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Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium and patients with serious infection can stay in intensive care unit (ICU) for weeks in a clinical scenario of systemic inflammatory response syndrome, likely related to the subsequent development of critical illness polyneuropathy (CIP). It is in fact now accepted that COVID-19 ICU surviving patients can develop CIP; moreover, prone positioning-related stretch may favor the onset of positioning-related peripheral nerve injuries (PNI). Therefore, the urgent need to test drug candidates for the treatment of these debilitating sequelae is emerged even more. For the first time in medical literature, we have successfully treated after informed consent a 71-year-old Italian man suffering from post-COVID-19 CIP burdened with positioning-related PNI of the left upper extremity by means of ultramicronized palmitoylethanolamide 400 mg plus ultramicronized luteolin 40 mg (Glìalia), two tablets a day 12 hours apart for 6 months. In the wake of our pilot study, a larger clinical trial to definitively ascertain the advantages of this neuroprotective, neurotrophic, and anti-inflammatory therapy is advocated.

In this study, extracts from non-psychoactive Cannabis sativa L. varieties were characterized by means of ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) and their antiproliferative activity was assessed in vitro. The human chronic myelogenous leukaemia cell line K562 was chosen to investigate the mechanism of cell death. The effect on the cell cycle and cell death was analysed by flow cytometry. Proteins related to apoptosis were studied by western blotting. Mechanical properties of cells were assessed using the Micropipette Aspiration Technique (MAT). The results indicated that the cannabidiol (CBD)-rich extract inhibited cell proliferation of K562 cell line in a dose-dependent manner and induced apoptosis via caspase 3 and 7 activation. A significant decrease in the mitochondrial membrane potential was detected, together with the release of cytochrome c into the cytosol. The main apoptotic markers were not involved in the mechanism of cell death. The extract was also able to modify the mechanical properties of cells. Thus, this hemp extract and its pure component CBD deserve further investigation for a possible application against myeloproliferative diseases, also in association with other anticancer drugs.

Coronavirus Disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium, and extraordinary measures concerning with health, law and policy are required around the world. One of these is without doubts the “green pass”, officially known in the European Union (EU) as EU Digital COVID Certificate (EUDCC). Initially conceived as a tool for overcoming the lockdown restrictions, it has unexpectedly turned into a means of discrimination between pass holders and non-holders, thus increasing social tension at the expense of solidarity and brotherhood. Here, we analyze in depth the dark sides of the “green pass” in the light of the European and international legislation and of the ongoing pandemic scenario.

It is news of 28 October 2022 that the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency has recommended to add heavy menstrual bleeding among the side effects of unknown frequency inside the package insert of nucleoside-modified messenger ribonucleic acid vaccines to prevent coronavirus disease 2019 (COVID-19). The decision has been made in the light of the numerous reports of unexpected menstrual changes or abnormal uterine bleeding following COVID-19 vaccination. Here we advance a possible involvement of the particular adenohypophyseal microcirculation in these strange and still unexplained events.

Among the 17 Sustainable Development Goals (SDG) of the United Nations 2030 Agenda, “good health and well-being” is point number 3 (SDG3), and all our efforts must be calibrated in this direction worldwide [...]

Pituitary apoplexy (PA) may complicate the course of coronavirus disease 2019 (COVID-19), posing a potential threat to life. Among vaccines designed to prevent COVID-19, there are those adenoviral vector-based, such as Vaxzevria® (formerly COVID-19 Vaccine AstraZeneca). The product insert states that it can cause very rare coagulation disorders, in particular thrombosis with thrombocytopenia syndrome in some cases accompanied by bleeding, cerebrovascular venous or sinus thrombosis, and thrombocytopenia, including immune thrombocytopenia, also associated with bleeding. Here, we report the onset of PA after Vaxzevria® in a 28-year-old healthy Caucasian female, who experienced long-lasting tension-type headache, hyperprolactinemia and menstrual changes, without thrombocytopenia or thrombosis.

