Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease: Observations and Dilemmas after 10 Years of Real-Life Experience.

Advanced Parkinson's disease (APD) cannot be treated efficiently using the classical medications however, in recent decades invasive therapeutical methods were implemented and confirmed as effective. One of these methods makes it possible to continue the levodopa (LD) supplementation as a gel administered directly into the upper intestine. However, there are a number of unanswered questions regarding this method. Therefore, we retrospectively analyzed a 10-year period of selected patients that were treated with levodopa/carbidopa intestinal gel (LCIG). We included all APD patients with motor fluctuations and dyskinesia at presentation. LCIG treatment was started in 150 patients: on average these patients received LD for 10.6 ± 4.4 years with a frequency of 5.2 ± 1.0/day until the introduction of LCIG. The estimated and the real LCIG dose differed significantly (mean: 1309 ± 321 mg vs. 1877 ± 769 mg). The mean duration of LCIG administration was 19.8 ± 3.6 h, but in a number of 62 patients we had to administer it for 24 h, to maximize the therapeutic benefit. A carefully and individually adjusted LCIG treatment improves the quality of life of APD patients, but questions remain unresolved even after treating a large number of patients. It is important to share the ideas and observations based on the real-life experience related to the optimal timing, the appropriate dose and duration of administration of the LCIG.

Management Challenges of Severe, Complex Dyskinesia. Data from a Large Cohort of Patients Treated with Levodopa-Carbidopa Intestinal Gel for Advanced Parkinson's Disease.

BACKGROUND: In the advanced stages of Parkinson's disease (APD), complex forms of dyskinesia may severely impair the patient's quality of life. OBJECTIVE: In the present study, we aimed to analyze the evolution under LCIG therapy of the most important motor fluctuations and complex disabling dyskinesias, including diphasic dyskinesia. METHODS: In this retrospective study, we analyzed the characteristics of patients with APD who had at least 30 min of diphasic dyskinesia (DID) in 3 consecutive days, were considered responders and were treated with LCIG in our clinic. Patients were evaluated before and after PEG and at 6, 12 and 18 months, when the changes in the therapy were recorded, and they completed a 7-point Global Patient Impression of Improvement (PGI-I) scale. RESULTS: Forty patients fulfilled the inclusion criteria-out of which, 34 performed all visits. There was a substantial difference between the calculated and real LCIG (1232 ± 337 mg vs. 1823 ± 728 mg). The motor fluctuations and most dyskinesias improved significantly after starting LCIG, but an increasing number of patients needed longer daily administrations of LCIG (24 instead of 16 h). CONCLUSIONS: Patients with APD with complex dyskinesias must be tested in dedicated hospitals, and they need a special therapeutic approach. The properly adapted LCIG treatment regarding the dose and time of administration completed with well-selected add-on medication should offer improvement for patients who want to or can only choose this DAT vs. others.

Levodopa-Carbidopa Intestinal Gel Infusion Therapy Discontinuation: A Ten-Year Retrospective Analysis of 204 Treated Patients.

BACKGROUND: Parkinson's disease (PD) is the second most common progressive neurodegenerative disease. In the advanced stages, the continuous delivery of levodopa (LD) as levodopa-carbidopa intestinal gel (LCIG) has demonstrated significant improvement of motor and nonmotor complications and improvement of the patients' quality of life (QoL). Despite the growing global experience with this treatment, anumber of unsolved practical issues remain, and currently, the data on the reasons that can lead to the discontinuation of LCIG are scarce. OBJECTIVE: In the present study, we aimed to analyze the causes that led to the discontinuation of LCIG therapy. METHODS: In this retrospective study, after 10 years of experience with LCIG as a therapeutic option in advanced PD, we analyzed the data of all dropout cases among the 204 patients that initiated LCIG therapy in two Romanian centers. RESULTS: Of the 204 patients enrolled, 43 patients dropped out. Disease duration until LCIG infusion was significantly longer (11.67±4.98 vs 9.44±3.44) and the overall clinical picture more sever (both regarding motor symptoms and cognitive decline) in dropout patients (compared to patients who continued treatment). The dropout patients also presented significant differences regarding the incidence of polyneuropathy (32.5% vs 11.18%). The main cause of discontinuation was death. CONCLUSION: The causes of discontinuation from LCIG therapy in Romanian patients are similar to those from other centers; however, the rate of dropouts is somewhat lower. The clinician's experience in selecting and treating the patients in advanced stages of PD can increase therapeutic adherence. Also, the presence of a well-trained caregiver along with the availability of a proper aftercare system is mandatory for maintaining the long-term benefits of the therapy and the overall best outcome possible. Targeted prospective studies are needed to confirm whether a more severe stage of the disease and cognitive impairment at the time of initiation, respectively, the association of polyneuropathy can be considered as predictive factors for dropout.

