Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome.

BACKGROUND: There are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. OBJECTIVE: To compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. METHODS: In this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18-47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. RESULTS: Nine patients completed the RCT. At group level, on-GPi - but not on-thal - resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. CONCLUSION: Our data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

Prognostic relevance of topoisomerase II α and minichromosome maintenance protein 6 expression in colorectal cancer.

BACKGROUND: Despite rising incidence rates of colorectal malignancies, only a few prognostic tools have been implemented in proven clinical routine. Cell division and proliferation play a significant role in malignancies. In terms of colorectal cancer, the impact of proliferation associated proteins is controversially debated. The aim of our study was to examine the expression of topoisomerase II α and minichromosome maintenance protein 6 and to correlate these findings with the clinical data. METHODS: Tissue samples of 619 patients in total were stained using the antibodies Ki-S4 and Ki-MCM6 targeting topoisomerase II α as well as minichromosome maintenance protein 6. The median rate of proliferation was correlated with clinical and follow up data. RESULTS: The expression rate of minichromosome maintenance protein 6 is significantly higher than the proportion of topoisomerase II α in tumour cells (p < 0.001). A high expression of both proteins coincides with a beneficial outcome for the patient, indicating a favourable prognostic marker (p < 0.001 and p = 0.008). CONCLUSIONS: We have demonstrated that high expression rates of proliferative markers is linked to a beneficial patient outcome. According to the general opinion, a high expression rate correlates with a poor patient outcome. In this study, we were able to refute this assertion.

[The Geriatric Patient with Parkinson's Disease - a Neurological Challenge]. / Der geriatrische Parkinson-Patient - eine neurologische Herausforderung.

Geriatric patients with Parkinson's disease (PD) represent a particular challenge in terms of diagnostics and treatment. This overview article addresses age-related characteristics of this patient group and discusses particularities in PD symptoms in this age group, frequent comorbidities and the resulting polypharmacy. Questions regarding the availability of specialist and therapist care as well as end-of-life aspects are discussed. While comprehensive care structures are not always available, this patient group requires a multidisciplinary treatment team supervised by neurologists with ample experience in PD treatment.

Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma.

BACKGROUND: Endoscopic mucosal resection (EMR) or radical surgical resection are the standard treatment options for patients with early Barrett's adenocarcinoma (EBAC). Endoscopic submucosal dissection (ESD) is a new endoscopic technique, which allows--in contrast to EMR--endoscopic en-bloc resection of neoplastic lesions greater than 2 cm with complete histological evaluation of the resected specimen. In contrast to Western countries, Barrett's esophagus is less common in Asia indicating the low volume of published data of ESD in EBAC in Japanese series. Therefore, the aim of the present study is to describe the results of ESD in patients with EBAC performed in a German tertiary referral center. METHODS: Between November 2009 and April 2014 ESDs were performed in 22 patients with histologically proven EBAC. Data were given for the en-bloc, the R0, the R0 en-bloc, and the curative resection rate as well as for the complication and the local recurrence rate. RESULTS: ESD was technically possible in all of the 22 patients. 20 of the resected EBAC were mucosal carcinomas, whereas in two patients the tumor showed submucosal invasion. The en-bloc, R0, R0 en-bloc, and curative resection rates were 95.5, 81.8, 81.8 %, and 77.3 %, resp. Complication rate was 27.3 % (perforation n = 1, bleeding n = 2, stenosis n = 3). In case of curative tumor resection, only one local tumor recurrence (5.9 %) occurred after a medium follow-up of 1.6 years. CONCLUSIONS: Despite the small number of patients and a relatively short follow-up, the present data underline the value of ESD, especially in case of curative resections in the definite and less invasive therapy of EBAC. Attention should be drawn toward subsquamous extension of EBAC requiring a sufficient safety margin as an obligate condition for curative R0 resections. Due to the required learning curve and the management of potential complications, ESD should be restricted to greater endoscopic centers.

The NF-κB pathway is rarely spontaneously activated in mantle cell lymphoma (MCL) cell lines and patient's samples.

