Endogenous melatonin protects L-DOPA from autoxidation in the striatal extracellular compartment of the freely moving rat: potential implication for long-term L-DOPA therapy in Parkinson's disease

We previously showed, using microdialysis, that autoxidation of exogenous L-dihydroxyphenylalanine (L-DOPA) occurs in vivo in the extracellular compartment of the freely moving rat, with a consequent formation of L-DOPA semiquinone (L-DOPA-SQ). In the present study, intrastriatal infusion of L-DOPA (1.0 microm for 200 min) increased dialysate L-DOPA concentrations (maximum increases up to 116-fold baseline values); moreover, L-DOPA-SQ was detected in dialysates. Individual dialysate concentrations of L-DOPA were negatively correlated with those of L-DOPA-SQ. Co-infusion of N-acetylcysteine (100 microm) or melatonin (50 microm) increased L-DOPA (up to 151- and 246-fold, respectively) and decreased L-DOPA-SQ (by about 53% and 87%, respectively) dialysate concentrations. Systemic L-DOPA [25 mg/kg intraperitoneally (i.p.) twice in a 12-h interval] significantly increased striatal baseline dialysate concentrations of L-DOPA and decreased dopamine (DA) and ascorbic acid (AsAc) concentrations, when compared with controls. Following systemic L-DOPA, L-DOPA-SQ was detected in dialysates. Endogenous melatonin was depleted in rats maintained on a 24-h light cycle for 1 wk. In melatonin-depleted rats, systemic L-DOPA induced a smaller increase in dialysate L-DOPA, a greater increase in L-DOPA-SQ formation, and a greater reduction in DA and AsAc dialysate concentrations. Co-administration of melatonin (5.0 mg/kg, i.p., twice in a 12-h interval) with L-DOPA, in control as well as in light-exposed rats, significantly increased dialysate L-DOPA concentrations, greatly inhibited L-DOPA-SQ formation, and restored up to the control values dialysate DA and AsAc concentrations. These findings demonstrate that endogenous melatonin protects exogenous L-DOPA from autoxidation in the extracellular compartment of the striatum of freely moving rats; moreover, systemic co-administration of melatonin with L-DOPA markedly increases striatal L-DOPA bioavailability in control as well as in melatonin-depleted rats. These results may be of relevance to the long-term L-DOPA therapy of Parkinson's disease.     

Liver Cancer-Specific Isoform of Serine Protease Inhibitor Kazal for the Detection of Hepatocellular Carcinoma: Results from a Pilot Study in Patients with Dysmetabolic Liver Disease

Reliable non-invasive biomarkers for the surveillance of patients at risk of hepatocellular carcinoma (HCC) development represent an unmet medical need. Recently, the liver-cancer-specific isoform of serine protease inhibitor Kazal (LC-SPIK) has been proposed as a valuable biomarker for the detection of HCC in patients with chronic liver disease of viral etiology. In the present study, we assessed the diagnostic accuracy of LC-SPIK, alone or in combination with standard serologic biomarkers (i.e., alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II, PIVKA-II), for the detection of HCC among patients with dysmetabolic liver disease. A total of 120 patients with non-alcoholic fatty liver disease (NAFLD), including 62 patients with a diagnosis of HCC and 58 with cirrhosis but without tumor, were retrospectively analyzed. The serum levels of LC-SPIK were measured by enzyme-linked immunosorbent assay (ImCare Biotech, Doylestown, PA). The serum LC-SPIK values were significantly different between patients with HCC (24.3, 17.6–39.8 ng/mL) and those with cirrhosis but without tumor (11.7, 8.7–18.2 ng/mL) (p < 0.001). By receiver operating characteristic curve analysis, we observed an area under the curve (AUC) of 0.841 for the detection of HCC; the combination with PIVKA-II further increased the accuracy to AUC = 0.926 (cross-validation). The promising results observed in the present pilot study foster additional research to investigate the usefulness of LC-SPIK for the stratification of the risk of HCC development in patients with NAFLD and advanced liver disease.     