Profile Of Patients With Advanced Parkinson's disease Suitable For Device-Aided Therapies: Restrospective Data Of A Large Cohort Of Romanian Patients.

BACKGROUND: There is insufficient data in the literature regarding the real-life, daily clinical practice evaluation of patients with advanced Parkinson's disease (APD). We are not sure what is the upper limit of dopaminergic medication, especially the levodopa (LD) dosage, and how it is influenced by access and suitability to the various add-on and device-aided therapies (DAT). OBJECTIVE: This retrospective study explored the profile of APD patients that were considered and systematically evaluated regarding the suitability for DAT. METHODS: We analyzed the data from 311 consecutive patients with APD hospitalized between 2011 and 2017 that 1) described at least 2 hrs/day off periods divided into at least two instances/day (except early morning akinesia), 2) were in stage 3 or above on the Hoehn and Yahr scale, 3) were with or without dyskinesia, and 4) received at least four levodopa doses/day combined with adjuvant therapy. RESULTS: Of the 311 patients enrolled initially, 286 patients showed up for the second visit, of which in 125 cases we assessed that DAT would be necessary. Finally, 107 patients were tested in our clinic to confirm the efficacy of LCIG. Patients selected for DAT had significantly longer off periods, more frequent dyskinesia, early morning akinesia, and freezing despite having significantly higher LD doses than those with an improved conservative therapy. CONCLUSION: Patients with APD can have a variety of symptoms, and because symptoms and therapeutical efficacy can be manifested in many different combinations, it is not possible to decide using a single, rigid set of criteria which APD patient is eligible for DAT. Nevertheless, treating physicians should refer APD patients to a specialized movement disorder center when patients with an average daily dose of LD of at least 750-1000 mg and maximal complementary therapies present daily motor complications that significantly reduce the quality of life.

Triplex High-Resolution Melting Assay for the Simultaneous Assessment of IFNL3 rs12979860, ABCB11 rs2287622, and RNF7 rs16851720 Genotypes in Chronic Hepatitis C Patients.

Chronic hepatitis C (CHC) is a leading cause of liver disease. Despite the improved efficacy of new antivirals, their high costs preclude their adoption in resource-limited settings, where CHC prevalence is highest. We developed a triplex high-resolution melting assay for the simultaneous assessment of three genetic polymorphisms related to the response to treatment and development of advanced fibrosis in CHC: IFNL3 rs12979860, ABCB11 rs2287622, and RNF7 rs16851720. We validated the assay in clinical samples from 130 CHC patients treated with classic therapy. The assay showed excellent reproducibility and 100% accuracy, sensitivity, and specificity against the gold standard Sanger sequencing. When added to routine examination data, genotype information significantly improved their performance for prediction of advanced liver fibrosis and sustained virological response (P = 0.041 and P = 0.011, respectively). Correspondingly, the full models had area under the receiver operating characteristic curve values of 0.842 (95% CI, 0.773-0.911) and 0.921 (95% CI, 0.870-0.972) and integrated discrimination improvements of 7.5% (95% CI, 2.5%-12.5%; P = 0.003) and 11.5% (95% CI, 5.8%-17.2%; P < 0.001), respectively. This is the first report on a diagnostic test for simultaneous genotyping of IFNL3, ABCB11, and RNF7 in CHC patients. Reliable and inexpensive, the assay should provide useful information for the clinical management of CHC, like identification of patients at risk of rapid disease progression or with high chances of response to classic therapy.