In this study, we investigated the role of NF-κB (canonical and alternative pathways) in the survival or proliferation of mantle cell lymphoma (MCL) cell lines. P50/p65 complexes were detectable by EMSA assays in 4/5 cell lines. Stable expression of a dominant-negative form of IkBa had no effect on proliferation nor on apoptosis in EBV-negative cell lines. Three out of 4 of the cell lines tested exhibited Phospho-p65 (Ser(536)). The alternative NF-κB pathway was not activated in 4/5 cell lines tested. Patient samples were also studied by Western blot, EMSA and Immunohistochemistry (IHC). No p50/p65 complexes were detected in cells freshly collected from 7 patients, but 1/7 cells exhibited Phospho-p65 (Ser(536)). We investigated immunohistochemically, the expression of NF-κB in 86 patients enrolled in two multicentre prospective trials. Patients with MCL exhibiting negative or positive cytoplasmic expression of NF-κB had a median overall survival of 35.7months compared to 22.4months for patients with nuclear NF-κB expression (p=0.0193). All these data suggest that NF-κB does not play a key role in proliferation and apoptotic processes in MCL cell lines. In patient samples, the presence of p65 in the nucleus reflecting NF-κB activation is rare but associated with a poor outcome.

Determinants of paraoxonase 1 status: genes, drugs and nutrition.

Paraoxonase 1 (PON1) is an enzyme which is mainly synthesized in the liver. PON1 circulates in the blood bound to HDL and delays or prevents the oxidation of LDL. Single nucleotide polymorphisms significantly determine PON1 status in humans. A high PON1 status may be associated with a reduced cardiovascular disease risk. By using in silico databases we suggest various transcription factors and micro RNA as putative regulators of PON1. Furthermore we predict functional partners of PON1 by using a text mining tool. Beside genetic and life style factors PON1 status may be determined by drugs (e.g., statins, fibrates) and dietary factors. Dietary modulators of PON1 status include fat and fatty acids, antioxidant vitamins (e.g. ascorbic acid, tocopherol), polyphenols and polyphenol-rich foods.

Effect of quercetin on paraoxonase 1 activity--studies in cultured cells, mice and humans.

There is increasing evidence that the HDL-associated enzyme paraoxonase 1 (PON1) may have a protective function in the atherosclerotic process. An enhancement of PON1 activity by dietary factors including flavonoids is therefore of interest. Quercetin, a flavonol frequently present in fruits and vegetables has been shown to induce PON1 in cultured liver cells, but the in vivo efficacy of a dietary quercetin supplementation has yet not been evaluated. To this end, we fed laboratory mice quercetin-enriched diets with quercetin concentrations ranging from 0.05 to 2 mg/g diet for 6 weeks and determined the expression of the hepatic PON1 gene and its protein levels. Since we could establish a moderate but significant induction of PON1 mRNA levels by dietary quercetin in mice, we aimed to proof whether healthy human volunteers, given graded supplementary quercetin (50, 100 or 150 mg/day) for two weeks, would respond with likewise enhanced plasma paraoxonase activities. However, PON1 activity towards phenylacetate and paraoxon was not changed following quercetin supplementation in humans. Differences between mice and humans regarding the PON1 inducing activity of quercetin may be related to differences in quercetin metabolism. In mice, unlike in humans, a large proportion of quercetin is methylated to isorhamnetin which exhibits, according to our reporter gene data in cultured liver cells, a potent PON1 inducing activity.

[Successful therapy with etanercept in relapsing polychondritis]. / Erfolgreiche Therapie mit Etanercept bei rezidivierender Polychondritis.

Relapsing polychondritis is a rare autoimmune disease associated with inflammation and destruction of cartilage and connective tissue.We report on a patient with a severe form of this disease that had a progressive and complicated course despite administration of a number of disease-modifying anti-rheumatic drugs.Finally, therapy with the TNF-alpha-antagonist etanercept was initiated, which led to a considerable decrease in disease activity. This case is further evidence for the efficiency of TNF-alpha-antagonists in relapsing polychondritis.

Evidence of lymphangiogenesis in Warthin's tumor of the parotid gland.

