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Vascular lesions of the breast comprise a heterogeneous group that includes a variety of benign, atypical, and malignant lesions. These are a diagnostic challenge given variable clinical, radiological and pathological presentation, especially when they are small and asymptomatic. We present 2 cases of these rare lesions of the breast which were occult to mammographics and ultrasound studies. Both the lesions were detected only on magnetic resonance imaging, most helpful in the diagnosis of these rare tumor. Histopathological examinations following the magnetic resonance guided biopsies, were initially interpreted as negative for breast cancer in both cases. These turned out to be respectively a low grade angiosarcoma and a benign vascular lesion after a new histopathological examination following a larger magnetic resonance guided biopsies performed in light of the radiology-pathology discordance. Although rare, it is important to consider vascular tumours of the breast; radiologists need to be aware such tumors may present non-specific imaging features.

Primary cutaneous CD30+ lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis. The prognosis of the disease is usually excellent but, in a minority of cases, it presents with extracutaneous involvement and aggressive behavior. The case we present—relapsed after surgical excision, immunosuppressive therapy, and conventional chemotherapy—is the first one treated with Autologous Stem Cell transplant followed by Brentuximab Vedotin consolidation, a scheme already used for high risk Hodgkin Lymphoma.

The highly dynamic nature of chromatin’s structure, due to the epigenetic alterations of histones and DNA, controls cellular plasticity and allows the rewiring of the epigenetic landscape required for either cell differentiation or cell (re)programming. To dissect the epigenetic switch enabling the programming of a cancer cell, we carried out wide genome analysis of Histone 3 (H3) modifications during osteogenic differentiation of SH-SY5Y neuroblastoma cells. The most significant modifications concerned H3K27me2/3, H3K9me2, H3K79me1/2, and H3K4me1 that specify the process of healthy adult stem cell differentiation. Next, we translated these findings in vivo, assessing H3K27, H3K9, and H3K79 methylation states in biopsies derived from patients affected by basalioma, head and neck carcinoma, and bladder tumors. Interestingly, we found a drastic decrease in H3K9me2 and H3K79me3 in cancer specimens with respect to their healthy counterparts and also a positive correlation between these two epigenetic flags in all three tumors. Therefore, we suggest that elevated global levels of H3K9me2 and H3K79me3, present in normal differentiated cells but lost in malignancy, may reflect an important epigenetic barrier to tumorigenesis. This suggestion is further corroborated, at least in part, by the deranged expression of the most relevant H3 modifier enzymes, as revealed by bioinformatic analysis. Overall, our study indicates that the simultaneous occurrence of H3K9me2 and H3K79me3 is fundamental to ensure the integrity of differentiated tissues and, thus, their combined evaluation may represent a novel diagnostic marker and potential therapeutic target.

Abstract 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.

Prostate cancer is the most frequently diagnosed cancer and the fifth leading cause of cancer death among men in 2020. The clinical decision making for prostate cancer patients is based on the stratification of the patients according to both clinical and pathological parameters such as Gleason score and prostate-specific antigen levels. However, these tools still do not adequately predict patient outcome. The aim of this study was to investigate whether ZNF750 could have a role in better stratifying patients, identifying those with a higher risk of metastasis and with the poorest prognosis. The data reported here revealed that ZNF750 protein levels are reduced in human prostate cancer samples, and this reduction is even higher in metastatic samples. Interestingly, nuclear positivity is significantly reduced in patients with metastatic prostate cancer, regardless of both Gleason score and grade group. More importantly, the bioinformatics analysis indicates that ZNF750 expression is positively correlated with better prognosis. Overall, our findings suggest that nuclear expression of ZNF750 may be a reliable prognostic biomarker for metastatic prostate cancer, which lays the foundation for the development of new biological therapies.

Immune checkpoint inhibitors (ICIs) have a modest clinical activity when administered as monotherapy against breast cancer (BC), the most common malignancy in women. Novel combinatorial strategies are currently being investigated to overcome resistance to ICIs and promote antitumor immune responses in a greater proportion of BC patients. Recent studies have shown that the BC abnormal vasculature is associated with immune suppression in patients, and hampers both drug delivery and immune effector cell trafficking to tumor nests. Thus, strategies directed at normalizing (i.e., at remodeling and stabilizing) the immature, abnormal tumor vessels are receiving much attention. In particular, the combination of ICIs with tumor vessel normalizing agents is thought to hold great promise for the treatment of BC patients. Indeed, a compelling body of evidence indicates that the addition of low doses of antiangiogenic drugs to ICIs substantially improves antitumor immunity. In this review, we outline the impact that the reciprocal interactions occurring between tumor angiogenesis and immune cells have on the immune evasion and clinical progression of BC. In addition, we overview preclinical and clinical studies that are presently evaluating the therapeutic effectiveness of combining ICIs with antiangiogenic drugs in BC patients.