A case of Sweet's syndrome associated with uveitis in a young male with ulcerative colitis.

Sweet's syndrome is rare acute febrile neutrophilic dermatosis whose onset is either idiopathic or associated with other underlying conditions, such as infections, autoimmune diseases, pregnancy, use of certain medications, or malignancy. We report the case of a young male with known history of ulcerative colitis and abrupt onset of high fever, malaise, blurred vision and eruption of painful erythematous nodules and papules, localized on the head, neck, trunk and upper limbs. Ophthalmological examination established the diagnosis of anterior uveitis. Inflammatory markers were positive. Histological examination of skin lesions revealed a dense neutrophilic infiltrate of the dermis. Clinical, laboratory and histological findings were suggestive for the diagnosis of Sweet's syndrome and uveitis on a background of ulcerative colitis. Systemic and ophthalmic administration of corticotherapy leads to a prompt resolution of symptoms and inflammatory syndrome. The particularity of this case is the occurrence of two simultaneous extraintestinal manifestations in a young male with inflammatory bowel disease and colonic involvement. Although a relatively rare condition, Sweet's syndrome should be considered as a differential diagnosis in patients with acute onset of high fever and skin rash, as it may have notable internal involvement and can be easily treated.

Duplex High-Resolution Melting Assay for the Simultaneous Genotyping of IL28B rs12979860 and PNPLA3 rs738409 Polymorphisms in Chronic Hepatitis C Patients.

Chronic hepatitis C (CHC) is a major burden for public health worldwide. Although newer direct-acting antivirals show good efficacy, their cost precludes their wide adoption in resource-limited regions. Thus, strategies are being developed to help identify patients with high susceptibility to response to classic PEG-interferon + ribavirin therapy. IL28B polymorphism rs12979860 C/T is an important predictor for an efficient response to interferon-based therapy. A genetic variant in adiponutrin (PNPLA3) gene, rs738409 C/G, is associated with steatosis, severity, and progression of liver fibrosis in CHC patients, and predicts treatment outcome in difficult-to-cure HCV-infected patients with advanced fibrosis. We developed a rapid and inexpensive assay based on duplex high-resolution melting (HRM) for the simultaneous genotyping of these two polymorphisms. The assay validation was performed on synthetic DNA templates and 132 clinical samples from CHC patients. When compared with allele-specific PCR and sequencing, our assay showed 100% (95% CI: 0.9724-1) accuracy, with 100% sensitivity and specificity. Our assay was robust against concentration and quality of DNA samples, melting curve normalization intervals, HRM analysis algorithm, and sequence variations near the targeted SNPs (single nucleotide polymorphism). This duplex assay should provide useful information for patient-oriented management and clinical decision-making in CHC.

Circulating RNA molecules as biomarkers in liver disease.

Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results.

Correlations between anthropometric and serologic elements of metabolic syndrome and histopathologic features of nonalcoholic fatty liver disease.

