Fatal acute graft-versus-host disease in Sézary Syndrome treated with Mogamulizumab and hematopoietic cell transplantation.

Sézary syndrome (SS) is a rare and aggressive T-cell lymphoma with a poor prognosis in advanced stages. Allogeneic hematopoietic cell transplantation (allo-HCT) offers a potential cure, but complications such as graft-versus-host disease (GvHD) remain a clinical challenge. Mogamulizumab, a humanized anti-CC chemokine receptor 4 (CCR4) antibody, is sometimes used as a bridge to transplantation, but its potential interactions with allo-HCT are unclear. This report describes the case of a 37-year-old man with advanced SS who received mogamulizumab therapy followed by allo-HCT from an HLA-identical sibling donor. The patient developed severe gastrointestinal acute GvHD, which was treated with steroids and infliximab. However, the condition rapidly progressed to severe intestinal symptoms and life-threatening haemorrhagic shock, ultimately resulting in the patient's death. This case highlights a potential link between mogamulizumab and severe acute GvHD promoted by drug-induced suppression of regulatory T cells. Further research is required to fully understand the interaction between mogamulizumab and allo-HCT and to determine whether it is an optimal approach as a bridge to transplant therapy. This paradigmatic case suggests the need of personalizing transplant strategies by selecting appropriate conditioning therapy and GvHD prophylaxis to minimize potential toxicity.

PD-L1 testing in metastatic triple negative breast cancer: Results of an Italian survey.

BACKGROUND: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers. Atezolizumab was approved for patients with metastatic triple-negative breast cancers whose tumors 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 six-month 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 cases close to cut-off value and the tested samples. RESULTS: The SP142 assay was available in only eight centers. In case of positive result, most centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to ⩽ 5%, with values close to the cut-off point (⩾ 1% or < 1%) being the greatest challenge.Most of the centers (6/8, 75%) tested material from both their own and other hospitals. In most centers, the evaluations were performed either on primary tumors or metastasis, in particular lymph nodes (5/8, 62.5%), followed by lung (3/8, 37.5%) and liver (1/8, 12.5%) metastasis. CONCLUSION: Our results raise some important issues concerning the evaluation of PD-L1 in the "real-life" setting, providing strategies for its implementation.

In Vivo Identification of H3K9me2/H3K79me3 as an Epigenetic Barrier to Carcinogenesis.

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.

Awake Breast Surgery: A Systematic Review.

BACKGROUND/AIM: Awake surgery has become a valid alternative to general anesthesia in many surgery fields. This technique played a very important role during the COVID-19 period. The growing use of this technique has many advantages. We performed a systematic review to study the potentialities of awake breast surgery. MATERIALS AND METHODS: We searched Pubmed, Embase, and Cochrane library database and retrieved a total of 109 records. Forty-nine of them were excluded as unsuitable. Finally, we selected a total of 12 records concerning different types of studies for topic appropriateness. Three reviewers reviewed independently each record. RESULTS: Five articles analyzing the sustainability of awake surgery during the COVID-19 period were selected. In addition, one article analyzing the impact on the immune system and six articles and eight case reports analyzing anesthetic techniques were also selected. The studies analyzing awake breast surgery during the COVID-19 period showed advantages in terms of sustainability and length of hospitalization. The study analyzing the immune response after awake breast surgery showed lesser lymphocyte response than the general anesthesia group. The studies analyzing anesthetic techniques in awake breast surgery showed that the nerve blocks allow good level of safety and postoperative pain control. CONCLUSION: The awake breast surgery and fast track implementation shortened hospital stays and reduced costs, without influencing the surgical results. Furthermore, awake breast surgery reduced surgical stress compared to general anesthesia. Among the various anesthetic techniques, nerve blocks are the most advantageous in terms of safety and efficacy compared to epidural anesthesia.

Acute Myeloid Leukemia with NPM1 Mutation and Disseminated Leukemia Cutis: Achievement of Molecular Complete Remission by Venetoclax/Azacitidine Combination in a Very Old Patient.

We describe a case of acute myeloid leukemia with NPM1 mutation and disseminated leukemia cutis in a very old patient, who achieved a long-lasting response to the azacitidine/venetoclax combination with molecular complete remission, given the potential value of this rarely observed clinical outcome.

ZNF750: A Novel Prognostic Biomarker in Metastatic Prostate Cancer.

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.

The Combination of Immune Checkpoint Blockade with Tumor Vessel Normalization as a Promising Therapeutic Strategy for Breast Cancer: An Overview of Preclinical and Clinical Studies.

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.

No Time to Die: How Kidney Cancer Evades Cell Death.

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.

Small vascular lesions of the breast diagnosed by magnetic resonance imaging-guided vacuum assisted biopsy: Report of 2 cases.

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.

Aggressive Primary Cutaneous Anaplastic T-Cell Lymphoma Successfully Treated with Autologous Stem Cell Transplant and Brentuximab Vedotin Consolidation: Case Report and Review of the Literature.

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 ETS Homologous Factor (EHF) Represents a Useful Immunohistochemical Marker for Predicting Prostate Cancer Metastasis.

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.

Coexistence of T-Large Granular Lymphocyte Leukemia and Peripheral T Cell Lymphoma-NOS with Indolent Behavior.

T-cell lymphomas and leukemias are highly heterogeneous groups of rare disorders. We report a case of a 68-year-old man patient who developed 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 the literature. Moreover, it 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 quite unusual behavior, with 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 from less aggressive treatment.

Macrophage Activation and M2 Polarization in Wound Bed of Diabetic Patients Treated by Dermal/Epidermal Substitute Nevelia.

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.

Adult onset Xanthogranuloma presenting as a solitary laryngeal localization: case report and review of literature.

Juvenile Xanthogranuloma (XG) is a rare disorder that belongs to the heterogeneous group of histiocytic neoplasms, characterized by a clonal expansion of non-Langerhans cell histiocytes that share a dermal macrophage phenotype. Although the head and neck region is the most common reported site of involvement by the Juvenile Xanthogranuloma family, laryngeal localization is extremely rare. We report a unique case of Adult Onset Xanthogranuloma with subglottic localization, presenting as a solitary laryngeal mass without other systemic or cutaneous lesions. A review of the previously described cases of laryngeal Xanthogranuloma has been performed, highlighting 7 cases of Juvenile Xanthogranuloma and only 3 cases of Adult Onset Xanthogranuloma. Despite the extreme rarity of laryngeal localization of XG, this histiocytic neoplasm should be considered as a differential diagnosis for laryngeal masses causing airway obstruction, even in the absence of other concomitant manifestations.

Juan Rosai as master of our comprehensive understanding of thymus and thymoma.

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.

High Sensitivity C-Reactive Protein Increases the Risk of Carotid Plaque Instability in Male Dyslipidemic Patients.

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.

A thymic hyperplasia-related reversible complete atrioventricular block: When compression is more important than compressor.

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.

Effects of Risk Factors on In Situ Expression of Proinflammatory Markers Correlated to Carotid Plaque Instability.

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.

The risk of carotid plaque instability in patients with metabolic syndrome is higher in women with hypertriglyceridemia.

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.

Persistence of SARS-CoV-2 Viral RNA in Nasopharyngeal Swabs after Death: An Observational Study.

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.