The details of the pathogenesis of cystadenolymphoma (Warthin's tumor) of the parotid gland are still unclear. Neovascularization is considered to be a pivotal factor for solid tumor progression and biological behavior of the tumor. Using double-labeling immunohistochemistry for LYVE-1 and CD34 (specific markers for lymphatic and vascular endothelial cells, respectively) this study analyzes lymphatic vessel density (LVD) and blood vessel density (BVD) in 10 Warthin's tumors and 10 pleomorphic adenomas of the parotid gland as well as in 5 normal parotid glands and 5 normal parotid lymph nodes. There was no significant difference in the intratumoral LVD and BVD among pleomorphic adenoma and normal parotid gland tissue. In contrast, the intratumoral LVD and BVD were significantly higher in Warthin's tumor than pleomorphic adenoma, normal parotid gland and parotid lymph node (P<0.0001 versus P<0.004). The increase in lymphatic vessels in Warthin's tumor suggests that epithelial tumor cells might promote lymphangiogenesis in this kind of lesions.

[Reference radiology in nephroblastoma: accuracy and relevance for preoperative chemotherapy]. / Referenzradiologie des Nephroblastoms: Diagnosegenauigkeit und Bedeutung für die präoperative Chemotherapie.

PURPOSE: A reference radiologic diagnosis was carried out for the purpose of quality control and in order to achieve high diagnostic accuracy in the ongoing trial and study SIOP 2001/GPOH for renal tumors during childhood. The aim of the present study is to evaluate the value of diagnostic imaging and the benefit of reference evaluation at a pediatric radiology center. MATERIALS AND METHODS: In 2004 the imaging studies of 97 patients suspected of having a renal tumor were presented at the beginning of therapy. Diagnostic imaging was compared to the primary imaging results and the histological findings and was analyzed in regard to the therapeutic consequence (primary chemotherapy without prior histology). 77 MRI, 35 CT and 67 ultrasound examinations of 47 girls and 50 boys (mean age 4 years; one day to 15.87 years old) were analyzed. In addition to the histological findings, the reference pathological results were submitted in 86 cases. Results from the primary imaging corresponding to the histology and results from the reference radiology corresponding to the histology were statistically compared in a binomial test. RESULTS: In 76 of the reference-diagnosed Wilms' tumors, 67 were confirmed histologically. In 72 cases preoperative chemotherapy was initiated. In 5 cases neither a Wilms' tumor nor a nephroblastomatosis was found. 16 of 21 cases (76 %) with reference-diagnosed non-Wilms' tumors were selected correctly. The results of the primary imaging corresponded to the histology in 71 cases, and those of the reference radiology in 82 cases. The statistical evaluation showed that the results of the reference radiology were significantly better (p = 0.03971). CONCLUSION: Reference radiological evaluation improved the diagnostic accuracy with therapeutic relevance. The differentiation of different renal tumors is not completely possible using imaging methods. The rate of patients with false preoperative chemotherapy for all renal neoplasms is currently 5.2 % and 1 % for benign renal tumors.

Lymphocyte subsets in irradiation-induced sialadenitis of the submandibular gland.

AIMS: Irradiation-induced sialadenitis is a significant cause of morbidity in head and neck cancer patients receiving radiotherapy. Neither the exact aetiopathology of chronic irradiation-induced sialadenitis nor the mechanisms leading to atrophy of the glandular cells associated with an increase in extracellular matrix are understood. The aim of our study was to determine the phenotype of the inflammatory infiltrate and to study its distribution in the affected submandibular glands. METHODS AND RESULTS: Paraffin-embedded submandibular glands from a homogeneous group of 19 patients with advanced oropharyngeal cancer who received conventional radiotherapy to the primary site and upper neck were analysed. In all patients the radiation dose and field were approximately equal. The submandibular glands were obtained during neck dissection. To characterize the lymphoid infiltrate, all tissue sections were immunostained for T cells (CD3, CD4, CD8), cytotoxic T cells (granzyme B), B cells (CD20), and macrophages (Ki-M1p). A histopathological classification into four grades was established based on the degree of glandular atrophy, fibrosis and lymphocytic infiltration. Phenotypic analysis of submandibular gland sections revealed that the great majority of lymphocytic infiltrates were cytotoxic T cells associated with acinar cell destruction. CONCLUSIONS: The significantly elevated frequencies of cytotoxic cells in the submandibular glands of patients with irradiation-induced sialadenitis suggest that cell-mediated immune mechanisms may play a part in the pathogenesis of this disease.