Transcutaneous sacral neuromodulation for pelvic pain and non-relaxing pelvic floor: Findings from a pilot study

We sought to evaluate the effectiveness and acceptability by patients of transcutaneous sacral roots neuromodulation (TSRN) by paravertebral placement of surface electrodes to treat pelvic pain and pelvic muscle stiffness. Pelvic pain is a disabling condition, often related to non-relaxing pelvic muscles. Causes for the onset are often unclear; noninvasive treatment targeted at maintenance factors can be administered by nurses in some countries. previous studies have investigated the role of invasive stimulation for pelvic pain; TSRN has proved successful in other pelvic disorders. We conducted a pilot study on a sample of consecutive patients of both genders, reporting pelvic pain (chronic or not). Weekly sessions of TSRN with surface electrodes were performed; pain was recorded with the numeric rating scale (NRS) at baseline and after the end of the rehabilitation plan. Therapeutic success was defined as a reduction of 50% in pain scores. Twenty patients were enrolled, most complaining multiple symptoms apart from pain. Seven males had primary prostate pain syndrome, one had history of orthopaedic surgery, and eight had muscle stiffness (Median = 3 out of 4, IQR = [3;3], range [2;4]). Sixteen patients (12 males and 4 females) had chronic pelvic pain. The median NRS values in the sample at baseline was 4[5.5–7.5] with no significant differences between genders (p = 0.144) and decreased significantly (Me = 0.5, IQR[0.0–1.0], p < 0.001) after a median of 20 weekly sessions (range [10–30]). The results indicated clinically relevant benefit for all patients (ω² = 0.689, 95%IC[0.505–0.793]) Decrease in pelvic muscle stiffness was significant (from Me = 3, IQR [3] to Me = 0, IQR[0–1], p < 0.0001) without differences between the genders (p = 0.711). No significant difference was found in the number of sessions required by males and females to achieve therapeutic success (p = 0.282). TSRN seems a promising treatment for pelvic pain and can be performed in outpatients' clinics with low costs and no invasivity. Further studies on larger, randomized samples are required to confirm these results.     

Correction: A Dedicated Tool for Presurgical Mapping of Brain Tumors and Mixed‐Reality Navigation During Neurosurgery

Journal of Digital Imaging -     

Reply to “successful early use of anti-SARS-CoV-2 monoclonal neutralizing antibodies in SARS-CoV-2 infected hematological patients—A Czech multicenter experience”: A case series of SARS-CoV-2 Omicron infection and aggressive lymphoma in the Sotrovimab era

A prospective multicentre experience of early administration of anti-SARS-CoV-2 spike protein neutralizing monoclonal antibodies (MA) with efficacy among patients with hematological malignancies and early-stage COVID- 19 was reported by Weinbergerová et al. The study validated the safety and efficacy of MA early use among hematological patients with newly diagnosed early-stage COVID-19 in terms of alleviating infection course and decreasing mortality. However no reference to new variant (Delta and Omicron) or other MA (e.g., Sotrovimab) has been reported. We reported our monocentric experience of 8 aggressive lymphoma patients with Omicron infection, 7 of whom treated with this MA in our Institution between December 2021 and February 2022. Among the patients treated with Sotrovimab nobody experienced neither SARS-CoV2 reactivation, nor other infectious events. One patients on active lymphoma treatment was hospitalized for pneumonia and treated with remdesivir. In 4/8 patients negativization of molecular swab occurred concomitantly to symptoms resolution with a median of 5.25 days, while the other 4 patients remained persistently positive with a median of 26.3 days. In this group, in order to maintain the chemo/chemoimmunotherapy (CT/CIT) dose-density, lymphoma treatment was reassumed independently on molecular swab analysis. SARS-CoV-2 negativization occurred with a median of 7.7 days after the resumption of CT/CIT. The one patient treated with remdesivir, although still positive to molecular swab, restarted R-COMP regimen at symptoms resolution too, but experienced an Omicron pneumonia exacerbation. This is the first case series reported in literature of patients affected by Omicron variant in which Sotrovimab seems to provide a resolution of COVID-19 disease, even in patient with molecular swab positive persistence too. Patients with aggressive lymphoma histologies should not be deprived of the best available treatment of their disease after sotrovimab administration, even in the presence of a still positive Omicron swab.     

