The cochleo-vestibular secretory senescence

The vestibular and cochlear senescence is a complex degenerative disease and one of the most prevalent chronic conditions of elderly, affecting tens of millions of people worldwide. In this review, we will try to summarize the most important sites and involved mechanism trying to figure out strategies to prevent its clinical consequences

Insolita causa di addome acuto in paziente adulto: l’ileo biliare

L’ileo biliare è una condizione morbosa rara descritta tra le complicanze della litiasi della colecisti. È causa dell’1-3% delle ostruzioni meccaniche del piccolo intestino. Interessa più frequentemente pazienti di età compresa tra 63 e 85 anni. La diagnosi pre-operatoria è generalmente posta con ritardo variabile da 1 a 10 giorni per l’assenza di una sintomatologia specifica. Caso clinico. Gli Autori riportano il caso di un uomo di 50 anni in cui è stata posta diagnosi di occlusione meccanica del piccolo intestino da voluminosa concrezione litiasica. L’occlusione ileale è stata dimostrata con la TC. Il paziente è stato sottoposto in urgenza ad intervento chirurgico, in un unico tempo, di enterolitotomia, colecistectomia e riparazione della fistola duodenale. Il decorso clinico è stato regolare e il paziente è stato dimesso in XIV giornata. Discussione. Nel nostro caso la diagnosi di ileo biliare è stata posta con un ritardo di 5 giorni. L’ecotomografia del fegato e delle vie biliari non è stata in grado di visualizzare la colecisti. La diagnosi è stata posta con la TC che si conferma gold standard diagnostico. Conclusioni. Lo stato clinico del paziente influenza la strategia chirurgica. Nel nostro paziente, considerato a basso rischio, è stato possibile l’intervento chirurgico in un unico tempo. La procedura in due tempi, enterolitotomia e successiva colecistectomia con riparazione della fistola, va riservata ai pazienti ad alto rischio

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Infezioni opportuniste gastrointestinali e HIV. Caso clinico

Gli ultimi dati della letteratura parlano di milioni di persone affette da AIDS nel mondo. Negli ultimi 5 anni il tasso di mortalità si è ridotto dal 20% al 15%; tuttavia circa 75000 pazienti moriranno di AIDS nell’anno in corso. I pazienti affetti da immunodeficienza acquisita da virus HIV sono a rischio di sviluppare neoplasie AIDS-correlate, come il sarcoma di Kaposi e i linfomi non Hodgkin, neoplasie sporadiche e infezioni secondarie. Tra queste le infezioni da Cytomegalovirus (CMV) sono spesso causa di corioretinite, polmoniti, ulcere perineali, esofagiti, lesioni renali e del sistema nervoso centrale. Descritta, ma non di frequente riscontro, la comparsa di sindromi addominali acute che talvolta necessitano di trattamento chirurgico d’urgenza. Le lesioni intestinali da sovrainfezione cytomegalica sono abbastanza frequenti (15-43%), riguardano per il 47% il colon, per il 21,7% il duodeno, per il 17,4% lo stomaco e per il 4,3% il piccolo intestino ma solo raramente sono a prognosi infausta. Gli Autori riportano il raro caso clinico di un paziente positivo per HIV, giunto alla loro osservazione con associata micobatteriosi e infezione multiorgano da CMV, sottoposto ad intervento chirurgico d’urgenza per perforazioni intestinali multipl

ANTITUMOR EFFECTS OF PAK4-INHIBITION IN IN VIVO AND IN VITRO PROSTATE CANCER MODELS

Background: Prostate cancer represents 11% of all cancers and 9% of cancer-related deaths in European men (1, 2). The treatment of prostate cancer includes radical prostatectomy, radiations and hormonal therapy (3). To date, although the improvements of care and of outcome of the disease, further efforts must to be put in place for increase the efficacy of treatment and reduction of the relapse. So, in the last years have been identified different molecular targets in prostate cancer, useful for the generation of new therapeutic strategies (4, 5). Among these new targets PAK4 raised a great interest for its importance in prostate cancer progression and survival (6, 7). In our work we resumed the antitumor effects of PAK4 inhibition in four prostate cancer cells (PC3, DU145 and 22RV1) through in vivo and in vitro experiments. Materials and Methods: PC3, DU145, and 22RV1 prostate cancer cells were subcutaneously injected in the flank of nu/nu CD1 mice, treated with PAK4-inhibitor and monitored over the time for tumor growth rate respect to untreated animals. In parallel, the prostate cancer cells were cultured and treated for the evaluation of different properties, such as proliferation, cell death induction, autophagy, migration, through western blotting, FACS analysis, and wound healing repair assays. Results: In vivo experiments showed that KPT-8752 reduced cancer growth of about 25-60% in relation to the cell line, respect to the untreated group. Indeed, 22RV1 cell lines seemed to be the most sensitive, while the PC3 cell line resulted to be very less sensitive to the inhibitor. The in vitro results, defined that apoptosis occurred in 22RV1 and DU145 cells when KPT8752 was administered proven by caspase 3 cleaved appearance, while in PC3 cells the activation of the autophagy program was very clear, testified by the increase of Beclin1 and LC3IIb levels. In all the cell lines the wound healing repair assay showed a reduction of migratory capacity, in a dose-dependent way with the inhibitor. Discussion: Our results indicate that PAK4-inhibitor KPT-8752 delayed tumor growth in treated mice, respect to the control group. In association to this, the overall tumor weight in treated animals resulted to be lower in comparison to untreated animals. Regarding in vitro results, they showed that the three prostate cancer cells exhibited a different behavior when exposed to the PAK4-inhibitor. Indeed, by the evaluation of two important mechanisms related to cancer survival, such as apoptosis and autophagy, the different prostate cancer cell seemed to be undertaking different faith. This, could be explained by the different genetic asset own of the cells. Moreover, in all the three cell lines used is evident a reduction of the migration when compared to control cells, when KPT-8752 was administered. Conclusion: Our results, in agreement with previous studies, confirm that PAK4 is a suitable therapeutic target for prostate cancer. The role of PAK4 in tumorigenesis and sustenance of prostate cancer is well known and these results spur us to continue to investigate the implication of the inhibition of this marker and identify new strategies for counteract its functions in the disease