[MRI-morphology and staging of congenital mesoblastic nephroma: evaluation of a collection with 20 patients]. / MRT-Morphologie und Staging des kongenitalen mesoblastischen Nephroms: Auswertung einer Fallsammlung mit 20 Patienten.

PURPOSE: To differentiate classic and cellular type of congenital mesoblastic nephroma (CMN) in MRI and to evaluate MRI for staging according to the Societe Internationale de Oncologie Pediatrique (SIOP). MATERIAL AND METHODS: MRI examinations of 20 children with CMN (age 1st to 16th months, classic type n = 11, cellular type n = 7, mixed type n = 2) were analyzed retrospectively. Cysts, necrosis, hemmorhage in the tumor, signal intensity, tumor structure, thrombosis and dilatation of renal vein, crossing of the body midline, peripheral contrast-enhancement, tumor volume and existence of a tumor pseudocapsule in contrast to the residual kidney were described. The radiologic stage was compared with the histopathologic stage (infiltration of perirenal fat and infiltration of the renal sinus). RESULTS: Tumors of the classic type (mean volume 67.9 ml) had necrosis in 1 case, crossed the midline in 1 case, had no cysts or bleeding, and had a peripheral contrast-enhancement in 1 case, and were heterogeneous in 9 cases. The cellular type (mean volume 302.8 ml) had tumor necrosis in 6 cases, bleeding in 3 cases, cysts in 3 cases, crossed the midline in 4 cases, and peripheral contrast enhancement in 2 cases, and was predominantly heterogeneous. Mixed tumor types (7 ml and 202 ml) had tumor necrosis in 1 case and crossed the midline in 1 case, a peripheral contrast enhancement in 2 cases and a homogenous structure in 1 case. The signal intensity in T1 w and T2 w images was not specific. The renal vein was inconspicuous in all children. The evaluation of the infiltration in perirenal fatty tissue was true positive in 1 case, true negative in 10 cases, false negative in 4 cases and false positive in 5 cases. The infiltration of the renal hilus was true positive in 10 children, false positive in 8 cases and true negative in 2 cases. CONCLUSION: A typical finding of CMN in MRI is a heterogeneous tumor without demarcation from the rest of the kidney parenchyma by a pseudocapsule. The cellular type of CMN tends to have a higher tumor volume and shows more necrosis, bleeding and cysts than the classic type in MRI. A peripheral contrast-enhancement in MRI is not characteristic for any type of CMN. Local tumor staging is not possible with MRI.

[Childhood kidney tumors -- the relevance of imaging]. / Kindliche Nierentumoren -- Relevanz der Bildgebung.

Kidney tumors represent 6.2% of malignant tumors in children. History, clinical course and radiological findings are necessary elements in the differential diagnosis of the different renal tumors. In the case of nephroblastoma, chemotherapy is based solely on the radiological diagnosis without prior histology. In therapy-optimizing studies of the Society of Pediatric Oncology and Hematology, preoperative chemotherapy is performed. Therapy monitoring is performed in the course of and after preoperative chemotherapy to verify tumor response. Radiological staging plays a significant role in deciding on further treatment and in operative planning. Three-dimensional visualization of the abdominal situs can assist preoperative planning. In summary, diagnostic imaging in renal tumors in children plays a role in differential diagnosis, staging, monitoring of therapy, and surgical planning.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma.

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P<0.001) and Ki-67 (P<0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P<0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes.

Mice deficient in various mismatch repair (MMR) enzymes were examined to determine whether this repair pathway is involved in antibody class switch recombination. Splenic B cells from mice deficient in Msh2, Mlh1, Pms2, or Mlh1 and Pms2 were stimulated in culture with lipopolysaccharide (LPS) to induce immunoglobulin (Ig)G2b and IgG3, LPS and interleukin (IL)-4 to induce IgG1, or LPS, anti-delta-dextran, IL-4, IL-5, and transforming growth factor (TGF)-beta1 to induce IgA. After 4 d in culture, cells were surface stained for IgM and non-IgM isotypes and analyzed by FACS((R)). B cells from MMR-deficient mice show a 35-75% reduction in isotype switching, depending on the isotype and on the particular MMR enzyme missing. IgG2b is the most affected, reduced by 75% in Mlh1-deficient animals. The switching defect is not due to a lack of maturation of the B cells, as purified IgM(+)IgD(+) B cells show the same reduction. MMR deficiency had no effect on cell proliferation, viability, or apoptosis, as detected by [(3)H]thymidine incorporation and by propidium iodide staining. The reduction in isotype switching was demonstrated to be at the level of DNA recombination by digestion-circularization polymerase chain reaction (DC-PCR). A model of the potential role for MMR enzymes in class switch recombination is presented.