Glucagon induces the hepatic expression of inflammatory markers in vitro and in vivo

Glucagon exerts multiple hepatic actions, including stimulation of glycogenolysis/gluconeogenesis. The liver plays a crucial role in chronic inflammation by synthesizing proinflammatory molecules, which are thought to contribute to insulin resistance and hyperglycaemia. Whether glucagon affects hepatic expression of proinflammatory cytokines and acute-phase reactants is unknown. Herein, we report a positive relationship between fasting glucagon levels and circulating interleukin (IL)-1β (r = 0.252, p = .042), IL-6 (r = 0.230, p = .026), fibrinogen (r = 0.193, p = .031), complement component 3 (r = 0.227, p = .024) and high sensitivity C-reactive protein (r = 0.230, p = .012) in individuals without diabetes. In CD1 mice, 4-week continuous treatment with glucagon induced a significant increase in circulating IL-1β (p = .02), and IL-6 (p = .001), which was countered by the contingent administration of the glucagon receptor antagonist, GRA-II. Consistent with these results, we detected a significant increase in the hepatic activation of inflammatory pathways, such as expression of NLRP3 (p < .02), and the phosphorylation of nuclear factor kappaB (NF-κB; p < .02) and STAT3 (p < .01). In HepG2 cells, we found that glucagon dose-dependently stimulated the expression of IL-1β (p < .002), IL-6 (p < .002), fibrinogen (p < .01), complement component 3 (p < .01) and C-reactive protein (p < .01), stimulated the activation of NLRP3 inflammasome (p < .01) and caspase-1 (p < .05), induced the phosphorylation of TRAF2 (p < .01), NF-κB (p < .01) and STAT3 (p < .01). Preincubating cells with GRA-II inhibited the ability of glucagon to induce an inflammatory response. Using HepaRG cells, we confirmed the dose-dependent ability of glucagon to stimulate the expression of NLRP3, the phosphorylation of NF-κB and STAT3, in the absence of GRA-II. These results suggest that glucagon has proinflammatory effects that may participate in the pathogenesis of hyperglycaemia and unfavourable cardiometabolic risk profile.     

Surgical complications of oncological treatments: A narrative review

Gastrointestinal complications are common in patients undergoing various forms of cancer treatments, including chemotherapy, radiation therapy, and molecular-targeted therapies. Surgical complications of oncologic therapies can occur in the upper gastrointestinal tract, small bowel, colon, and rectum. The mechanisms of action of these therapies are different. Chemotherapy includes cytotoxic drugs, which block the activity of cancer cells by targeting intracellular DNA, RNA, or proteins. Gastrointestinal symptoms are very common during chemotherapy, due to a direct effect on the intestinal mucosa resulting in edema, inflammation, ulceration, and stricture. Serious adverse events have been described as complications of molecular targeted therapies, including bowel perforation, bleeding, and pneumatosis intestinalis, which may require surgical evaluation. Radiotherapy is a local anti-cancer therapy, which uses ionizing radiation to cause inhibition of cell division and ultimately lead to cell death. Complications related to radiotherapy can be both acute and chronic. Ablative therapies, including radiofrequency, laser, microwave, cryoablation, and chemical ablation with acetic acid or ethanol, can cause thermal or chemical injuries to the nearby structures. Treatment of the different gastrointestinal complications should be tailored to the individual patient and based on the underlying pathophysiology of the complication. Furthermore, it is important to know the stage and prognosis of the disease, and a multidisciplinary approach is necessary to personalize the surgical treatment. The purpose of this narrative review is to describe complications related to different oncologic therapies that may require surgical interventions.