The role of calcification for staging cystic echinococcosis (CE)

The prevalence of calcified cysts and the significance of calcification as a sign of cyst inactivity in cystic echinococcosis (CE) was evaluated. Seventy-eight patients (36 females, 42 males, mean age 40.8 +/- 16.9 years) with CE, having a total of 137 abdominal cysts (116 hepatic, three splenic, one renal and 17 peritoneal cysts), were diagnosed and followed-up by ultrasound during and after albendazole treatment or as part of the watch-and-wait approach recording changes in the cyst wall and content. In 48 patients with 94 cysts, computed tomography (CT) imaging was additionally available and was correlated with ultrasound findings. Cyst wall calcification was classified into (1) "sprinkled", (2) "eggshell-like", and (3) "circular". Calcification of the cyst wall and/or cyst content was detected in 67 echinococcal cysts (48.9% of all cysts) in 39 patients (15 females, 24 males, mean age 40.8 +/- 14.8 years). Of the total of 67 calcified cysts, only 23 were compatible with WHO type CE5, 18 with WHO type CE4. Judged by cyst content, the remaining 26 were of WHO type CE1, CE2 and CE3 (n = 1, n = 8, and n = 17, respectively). During a mean period of 34.3 months (+/- 21.3 months) the majority of cysts (n = 32) did not exhibit any change in cyst content and wall properties. Fourteen cysts showed signs of progressive involution, five cysts (all of WHO type CE3) of renewed activity defined by recurring fluid collection. In 16 cysts, no follow-up was available due to surgery or drop out. Calcification of the cyst is not restricted to the inactive WHO cyst types CE4 and CE5, but occurs in all stages and in up to 50% of cysts. The completeness and, most importantly, the stability of consolidation of cyst content over time predicts cyst inactivity more reliably.     

Divergent Squamous Differentiation in Upper Urothelial Carcinoma—Comparative Clinicopathological and Molecular Study

Upper urothelial carcinoma (UUC) has a plasticity to demonstrate divergent differentiation with squamous metaplastic elements. There was no previous study exploring profiling of molecular markers in metaplastic squamous upper urothelial carcinoma (SUUC) and conventional upper urothelial carcinoma (CUUC). The aims of this study was to compare expression of the phenotypic characteristics of tumors and molecular markers (p53, p16, cyclin D1, E-cadherin, HER-2, Ki-67, Bcl-2, Bax) in SUUC and CUUC. SUUC was detected in 20% of 44 patients. There was significant difference between SUUC and CUUC in the pathological stage, grade, growth and presence of lymphovasular invasion (p < 0.05; 0.05; 0.05; 0.01 respectively). The mean Ki-67 and p53 labeling index was significantly higher in SUUC than in CUUC (p < 0.05; 0.05). There was no significant difference in the expression of p16, cyclin D1, E-cadherin, HER-2, Bcl-2 and Bax between SUUC and CUUC. Univariant model showed that SUUC was significantly associated with lymphovascular invasion (p = 0.007), Ki-67 activity (p = 0.016) and growth (p = 0.026). Exploration of UUC with squamous divergent differentiation showed changes in phenotypic characteristics and Ki-67, as well as similar molecular profile with CUUC.     

Relationship between fluoride intake in Serbian children living in two areas with different natural levels of fluorides and occurrence of dental fluorosis

The amount of fluoride present naturally in drinking water is highly variable, being dependent upon the individual geological environment from which the water is obtained. Chronic exposure to exceeding fluoride doses induces set of toxic effects, i.e. fluorosis. The aim of this study was to examine fluoride content in water and in the most frequently used vegetables, potato and bean, grown in two different Serbian regions, i.e. control region (Valjevo) and high naturally occurring fluoride region (Vranjska Banja), and moreover, to correlate estimated daily intake with dental fluorosis occurrence as an adverse effect of fluoride exposure of schoolchildren in Serbia. Study confirmed significant difference in fluoride content in water, potato and bean, consumed by 12-year-old children in two investigated municipalities. Results of the study indicated positive and statistically significant correlation between daily intake of fluoride and dental fluorosis level in the fluorotic municipality of Vranjska Banja (r = 0.61; p = 0.000017). Obtained relationship could be evaluated by means of binary logistic regression analysis, whereas probability for fluorosis occurrence could be predicted using the following equation: fluorosis occurence (%) = (34.852 × C_water − 12.644 × C_potato − 9.362 × C_bean − 7.673) × 100 (Chi-Square (3) = 33.033; p < 0.001).     