Endometriosi primitiva ombelicale. Caso clinico

L’endometrioma primitivo ombelicale è una rara localizzazione extrauterina di tessuto endometriale funzionante. L’importanza della patologia è nel rischio di trasformazione maligna. In molti casi, essa pone inoltre problemi di diagnostica differenziale con le tumefazioni benigne e maligne, primitive e secondarie della parete addominale. Gli Autori riportano un raro caso di endometriosi ombelicale in una donna di 36 anni. La diagnosi clinica è stata facilitata dalle variazioni delle caratteristiche semeiologiche della lesione e dallo stillicidio ematico correlati al ciclo mestruale, diagnosi successivamente confermata dall’esame istologico. L’indagine TC ha escluso una endometriosi extrapelvica associata. L’approccio è stato chirurgico in anestesia generale. Si è proceduto ad un’ampia escissione della cicatrice ombelicale, dei tessuti soprafasciali, della fascia e del peritoneo con ricostruzione mediante plastica senza utilizzo di materiale protesico. L’entità dell’exeresi è stata finalizzata alla riduzione del rischio di recidiva locale. Gli Autori consigliano di eseguire l’intervento di escissione nei primi 3-4 giorni della fase follicolare del ciclo mestruale per minimizzare il rischio di disseminazione di cellule endometriosiche per via ematica o linfatic

Morphine withdrawal modifies PrP expression in rat hippocampus

Aims. Prion protein (PrPC), like many GPI-anchored protein, is found in sphingolipid-rich membrane microdomains known as lipid raft. This membrane-bound isoform dimerizes and can act as cell surface receptor, co-receptor or form multimolecular complexes and recruit downstream signal transduction pathways. As known, dimerization of membrane-bound PrPC leads to clustering in multimolecular complexes and serves to regulate different aspect of neuronal homeostasis, while intracellular dimerization appears to be the most relevant event in neuroprotection, via N1 and C1 prion metabolites. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for restoration of physiological state. During morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity and affect metaplasticity. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the expression of PrPC. Methods. Male Sprague–Dawley rats were treated with morphine hydrochloride twice daily for 14 days and divided in seven groups with different withdrawals. Homogenized hippocampi and prefrontal cortices were subjected to western blot analisys with different PrP antibodies. We evaluated the generation of PrPC oligomeric species, such as dimers, which could further aggregate into resistant form of PrP. Results. Although neither acute, nor chronic morphine exposure, influenced PrPC expression in hippocampus or prefrontal cortex, abstinence from opiate induced a time-dependent and region-specific modification in PrPC content. In fact, one week after morphine withdrawal, PrPC expression in the hippocampus, but not in the prefrontal cortex, was significantly increased, and this effect was still present 14 days after last morphine exposure. This PrPC overexpression in hippocampal tissue may be linked to generation of PrPC dimeric structure moreover opiate withdrawal led to α-cleavage at the PrPC hydrophobic domain and consequent PrPN1/C1 fragments production. Conclusions. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of PrPC. We show the aggregation of PrPC in a biological process not related to neurodegeneration. Our results may suggest that PrPC dimerization, and its further aggregation in partially resistant oligomers, may play a role in the restoration of network homeostasis associated with withdrawal from morphine

Morphine withdrawal modifies prion protein expression in rat hippocampus

The hippocampus is a vulnerable brain structure susceptible to damage during aging and chronic stress. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for the restoration of the physiological state. Abuse of morphine may lead to Reacting Oxygen Species-induced neurodegeneration and apoptosis. It has been proposed that during morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity. Since prion protein is involved in both, Reacting Oxygen Species mediated stress responses and synaptic plasticity, in this work we investigate the effect of opiate withdrawal in rats after morphine treatment. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the Prion protein expression. Our results indicate that abstinence from the opiate induced a time-dependent and region-specific modification in Prion protein content, indeed during morphine withdrawal a selective unbalance of hippocampal Prion Protein is observable. Moreover, Prion protein overexpression in hippocampal tissue seems to generate a dimeric structure of Prion protein and á-cleavage at the hydrophobic domain. Stress factors or toxic insults can induce cytosolic dimerization of Prion Protein through the hydrophobic domain, which in turn, it stimulates the á-cleavage and the production of neuroprotective Prion protein fragments. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of Prion protein