BACKGROUND Tumor-infiltrating lymphocytes (TILs) are B, T-helper, and T-cytotoxic lymphocytes migrated from the blood or lymph stream toward a tumor with the aim to infiltrate and destroy it. They can be histologically graded as brisk, nonbrisk, or absent. Malignant melanoma has been the first malignancy found to be correlated with TILs status, being brisk TILs associated with better clinical outcomes. By the terminology of "adoptive cell transfer" (ACT), the medical oncology refers to the transfer of cells in a tumor-bearing patient from the same recipient or a healthy donor. METHODS A PubMed literature search on the topic has been performed. Additional documents known to the authors and identified from the reference list of cited publications have been included. RESULTS In the past, autologous TILs ACT was successfully tested for the treatment of malignant melanoma and, today, it is a standardized procedure in several centers around the world. It represents the first research step toward the bioengineered chimeric antigen receptor T (CAR-T) cell therapy from autologous donor. CONCLUSIONS Both autologous TILs ACT and CAR-T cell therapy from autologous donor exploit the anticancer power of targeted self-lymphocytes, but CAR-T cell technology also virtually allows treatment of those melanomas devoid of TILs or with so few cytotoxic TILs that are difficult to identify.

By definition, Richter's syndrome represents the transformation of low-grade B-cell lymphoma into high-grade B-cell lymphoma, usually refractory to treatment. Exceptional cases of transformation into very aggressive mature T-cell lymphomas have been described as an unusual manifestation of the syndrome in patients died after few months from the diagnosis, despite chemotherapy. The time is ripe to regroup these T lymphomas under a new pathological subset, through the unequivocal alternate naming of 'T rex lymphoma', by analogy with the aggressive behavior of the famous dinosaur (T. rex). In practice, it represents the transformation of low-grade B-cell lymphoma into high-grade T-cell lymphoma, burdened by a very poor prognosis, because of the underlying B-cell lymphoma, which negatively interferes with the immune response of the patient. Against this distinct lymphomatous T clone, the major therapeutic efforts should be addressed.

MEITL is a very rare and highly aggressive peripheral T cell lymphoma with poor prognosis and for which there is no standard treatment. Treatment options for patients patients with relapsed/refractory disease are scarce and the choice of an appropriate rescue still represents an unmet need.Here, we report the case of a 65-year-old woman affected by MEITL, progressing after initial treatment with an anthracycline-based chemotherapy and surgery, who received single-agent PEG-asparaginase salvage therapy at our institution.PEG-asparaginase single-agent rescue proved to be rapidly effective in controlling the disease and its associated paraneoplastic features. Nevertheless, toxicity was high and the patient died due to a treatment-related complication.The case we described brings new evidences on the effectiveness of PEG-asparaginase therapy in MEITL patients. Whether PEG-asparaginase should be included in the treatment course of MEITL patients could be the subject of future studies.

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first “endotheliitis,” is often followed by production of “Neutrophil Extracellular Trap,” and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible “LC” disease.

A splenic arteriovenous fistula causes a ‘pre-hepatic’ hypertension in the portal venous system with the double mechanism of an increased blood amount and mainly its high pressure inflow. It aggravates for a secondary fibrosis of the portal vein branches and ‘capillarization’ of the hepatic sinusoids, adding a further ‘intra-hepatic’ component. The subsequent development of porto-systemic collaterals induces the risk of gastrointestinal hemorrhages All this suggests to perform a close monitoring of every case of splanchnic aneurysm or pseudo-aneurysm, through the current cross-section imaging tools, for their possible evolution in an arteriovenous fistula, and to consider an early therapy, also endovascular, before any secondary damage of the liver parenchyma. In this case the treatment of the portal vein hypertension can be ‘ethiological’ and resolutive.