Cognitive impact of mitoxantrone and methylprednisolone in multiple sclerosis: an open label study

Interferons beta have shown some positive effects on cognitive function in multiple sclerosis (MS). The potential immunosuppressive impact of mitoxantrone on cognitive dysfunction in MS has never been evaluated. We assessed changes in cognitive dysfunction in patients with very active MS treated with mitoxantrone combined with methylprednisolone. We assessed a non randomized controlled trial including successively 15 consecutive MS patients. Very active MS was defined by a progression of at least two EDSS points or more than two relapses during the previous year and at least one enhanced lesion after gadolinium infusion on MRI. All patients received a monthly intravenous pulse of mitoxantrone (20mg) for six months with methylprednisolone (1g). Global cognitive efficiency, memory and executive function were assessed before treatment (M0) and after six months (M6) and 12 months (M12) of treatment. To evaluate the learning effect, 15 healthy subjects also participated. A significant improvement in global cognitive efficiency was observed at M6 and was sustained at M12, as a few parameters on memory and executive functions. We suggest that mitoxantrone combined with methylprednisolone has a potential positive effect on cognitive functions.     

A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings

Mutations in dynamin 2 (DNM2) have been associated with autosomal dominant centronuclear myopathy, dominant intermediate Charcot-Marie-Tooth (CMT) type B and CMT2. Here, we report a novel DNM2 mutation in the Pleckstrin homology domain of DNM2 (p.K559del) in a patient with an axonal length-dependent sensorimotor polyneuropathy predominantly affecting the lower limbs. Neuropathy is associated with congenital cataracts, ophthalmoparesis, ptosis and neutropenia. There was no evidence of a skeletal myopathy on EMG or muscle biopsy. We suggest that this constellation of clinical features can help the diagnosis and selection of patients for direct DNM2 genetic analysis.     

The expression of Ki-67 and Bcl-2 in hodgkin’s lymphoma: Correlation with the international prognostic score and bulky disease

The prognosis of Hodgkin’s lymphoma has been improved over last 10 yr due to identification of prognostic parameters. These factors may predict the clinical outcome and therefore may have influence on the selection of appropriate treatment. In a cohort of 40 patients with Hodgkin’s lymphoma of nodular sclerosis subtype, treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen, we analyzed prognostic relevance of the expression of Ki-67 and Bcl-2 at diagnosis as well as other clinical parameters: International Prognostic Score, bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate. Significance was tested according to response rate and overall survival. Patients with a high proliferative fraction (Ki-67 > 50%) had worse overall survival compared with those with low proliferation, 56% vs 91%. There was a correlation between Ki-67 positivity and the achievement of complete remission. Cox’s multivariate model revealed that Ki-67 positivity at threshold of 50% was a significant independent prognostic factor. The Bcl-2 expression in less than 50% of tumor cells was detected in 65.5% of patients, and in a majority of cases it was associated with complete remission. Patients with high IPS had more progressive disease and shorter survival. Bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate had no significant influence on complete remission and survival. However, there was a marked divergence in survival curves after 4 yr follow-up for each of these parameters. Patients with high Ki-67, IPS > 3, bulky disease, tissue eosinophilia, and high sedimentation rate are at a higher risk of treatment failure and relapse and therefore might be eligible for other aggressive therapeutic approach.     

Adverse Events During Immunotherapy in Slovenian Patients with Metastatic Melanoma Reveal a Positive Correlation with Better Treatment Outcomes

BackgroundImmunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy.Patients and methodsA retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups.ResultsAmong the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.ConclusionsPatients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.Key words: immune related adverse events, immunotherapy, melanoma, metastases, response, survival     

FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems

IntroductionImmunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI.AimTo investigate the roles of Trx reductase 2 (TrxR2) and S‐Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.MethodsAdult male rats, wild‐type (WT) mice, and GSNOR deficient (GSNOR ‐/‐) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl‐2, and for immunolocalization of TrxR2 and GSNOR.Main Outcome MeasuresEF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue.ResultsEF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR ‐/‐ mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR ‐/‐ mice. In rats, GSNOR (P < 0.01) and Bcl‐2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN‐injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl‐2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle).ConclusionsThe neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems. Lagoda G, Xie Y, Sezen SF, Hurt KJ, Liu L, Musicki B, and Burnett AL. FK506 neuroprotection after cavernous nerve injury is mediated by thioredoxin and glutathione redox systems. J Sex Med **;**:**–**.