Defects in achieving a fully differentiated state and aberrant expression of genes and microRNAs (miRs) involved in differentiation are common to virtually all tumor types. Here, we demonstrate that the zinc finger transcription factor ZNF281/Zfp281 is down‐regulated during epithelial, muscle, and granulocytic differentiation in vitro. The expression of this gene is absent in terminally differentiated human tissues, in contrast to the elevated expression in proliferating/differentiating ones. Analysis of the 3’UTR of ZNF281/Zfp281 revealed the presence of numerous previously undescribed miR binding sites that were proved to be functional for miR‐mediated post‐transcriptional regulation. Many of these miRs are involved in differentiation pathways of distinct cell lineages. Of interest, ZNF281/Zfp281 is able to inhibit muscle differentiation promoted by miR‐1, of which ZNF281/Zfp281 is a direct target. These data suggest that down‐regulation of ZNF281/Zfp281 during differentiation in various cell types may occur through specific miRs whose expression is tissue‐restricted. In addition, we found that in rhabdomyosarcoma and leiomyosarcoma tumors, the expression of ZNF281/Zfp281 is significantly higher compared with normal counterparts. We extended our analysis to other human soft tissue sarcomas, in which the expression of ZNF281 is associated with a worse prognosis. In summary, we highlight here a new role of ZNF281/Zfp281 in counteracting muscle differentiation; its down‐regulation is at least in part mediated by miR‐1. The elevated expression of ZNF281/Zfp281 in soft tissue sarcomas warrants further analysis for its possible exploitation as a prognostic marker in this class of tumors.

T-cell lymphomas and leukemias are highly heterogeneous groups of rare disorders. We report a case of a 68-year-old man patient who develops two different T-cell neoplasms (Large Granular Lymphocyte Leukemia [LGLL] in 2018 and Peripheral T-cell non-Hodgkin lymphoma not otherwise specified [PTCL-NOS] in 2019) with a previous diagnosis of B-cell marginal zone lymphoma in 2010, treated with two lines of chemo-immunotherapy. The coexistence of these different T-cell neoplasms is rarely reported in literature and, moreover, is usually described as an LGLL transformation into PTCL-NOS; differently from these examples, herein the simultaneous conditions appear to be driven by different T-cell clones. Furthermore, the PTCL-NOS had a quite unusual behaviour, with a good disease control without intensive treatment. Because of these features, it could belong to a subgroup of indolent PTCL-NOS, not yet described in the WHO classification of T-cell neoplasms, which could benefit of less aggressive treatment.

The understanding of the pathogenesis of renal cell carcinoma led to the development of targeted therapies, which dramatically changed the overall survival rate. Nonetheless, despite innovative lines of therapy accessible to patients, the prognosis remains severe in most cases. Kidney cancer rarely shows mutations in the genes coding for proteins involved in programmed cell death, including p53. In this paper, we show that the molecular machinery responsible for different forms of cell death, such as apoptosis, ferroptosis, pyroptosis, and necroptosis, which are somehow impaired in kidney cancer to allow cancer cell growth and development, was reactivated by targeted pharmacological intervention. The aim of the present review was to summarize the modality of programmed cell death in the pathogenesis of renal cell carcinoma, showing in vitro and in vivo evidence of their potential role in controlling kidney cancer growth, and highlighting their possible therapeutic value.