Malignant melanoma (M) can be defined, quite simply, as a malignant neoplasm derived from melanocytes; however, there is great histological and, consequently, clinical variability from case to case (1). In order to try to overcome this intrinsic difficulty, various classification systems have been proposed over the years; as part of this effort, the World Health Organization (WHO) introduced its famous classification about half a century ago (2). Currently, the International Classification of Diseases for Oncology (ICD-O), provided by the WHO International Agency for Research on Cancer (IARC), distinguishes the in situ forms from invasive ones, recognizing four main morphological subtypes: nodular M, superficial spreading M, lentigo maligna M, and acral lentiginous M (3). The ICD-O classification includes further morphological codes, such as: balloon cell M, regressing M, amelanotic M, M in junctional nevus, M in precancerous melanosis, desmoplastic M, neurotropic M, mucosal lentiginous M, M in giant pigmented nevus / congenital melanocytic nevus, mixed epithelioid and spindle cell M, epithelioid cell M, spindle cell M (not otherwise specified), spindle cell melanoma (type A), spindle cell M (type B), and malignant blue nevus (3). Alongside a strictly morphological classification, a histogenetic model, based on the concept of tumor progression, has been regaining ground (4,5). In fact, at the onset, M is characterized by a non-tumorigenic radial growth phase (RGP), inside the epidermis (intraepidermal) or within the papillary dermis (microinvasive), which is devoid of metastatic potential and which may be followed, early or late, by a tumorigenic vertical growth phase (VGP), with deeper extension in the dermis or beyond, nodular confluence, mitotic activity, and metastatic capacity (Table 1). The unique exception to this is nodular M, in which either RGP is rapidly overrun by VGP or the tumor arises directly from dermal melanocytes (6). Today, Breslow depth remains the single most important prognostic factor for clinically localized primary M: it allows us to distinguish M as ultra-thin (≤0.5 mm), thin (≤1 mm), thick (1 mm), or ultra-thick (6 mm) (7-10). The systematic application of the histogenetic model to Breslow depth allows us to explain the oft-debated question why some thin M behave aggressively: because they possess an early tumorigenic VGP inside them (11). Moreover, any diagnostic report should be also accompanied by further well-known microstaging attributes, such as Clark level, mitotic count, lymphovascular invasion, perineural infiltration, ulceration, satellitosis, tumor infiltrating lymphocytes, and, if available, sentinel lymph node status (12,13). In conclusion, we believe that a renewed histogenetic approach to M diagnosis deserves wide scientific dissemination in order to achieve better clinical management of individual cases in the era of personalized medicine.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium. To counter it, specific vaccines have been launched in record time under emergency use authorization or conditional marketing authorization and have been subjected to additional monitoring. The European Medicines Agency recommend reporting any suspected adverse reactions during this additional monitoring phase. For the first time in the available medical literature, we report a left cubital tunnel syndrome in a 28-year-old right-handed healthy male after seven days from the first dose of Spikevax® (formerly Moderna COVID-19 Vaccine). Histochemistry for Alcian Blue performed on the tissue harvested from the cubital site reveals myxoid degeneration of the small nerve collaterals, a clear sign of nerve injury. It still remains unclear why the syndrome occurs in a localized and not generalized form to all osteofibrous tunnels. Today, modified messenger ribonucleic acid vaccines as Spikevax® represent an avantgarde technological platform with a lot of potential, but one which needs careful monitoring in order to identify in advance those patients who may experience adverse events after their administration.

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium; to counteract it, specific vaccines have been launched in record time under emergency use authorization or conditional marketing authorization by virtue of a favorable risk/benefit balance. Among the various technological platforms, there is that exploiting a nucleoside-modified messenger RNA (modRNA), such as Comirnaty®, and that which is adenoviral vector-based. In the ongoing pharmacovigilance, the product information of the latter has been updated about the risk of thrombotic thrombocytopenia, venous thromboembolism without thrombocytopenia and immune thrombocytopenia without thrombosis. However, from an in-depth literature review, the same adverse events can rarely occur with modRNA vaccines too. In support of this, we here report a three-case series of thrombotic deaths in patients over 50 with comorbidities temporally after Comirnaty®, investigated by means of post-mortem histopathology and immunohistochemistry. In two out of three cases, the cause of death is traced back to pulmonary microthromboses rich in activated platelets, quite similar morphologically to those described in patients who died from severe COVID-19. Even if remote in the face of millions of administered doses, clinicians should be aware of the possible thrombotic risk also after Comirnaty®, in order to avoid a misdiagnosis with potentially lethal consequences. Since COVID-19 vaccines are inoculated in subjects to be protected, maximum attention must be paid to their safety, and prophylactic measures to increase it are always welcome. In light of the evidence, the product information of modRNA COVID-19 vaccines should be updated about the thrombotic risk, as happened for adenoviral vector-based vaccines.