AIM OF THE STUDY: Studying the correlation between elements of metabolic syndrome and histological changes of the liver in nonalcoholic fatty liver disease. PATIENTS AND METHODS: Thirty-nine patients with nonalcoholic fatty liver disease were included in our study. Inclusion criteria were: presence of liver steatosis on ultrasound in patients with waist circumference over 94 cm in men and over 80 cm in women and with serologic elements of metabolic syndrome. Exclusion criteria were: chronic viral hepatitis, autoimmune hepatitis, Wilson disease, hemochromatosis, regular alcohol consumption. Body mass index, waist circumference, fasting plasma glucose, serum triglyceride and cholesterol levels and serum ALT were determined. On liver biopsy specimens, performed in each patient, the NASH score, representing the sum of fibrosis, steatosis, lobular inflammation and ballooning, was calculated. RESULTS: Necroinflammation was mild in 15 patients, medium in 19 patients and severe in five patients. Mild fibrosis was present in four cases, medium in 14 cases, severe in six, and two patients were diagnosed with cirrhosis. We found statistically significant correlation between waist circumference and the grade of histological activity, the presence of diabetes and both fibrosis grade and histological activity, and the serum ALT and histological activity. CONCLUSIONS: Noninvasive assessment of the severity of hepatic histological changes in nonalcoholic fatty liver disease could be made by anthropometric parameters or by serologic components of metabolic syndrome, but it is not an accurate method to identify patients with high-risk for disease progression. These noninvasive parameters cannot replace liver biopsy.

[Spleno-renal distal and proximal shunts for hypersplenism due to hepatic cirrhosis]. / Suntul spleno-renal distal si proximal pentru hipersplenismul datorat cirozei hepatice.

The secondary hypersplenism appears from 30-50% in liver cirrhosis with portal hypertension. The mechanism of the complication is the splenic congestion as the result of the progress of the portal hypertension. Between 1997-2005, 16 patients with hypersplenism due to liver cirrhosis were operated in the service. The aim of the operation was to decompress the portal hypertension, by spleno-renal shunt (Warren), in 6 patients, truncular shunts in 2 patients, and splenectomy with spleno-renal shunts in 8 patients. No postoperative death was noted on the series. The platelets number and the white blood cells, destroyed by the reticuloendothelial system of the spleen, were counted in the first month and the first year, as well as the spleen volume. In patients with non-splenectomy operations the improvement of the blood elements number was remarked in the first week, but the volume of the spleen remained increased during 1-6 month. In patients with splenectomy the platelets and the white cells dramatically increased, with the risk of coagulation disfunction. The survival rate at five years was 12 patients.

[Cervical anastomotic fistula in surgery of the esophagus]. / Fistulele anastomozelor cervicale din chirurgia esofagului.

Cervical anastomotic fistula are reported in the surgical literature in 10-30% of the patients, providing a much longer hospitalisation, a higher morbidity and in some cases even mortality. Between 1997-2003, 91 patients underwent surgical treatment for esophageal cancers and 14 patients for chemical burns. In the cancer group the rate of resection was 67,03% (61 patients). In 8 patients with non-resection tumours a retrosternal esophageal by-pass with stomach was carried out. Cervical anastomosis were performed in 68 patients, by hand sutures. Anastomotic fistula were noted in 9 patients (13,24%). In 6 cases temporarily fistula occurred, with spontaneous healing by local treatment, in 8-28 days. 2 patients required reoperation and one patient a definitive feeding jejunostomy. Most common causes of fistula are technical problems, ischemic gastric or colonic tube, postoperative respiratory failure, with prolonged hypoxia. An anastomosis in the neck results in less postoperative complications than one of the lower level.

[Multivisceral operations for carcinoma of the upper stomach and cardia]. / Operatii multiviscerale pentru cancerul gastric al polului superior si al cardiei.

In this study are noted technical problems regarding "en bloc" multiple organ resections and the anatomic and functional reconstruction for carcinoma of the upper stomach and cardia. From 1997 to 2002, a total of 264 patients with cancers of the stomach were operated in the service. 75 patients presented cancers localized at the proximal stomach and cardia (97.33% adenocc.). The rate of resectability was 27.77% (27 pt.). Types of operations in this series were: standard esophagogastrectomy in 7 patients; total gastrectomy with regional lymphadenectomy in 9 patients; 11 patients underwent "en bloc" multiple organ resection, with the removal of the stomach, partial or total esophagectomy and, occasionally, ablation of the spleen, pancreas, left hepatectomy, resection of the diaphragm and an extensive lymphadenectomy. Surgical mortality for the complex multivisceral resections was noted in 3 patients (8.88%). The global 5 years survival in the service is poor: 15.9%.