Evaluation of vesico-urethral and sweating function in disorders presenting with parkinsonism

Investigation of vesico-urethral and sweating function was performed in twelve patients with classical idiopathic Parkinson's disease and ten patients with parkinsonism associated with features suggestive of more extensive involvement of the nervous system, as in the Shy—Drager syndrome. The urodynamic studies revealed detrusor hyperreflexia with reduction of maximal cystometric capacity in only one patient with Parkinson's disease (8%), but in nine patients with parkinsonism associated with other features (90%). Urethral sphincter electromyography did not indicate denervation in any patient of either group. Delayed or incomplete relaxation of the urethral sphincter during micturition was observed in seven patients with Parkinson's disease (58%) and in two patients of the other group (20%). Decreased sweating responses were found in both groups of patients when compared with control subjects. Hypohidrosis was more pronounced in parkinsonism associated with other features than in Parkinson's disease. Differences in sweating between the two sides of the body were observed in both groups of patients. Although there are differences in vesico-urethral and sweating function, they do not precisely differentiate between patients with classical Parkinson's disease and those with parkinsonism associated with features suggestive of more extensive involvement of the nervous system.     

NEOPLASTIC DISEASE AND DELETION 22q11.2: A MULTICENTRIC STUDY AND REPORT OF TWO CASES

Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.     

Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models.

PURPOSE: Melanoma is a highly malignant and increasingly common tumor. Because the cure rate of metastatic melanoma by conventional treatment is very low, new therapeutic approaches are needed. We previously reported that coated cationic liposomes (CCL) targeted with a monoclonal antibody against the disialoganglioside (GD(2)) and containing c-myb antisense oligodeoxynucleotides (asODNs) resulted in a selective inhibition of the proliferation of GD(2)-positive neuroblastoma cells in vitro. EXPERIMENTAL DESIGN: Here, we tested the in vivo antitumor effects of this novel antisense liposomal formulation by targeting the c-myc oncogene on melanoma, a neuroectodermal tumor sharing with neuroblastoma the expression of GD(2). RESULTS: Our methods produced GD(2)-targeted liposomes that stably entrapped 90% of added c-myc asODNs. These liposomes showed a selective binding for GD(2)-positive melanoma cells in vitro. Melanoma cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes containing c-myc asODNs (aGD(2)-CCL-myc-as) than by nontargeted liposomes or free asODNs. The pharmacokinetic results obtained after i.v. injection of [(3)H]-myc-asODNs, free or encapsulated in nontargeted CCLs or GD(2)-targeted CCLs, showed that free c-myc-asODNs were rapidly cleared, with less than 10% of the injected dose remaining in blood at 30 min after injection. c-myc-asODNs encapsulated within either CCL or aGD(2)-CCL demonstrated a more favorable profile in blood, with about 20% of the injected dose of each preparation remaining in vivo at 24 h after injection. In an in vivo melanoma experimental metastatic model, aGD(2)-CCL-myc-as, at a total dose of only 10 mg of asODN per kilogram, significantly inhibited the development of microscopic metastases in the lung compared with animals treated with myc-asODNs, free or entrapped in nontargeted liposomes, or aGD(2)-CCL encapsulating scrambled asODNs (P < 0.01). Moreover, mice bearing established s.c. human melanoma xenografts treated with aGD(2)-CCL-myc-as exhibited significantly reduced tumor growth and increased survival (P < 0.01 versus control mice). The mechanism for the antitumor effects appears to be down-regulation of the expression of the c-myc protein and interruption of c-myc-mediated signaling: induction of p53 and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. CONCLUSION: These results suggest that inhibition of c-myc proto-oncogene by GD(2)-targeted antisense therapy could provide an effective approach for the treatment of melanoma in an adjuvant setting.     

Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.

PURPOSE: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.     

Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non–Small-cell Lung Cancer: A Systematic Review and Meta-analysis

Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non–small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G₁ cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.     

Preoperative Chemoradiation for Extraperitoneal T3 Rectal Cancer: Acute Toxicity, Tumor Response, and Sphincter Preservation

Purpose: To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control.