The pathological features of the appendix tumors fundamentally recall those of the more frequent colorectal neoplasms, although with a higher relative incidence of carcinoids, due to the abundant presence of enteroendocrine cells in the appendix wall. Moreover, different types of lymphomas, Hodgkin and non-Hodgkin, arising from the extra-nodal mucosal-associated lymphatic tissue, can be encountered. The appendix tumor microenvironment (TME) consists of a cellular component and of a noncellular component: the former includes the immunocompetent cells, while the latter represents the support stroma. Particularly in carcinoids, the immune cell reaction can be explicated by tumor-infiltrating lymphocytes, which, in some circumstances, may arrange around and inside the tumor in a brisk fashion influencing favorably the prognosis. This active reaction has to be distinguished from any preexisting inflammatory condition of the appendix and from superimposed tumor complications, such as infection or ischemia. In practice, we consider the appendix TME a complex framework with immunological, mechanic, and metabolic functions, all supported by a marked neo-lymphoangiogenesis.

The pathological features of the appendix tumors fundamentally recall those of the more frequent colorectal neoplasms, although with a higher relative incidence of carcinoids, due to the abundant presence of enteroendocrine cells in the appendix wall. Moreover, different types of lymphomas, Hodgkin and non-Hodgkin, arising from the extra-nodal mucosal-associated lymphatic tissue, can be encountered. The appendix tumor microenvironment (TME) consists of a cellular component and of a noncellular component: the former includes the immunocompetent cells, while the latter represents the support stroma. Particularly in carcinoids, the immune cell reaction can be explicated by tumor-infiltrating lymphocytes, which, in some circumstances, may arrange around and inside the tumor in a brisk fashion influencing favorably the prognosis. This active reaction has to be distinguished from any preexisting inflammatory condition of the appendix and from superimposed tumor complications, such as infection or ischemia. In practice, we consider the appendix TME a complex framework with immunological, mechanic, and metabolic functions, all supported by a marked neo-lymphoangiogenesis.

COVID-19 is a complex disease with many clinicopathological issues, including respiratory, gastrointestinal, neurological, renal, cutaneous, and coagulative ones; in addition, reactive arthritis has been reported by different authors. Here, we hypothesize that a peripheral microangiopathy involving nerve supply, a viral demyelination, or an immune-mediated irritating antigenic stimulus on synovial sheaths after SARS-CoV-2 infection may all induce a carpal, cubital or tarsal tunnel syndrome of variable entity in genetically predisposed subjects associated with myxoid nerve degeneration.

An updated neuropathological protocol for the examination of the nervous system in case of unexplained stillbirth has been elaborated and presented in this review. It is focused on the examination of the nervous centers located in the brainstem, which are involved in monitoring the vital functions. Only through a deep analysis of the brainstem it is possible to highlight developmental alterations of these essential centers, and then provide a plausible explanation of the pathogenetic mechanism behind the death. The guidelines, drawn up on the basis of numerous researches performed by the authors, include a histopathological protocol, with an indication of standardized samples, and an immunohistochemical protocol for the study of biological markers, frequently involved in these deaths. The main risk factors that can be related to the neuronal alterations are also reported, together with the indications for the toxicological examination, which should be possibly applied. The authors hope that this protocol will be soon adopted in all the institutions where a fetal death, after a routine autopsy procedure, is diagnosed as "unexplained", in order to make standardized investigations on stillbirth. Nowadays, preventive strategies to decrease the incidence of these very distressing events for both parents and clinicians are necessary. .

Background The authors identified as ‘acute vascular chest’ a syndrome characterized by respiratory-thoracic signs, mimicking pleuro-pulmonary or chest wall diseases, that, on the contrary, are caused by proper acute thoracic vascular lesions, traumatic or not, but not cardiac. Results As typical examples, we mention two cases: one of traumatic left extrapleural hematoma, secondary to rupture of the subclavian artery, and another concerning an aneurysm of the mid descending thoracic aorta, fissured into the upper left pulmonary lobe. In both these cases, angiographic examinations allowed a prompt and correct diagnosis. Conclusion Today, precise radiological studies of the extrapleural and upper thoracic spaces support the identification of this particular syndrome.

In literature there are no data related to mitochondrial DNA (mtDNA) content in sudden intrauterine unexplained death syndrome (SIUDS). To test the hypothesis that a quantitative excess of mtDNA could play a role in the pathogenesis of SIUDS, mtDNA content was measured in cerebral cortex of 9 SIUDS and in 7 controls. The median (interquartile range) mtDNA in SIUDS and controls was 14,000 (8600-33,500), 3400 (0-8500) copies per nuclear DNA, respectively (p=0.007). If mitochondria are involved in SIUDS, then higher mitochondrial DNA content may be a biomarker of this syndrome.