Cognate T cell help for CD40-deficient B cells induces c-myc RNA expression, but DNA synthesis requires an additional signal through surface Ig.

To investigate the role of CD40 ligand in the delivery of help to B cells, we examined the Ag-specific interaction of B cells from CD40-deficient mice with a Th2 cell line in vitro. Small resting B cells from normal mice are stimulated to synthesize DNA when they present monovalent Ag (rabbit Fab anti-Ig) to a rabbit Ig-specific Th cell line. This response, which is independent of a signal through the B cell Ag receptor (sIg), is nearly absent in B cells from CD40-deficient mice. The CD40-deficient B cells are not defective in Ag presentation because they induce T cell IL-4 synthesis as well as normal B cells. Also, CD40-deficient B cells respond to T cell help with DNA synthesis almost as well as normal B cells if an additional signal is provided through sIg. In conjunction with a sIg signal, cell contact with helper T cells induces DNA synthesis more effectively than soluble cytokines. CD40-independent T cell help can also be measured as an early increase in c-myc mRNA levels in CD40-deficient B cells presenting Ag to helper T cells, although the levels of c-myc RNA expression are lower than those in normal B cells. However, c-myc RNA induced by noncognate interaction with anti-CD3-activated T cells is completely CD40 dependent. We conclude that early growth signals from activated Th cells are received by CD40-/- B cells, but that CD40 and/or sIg signals are required for efficient induction of DNA synthesis.

Tratamiento quirúrgico de la hemoptisis masiva / Surgical treatment of massive hemoptysis

El proposito del presente estudio es conocer las caracteristicas clinicas de un grupo de pacientes con hemoptisis masiva, su etiologia, el metodo diagnóstico más efectivo y la bondad del tratamiento quirurgico. Se presenta la experiencia quirurgica del Hospital Santa Clara de Bogota relacionada con el tratamiento de la Hemoptisis de caracter masivo (600 mL en 24 horas). Se analizaron las historias clinicas de 90 pacientes intervenidos durante el periodo comprendido entre enero de 1981 y enero de 1991. Un total de 50 (55.5 por ciento) pacientes presentaron hemoptisis masiva. Treinta y tres de ellos (66 por ciento) eran del sexo masculino y 17 (34 por ciento) del femenino; no se encontró diferencia estadistica significativa por grupos de edad. Se identifico como la principal causa de dicha entidad la tuberculosis en 40 casos (80 por ciento), de los cuales 18 (45 por ciento) eran tuberculoses activos y 22 (55 por ciento) no. Entre las otras causas se anotan: bronquiectasias en 4 (8 por ciento), cancer pulmonar en 1 (2 por ciento), secuestro pulmonar intralobar en 1 (2 por ciento), neumonia de reabsorcion lenta en 1 (2 por ciento) y criptogenicas en 3 (6 por ciento). La evolucion de la sintomatologia fue variada, encontrándose entre las manifestaciones más importantes, la tos productiva y hemoptoica, la fiebre y la disnea. Todos los pacientes fueron estudiados radiografica y endoscopicamente, obteniendose una efectividad diagnóstica del 92 por ciento. Todos los pacientes con tuberculosis activa recibieron tratamiento farmacologico. Se practicaron 33 lobectomias, 8 bilobectomias, 6 neumonectomias y 1 resección segmentaria. Los controles actuales se llevan a cabo por cirugía y neumologia y van desde los 3 meses hasta los 7 años. La morbilidad global en la presente serie fue del 14 por ciento (7 casos) y la mortalidad del 26 por ciento (13 casos).