Methods and Materials: Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m², Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m², Days 1–4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4–6 weeks after the end of chemoradiation.

Results: Total Grade 3–4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% [7] of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a sphincter-saving surgical procedure. In 12 (44%) of 27 patients candidate for an APR, the sphincter was preserved, as it was in 19 (95%) of 20 probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > 20 mm was observed in 21 patients (26%). Of 63 patients, 4 (6%) had moderate soilage after the sphincter-saving procedure.

Conclusion: Preoperative combined modality therapy seems to afford some potential advantages in nonrandomized trials: patients are able to tolerate higher chemotherapy doses and they experience a lower acute toxicity. Tumor downstaging and resectability rates are high; sphincter preservation is feasible. Larger T3 tumors remained less influenced by this treatment; thus, taking into account the low toxicity rate recorded, a more aggressive schedule should be applied in these resectable tumors.     

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study

Background

Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a “real-life” Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study.

Novel SrO-Containing Glass-Ceramic Sealants for Solid Oxide Electrolysis Cells (SOEC): Their Design and Characterization under Relevant Conditions

This study presents results on the development of strontium oxide (SrO) containing glass sealants used to join Crofer22APU to yttria-stabilized zirconia (3YSZ), in which the main glass components, that is, silicon oxide (SiO₂), strontium oxide (SrO), calcium oxide (CaO) and aluminum oxide (Al₂O₃), have been varied appropriately. Certain properties, such as the crystallization behavior, the coefficient of thermal expansion, adhesion, and reactivity of the sealants in contact with Crofer22APU, have been reviewed and discussed. The optimized glass composition (with CTE in the 9.8–10.3 × 10⁻⁶ K⁻¹ range) results in a good joining behavior by hindering the formation of undesirable strontium chromate (SrCrO₄) on contact with the Crofer22APU steel after 1000 h. at 850 °C. High specific resistivity values of about 10⁶ Ohm.cm have been obtained, thus demonstrating good insulating properties at 850 °C under an applied voltage of 1.6 V. A negligible degradation in the electrical resistivity trend was measured during the test up to 1000 h, thus excluding the presence of detrimental reactions of the glass-ceramic sealant in contact with Crofer22APU under a dual atmosphere, as confirmed using SEM-EDS post-mortem analyses.     

Takotsubo Syndrome during COVID-19 Pandemic in the Veneto Region,Italy

Background: During the COVID-19 pandemic, the risk of SARS-CoV-2 infection, the public health measures of social distancing, the freedom limitations, quarantine, and the enforced homeworking under the lockdown period, as well as medical causes including COVID-19 infection per se, may have caused major emotional distress, especially in the most vulnerable patients. We aimed to evaluate the variations in the number of admissions due to Takotsubo syndrome (TTS) during the COVID-19 pandemic in the Veneto region. Methods: We retrospectively reviewed and analyzed the number of admissions because of TTS in 13 Divisions of Cardiology located in the Veneto region, the northeastern area of Italy, covering a population of more than 2.5 million inhabitants, during the two major pandemic waves of COVID-19 (the first between 15 March and 30 April 2020 and the second between 15 November and 30 December 2020) that occurred in 2020. Results: In total, 807 acute coronary syndromes were admitted in the 13 enrolling hospitals. Among these, 3.9% had TTS. Compared to the corresponding 2018 and 2019 time periods, we observed a significant increase in the number of TTS cases (+15.6%, p = 0.03 and +12.5%, p = 0.04, comparing 2018 to 2020 and 2019 to 2020, respectively). Geographical distribution of the TTS cases reflected the broad spread of the SARS-CoV-2 infection with a significant direct relationship between TTS incidence and the number of COVID-19 infections according to Pearson’s correlation (r = 0.798, p < 0.001). Conclusions: The higher incidence of TTS during the 2020 COVID-19 pandemic waves, especially in the areas that were hit hardest in terms of morbidity and mortality by the SARS-CoV-2 infection, suggest a strong direct and/or indirect role of COVID-19 in the pathogenesis of TTS.