-17. Besides the female sex, none of the risk factors analyzed showed a significant association between the in situ expression of these markers and unstable plaques. A significant increase of IL-6-positive and IL-17-positive cells was observed in unstable atheromatous plaques of female patients, as compared with unstable plaques of male patients. CONCLUSIONS Plaque destabilization is certainly correlated with the presence of the major cardiovascular risk factors, however, our results showed that, with the exception of sex, their action in the evolutive process of plaque instability seems rather nonspecific, favoring a general release of proinflammatory cytokines.

Background/aim Neoadjuvant chemotherapy (NAC) for breast cancer (BC) is the gold standard treatment for locally advanced tumors (LABC) that aims at achieving a complete pathological response (pCR). Studies have been conducted to evaluate and identify te concordance between radiological, histopathological and biological variables of BC and final response to therapy, verified by definitive histological examination after surgery. Patients and methods Ninety-five BC patients were examined and subjected to NAC. Immunohistochemical markers including oestrogen-receptor (ER), progesterone-receptor (PR), Ki67 index, and human epidermal growth factor receptor 2 (HER2) score were examined before and after neoadjuvant treatment. Results Younger age and a significant decrease in ER expression were associated with better prognosis. Triple Negative (TN) and Her2-type breast cancers benefited most from neoadjuvant chemotherapy with higher frequency of pCR. Conclusion HER2-type and TN BC are correlated with best response to NAC. A statistically significant correlation between radiological images and definitive histological examination was not observed.

Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell–cell and cell–matrix adhesion programmes. However, limited knowledge exists on the relevant cell–cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell–cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell–cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.

BACKGROUND/AIM The research objectives of this study were the estimation of the number of misdiagnosed breast lesions by non-expert-center-breast-radiologists (NEBR) and the investigation of the discordant rate (DR) calculated between initial and second opinion. Moreover, this study evaluated the impact of second opinion and the factors associated with DR. MATERIALS AND METHODS A total of 399 patients were sent to our Tertiary Breast Cancer (BC) Center to perform fine needle aspiration/core needle biopsy (FNAC/CNB) after external examination. Lesions were reclassified according to Breast Imaging-Reporting and Data System (BI-RADS). External examinations were classified as breast-expert, not-breast-expert and physicians as expert-center-breast-radiologists (EBR), NEBR, and non-radiologists (NR). Personal/family history of breast cancer (BC), breast-density and presence of prior imaging were collected. RESULTS DR was 74.3%. After second opinion, FNAC/CNB was proposed in 25.7% of cases and 2 additional cancers were detected. About 59.5% of unnecessary FNAC/CNB were avoided. Dense breast, no prior imaging examination and BC family-history were associated with higher DR (p-value

Bone marrow histological features of sickle cell anaemia (SCA) patients during early stages and in the asymptomatic phase of the disease appear an interesting area of study, representing early-stage consequences of SCA with a close relation to its pathophysiology. Unfortunately, this field of research has never been specifically addressed before. Bone marrow biopsies from 26 consecutive Black African SCA patients (M:F=1.6:1; age 2-17 years), free of clinical signs of chronic bone marrow damage, with no recent history of symptomatic vaso-occlusive episodes, and waiting for haematopoietic stem cell transplantation (HSCT), underwent morphological, immunohistochemical and electron microscopy evaluation. Additional comparison with three bone marrow specimens from post-HSCT SCA patients and 10 bone marrow specimens from AS healthy carriers was performed. Bone marrow of SCA patients was normocellular or slighly hypercellular in all cases. Erythroid hyperplasia was a common feature. Myeloid lineage was slightly decreased with normal to slightly diminished neutrophilic granulocytes; CD68 positive monocytic-macrophagic cells appeared slightly increased, with a predominant CD163 positive M2/M(Hb) phenotype. A positive correlation was found between haemoglobin values and number of bone marrow erythroid cells (R2=0.15, p=0.05). Intravascular and interstitial clusters of erythroid sickle cells were found in bone marrow of pre-HSCT homozygous SS SCA patients, as well as heterozygous AS healthy carriers, and the single post-HSCT patient matched to an AS health carrier donor.

A 74-year-old male with diffuse large B-cell lymphoma, with an Ann Arbor stage IV-A, was submitted to immune-chemotherapy in 2014, with complete remission of the disease. Two years later, he presented with a left eye swelling leading to exophthalmos and blurred vision. A core biopsy was performed and revealed a local relapse of the disease. He was considered unfit for intensive salvage chemotherapy and was treated with a combination of rituximab and lenalidomide. After six courses of rituximab plus lenalidomide, the patient showed complete remission and was submitted to maintenance therapy with lenalidomide. After 24 months since the start of lenalidomide monotherapy, we did not observe any progression. In this experience, rituximab plus lenalidomide, without radiotherapy, was a safe and effective therapeutic combination in an elderly patient with a localized relapse of DLBCL who was unfit to receive more aggressive therapies.

Breast cancer is the second leading cause of cancer-related deaths among women, largely due to the progression of a significant fraction of primary tumours to the metastatic stage. Here, we show that zinc-finger protein 750 (ZNF750) opposes the migration and invasion of breast cancer cells by repressing a prometastatic transcriptional programme, which includes genes involved in focal adhesion and extracellular matrix interactions, such as LAMB3 and CTNNAL1. Mechanistically, ZNF750 recruits the epigenetic modifiers KDM1A and HDAC1 to the promoter regions of LAMB3 and CTNNAL1, influencing histone marks and transactivating these genomic sites. Gene expression analysis in cancer patient datasets indicated that ZNF750 and its targets were negative prognostic factors in breast cancer. Together, our findings shed light on the molecular mechanism by which ZNF750 regulates cell migration and invasion, suggesting a role in breast cancer metastasis.

Several evidences support the hypothesis that patients affected by autosomal dominant polycystic kidney disease (ASPKD) show a sympathetic renal hyperactivity. Nevertheless, no morphological evidences are available yet. Therefore, the aim of the study was to demonstrate that an increase in sympathetic renal artery innervation was present in the ADPKD patients by using histological methods. In addition, here we correlated the sympathetic renal artery innervation with the evolutionary state of ADPKD (increase in volume of kidney, onset of chronic renal failure and hypertension). To this end, peri-adventitial innervation of renal arteries was studied using morphological methods from 49 patients in total: 29 underwent surgical nephrectomies for ADPKD and 20 non-dialysis patients (CTRL group) undergoing nephrectomy for other diseases. Nerve density (number of nerves per mm2) was evaluated in the peri-adventitial tissue in a concentric ring that was located within 2 mm from the beginning of the adventitia by using immunohistochemistry. The total nerve density was significantly increased in the ADPKD group (1.26 ± 0.82 × mm2) as compared to controls (0.78 ± 0.40 × mm2) (p = 0.02). Hypertensive patients with ADPKD showed a greater nerve density than control hypertensives. However, the increase in renal sympathetic innervation in the ADPKD patients was found to be independent of hypertension, resistance to antihypertensive therapy, age, sex and kidney volume, as demonstrated by the uni and multivariate analysis. In conclusion, our study better clarifies the effect of sympathetic hyperactivity in the progression of polycystic disease.