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: The purpose of this preliminary study is to evaluate the feasibility of the excisional ultrasound (US) guided vacuum-assisted breast biopsy (VAE), followed by US-guided Laser Interstitial Thermal Therapy (LITT) in the treatment of unifocal ductal breast carcinomas ≤ 1 cm and estimate the ablation rate analyzing the final histopathological results after subsequent surgical excision. Methods: In a single session 11 female patients with unifocal less than a centimeter breast cancer underwent 2 different minimally invasive percutaneous US-guided techniques: a VAE breast biopsy with an 8 G needle to remove the lesion and, immediately after, a LITT ablation in the biopsy site. Four weeks later, all patients underwent radiological follow-up. Afterward, a systematic surgery was performed, the ablation rate was calculated, and iconographic and histological features were correlated. Results: Average maximum diameter of the lesions was 7.6 mm (5-10 mm). No patient reported pain or discomfort during procedure. 1/11 patient (9.1%) reported an early minor complication (a small superficial skin burn). After surgical excision, the histopathological evaluation reported in 10/11 cases (90.9%) complete ablation of the target lesion. In only one case (9.1%) residual cancer was detected. The necrotic-hemorrhagic cavities showed a mean maximum diameter of 27.3 mm (20-35 mm). Conclusions: Laser ablation performed after excisional biopsy could be considered a valid alternative to surgical excision for the treatment of lesions ≤ 1 cm, if carried out by expert radiologists. The association of these minimally invasive percutaneous methods has proven to be reliable, fast, and safe with an ablation rate of 90.9% and excellent aesthetic results. RM and CESM are potentially able to quantifying treatment results and to follow-up the ablation effects.

The main aim of this study was to investigate the risk of prostate cancer metastasis formation associated with the expression of ETS homologous factor (EHF) in a cohort of bioptic samples. To this end, the expression of EHF was evaluated in a cohort of 152 prostate biopsies including primary prostate cancers that developed metastatic lesions, primary prostate cancers that did not develop metastasis, and benign lesions. Data here reported EHF as a candidate immunohistochemical prognostic biomarker for prostate cancer metastasis formation regardless of the Gleason scoring system. Indeed, our data clearly show that primary lesions with EHF positive cells ≥40% had a great risk of developing metastasis within five years from the first diagnosis. Patients with these lesions had about a 40-fold increased risk of developing metastasis as compared with patients with prostate lesions characterized by a percentage of EHF positive cells ≤30%. In conclusion, the immunohistochemical evaluation of EHF could significantly improve the management of prostate cancer patients by optimizing the diagnostic and therapeutic health procedures and, more important, ameliorating the patient’s quality of life.

Abstract Background In the last decade, several studies have reported an unexpected and seemingly paradoxical inverse correlation between BMI and incidence of cardiovascular diseases. This so called “obesity paradox effect” has been mainly investigated through imaging methods instead of histologic evaluation, which is still the best method to study the instability of carotid plaque. Therefore, the purpose of our study was to evaluate by histology the role of obesity in destabilization of carotid plaques and the interaction with age, gender and other major cerebrovascular risk factors. Methods A total of 390 carotid plaques from symptomatic and asymptomatic patients submitted to endarterectomy, for whom complete clinical and laboratory assessment of major cardiovascular risk factors was available, were studied by histology. Patients with a BMI ≥ 30.0 kg/m2 were considered as obese. Data were analyzed by multivariate logistic regression and for each variable in the equation the estimated odds ratio (OR) was calculated. Results Unstable carotid plaque OR for obese patients with age

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.

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. 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 h; T2 12 h; T3 24 h) by real-time PCR. Detection of antibodies to SARS-CoV-2 was performed by Maglumi 2019-nCoV IgM/IgG chemiluminescence assay. SARS-CoV-2 viral RNA was still detectable in 70.3% of cases within 2 h after death and in 66,6% of cases up to 24 h after death. Our data showed an increase of the viral load in 78,6% of positive individuals 24 h post-mortem (T3) in comparison to that evaluated 2 h after death (T1). Noteworthy, we detected a positive T3 post-mortem swab (24 h after death) from 4 subjects who were negative at T1 (2 h after death). 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.

Background: this study aims to investigate the possible association among the histopathologic features of carotid plaque instability, the presence of micro- or macrocalcifications, the expression of in situ inflammatory biomarkers, and the occurrence of the major risk factors in this process in a large series of carotid plaques. Methods: a total of 687 carotid plaques from symptomatic and asymptomatic patients were collected. Histological evaluation was performed to classify the calcium deposits in micro or macrocalcifications according to their morphological features (location and size). Immunohistochemistry was performed to study the expression of the main inflammatory biomarkers. Results: results here reported demonstrated that calcifications are very frequent in carotid plaques, with a significant difference between the presence of micro- and macrocalcifications. Specifically, microcalcifications were significantly associated to high inflamed unstable plaques. Paradoxically, macrocalcifications seem to stabilize the plaque and are associated to a M2 macrophage polarization instead. Discussion: the characterization of mechanisms involved in the formation of carotid calcifications can lay the foundation for developing new strategies for the management of patients affected by carotid atherosclerosis. Data of this study could provide key elements for an exhaustive evaluation of carotid plaque calcifications allowing to establish the risk of associated clinical events.

Skin cancer is the most common type of cancer worldwide. Ozone depletion and climate changes might cause a further increase in the incidence rate in the future. Although the early detection of skin cancer enables it to be treated successfully, some tumours can evolve and become more aggressive, especially in the case of melanoma. Therefore, good diagnostic and prognostic markers are needed to ensure correct detection and treatment. Transcription factor p63, a member of the p53 family of proteins, plays an essential role in the development of stratified epithelia such as skin. In this paper, we conduct a comprehensive review of p63 expression in different types of skin cancer and discuss its possible use in the diagnosis and prognosis of cutaneous tumours.

WHIM syndrome is a condition in which affected persons have chronic peripheral neutropenia, lymphopenia, abnormal susceptibility to human papilloma virus infection, and myelokathexis. Myelokathexis refers to the retention of mature neutrophils in the bone marrow (BM), which accounts for degenerative changes and hypersegmentation. Most patients present heterozygous autosomal dominant mutations of the gene encoding CXCR4. Consequently, aberrant CXCL12/CXCR4 signaling impairs the receptor downregulation causing hyperactivation (gain-of-function) that affects BM homing for myelopoiesis and lymphopoiesis and the release of neutrophils in the bloodstream. We report the case of a 26-year-old female with severe foot and hand cutaneous warts since childhood, recalcitrant genital condylomatas, bacterial infections, and intraepithelial cervical neoplasia. Laboratory tests revealed severe B lymphopenia and HPV high and low risk types. HIV testing was negative. Not only CXCR4 but also GATA2, NEMO, and CD40L gene mutations were excluded. BM smears revealed, in the presence of a normal cellularity, hyperplasia of myeloid cells (MPO positive) and karyorrhexis, especially in neutrophils and eosinophils. Of note, neutrophils with altered lobation of nuclei connected by long thin chromatin filaments were observed. Our patient presented a clinical and histological picture reminiscent of WHIM in the presence of normal peripheral neutrophil counts and wild-type CXCR4 gene. Although the BM did not reveal a classical pattern of myelokathexis, the observation of consistent signs of neutrophil dysplasia has fuelled the hypothesis of a novel WHIM variant or a novel immunodeficiency. We speculate that abnormalities that affect CXCR4/CXCL12 pair, including GRK levels or activity, might be responsible for this WHIM-like disorder.

Background Renal denervation represents an emerging treatment for resistant hypertension in patients with end‐stage renal disease, but data about the anatomic substrate of this treatment are lacking. Therefore, the aim of this study was to investigate the morphological basis of sympathetic hyperactivity in the setting of hemodialysis patients to identify an anatomical substrate that could warrant the use of this new therapeutic approach. Methods and Results The distribution of sympathetic nerves was evaluated in the adventitia of 38 renal arteries that were collected at autopsy or during surgery from 25 patients: 9 with end‐stage renal disease on dialysis (DIAL group) and 16 age‐matched control nondialysis patients (CTRL group). Patients in the DIAL group showed a significant increase in nerve density in the internal area of the peri‐adventitial tissue (within the first 0.5 mm of the beginning of the adventitia) compared with the CTRL group (4.01±0.30 versus 2.87±0.28×mm2, P=0.01). Regardless of dialysis, hypertensive patients with signs of severe arteriolar damage had a greater number of nerve endings in the most internal adventitia, and this number was significantly higher than in patients without hypertensive arteriolar damage (3.90±0.36 versus 2.87±0.41×mm2, P=0.04), showing a correlation with hypertensive arteriolar damage rather than with hypertensive clinical history. Conclusions The findings from this study provide a morphological basis underlying sympathetic hyperactivity in patients with end‐stage renal disease and might offer useful information to improve the use of renal denervation in this group of patients.

Occasionally, non‐Hodgkin lymphomas (NHL) occur simultaneously or subsequently to Hodgkin disease. We report on a case of a woman with Hodgkin lymphoma treated with ABVD, who developed 4 years later T‐cell NHL with both nodal and extranodal involvement. Brentuximab vedotin could be an effective choice in treating metachronous T‐cell NHL. [ABSTRACT FROM AUTHOR]