Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder with no effective treatment. Geldanamycin is a benzoquinone ansamycin that binds to the heat shock protein Hsp90 and activates a heat shock response in mammalian cells. In this study, we show by using a filter retardation assay and immunofluorescence microscopy that treatment of mammalian cells with geldanamycin at nanomolar concentrations induces the expression of Hsp40, Hsp70 and Hsp90 and inhibits HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. This is the first demonstration that huntingtin protein aggregation in cells can be suppressed by chemical compounds activating a specific heat shock response. These findings may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.     

Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis

CONTEXT: Reliable prognostic factors are needed in papillary thyroid cancer patients to adapt initial therapy and follow-up schemes to the risks of persistent and recurrent disease. OBJECTIVE AND SETTINGS: To evaluate the respective prognostic impact of the extent of lymph node (LN) involvement and tumor extension beyond the thyroid capsule, we studied a group of 148 consecutive papillary thyroid cancer patients with LN metastases and/or extrathyroidal tumor extension. Initial treatment, performed at the Institut Gustave Roussy between 1987 and 1997, included in all patients a total thyroidectomy with central and ipsilateral en bloc neck dissection followed by radioactive iodine ablation. RESULTS: Uptake outside the thyroid bed, demonstrating persistent disease, was found on the postablation total body scan (TBS) in 22% of the patients. With a mean follow-up of 8 yr, eight patients (7%) with a normal postablation TBS experienced a recurrence. Ten-year disease-specific survival rate was 99% (confidence interval, 97-100%). Significant risk factors for persistent disease included the numbers of LN metastases (>10) and LN metastases with extracapsular extension (ECE-LN >3), tumor size (>4 cm), and LN metastases location (central). Significant risk factors for recurrent disease included the numbers of LN metastases (>10), ECE-LN (>3), and thyroglobulin level measured 6-12 months after initial treatment after T4 withdrawal. CONCLUSION: We highlight an excellent survival rate and suggest risk classifications of persistent and recurrent disease based on the numbers of LN metastases and ECE-LN, LN metastases location, tumor size, and thyroglobulin level.     

Morphologic Parameters of Normal Swallowing Events Using Single-Shot Fast Spin Echo Dynamic MRI

This study was designed to determine visible and measurable morphological parameters in normal swallowing using dynamic MRI with single-shot fast spin echo (SSFSE), as a preliminary study in view of noninvasive MRI swallowing evaluation in patients with dysphagia. Seven healthy volunteers aged 24–40 underwent dynamic MRI with SSFSE, with a 1.5-T unit, using a head and neck antenna. Patients repeated dry swallow, water swallow, marshmallow swallow, cake swallow, and cookie chewing for a total of five series, with 15 acquisitions per series at a rate of 700 ms per acquisition. A checklist of swallowing events and anatomic landmarks was used to determine which anatomic landmarks are always visible, which phases or swallowing movements are always visible, and which landmarks can be used to measure oral and pharyngeal motion in swallowing. The oral preparatory, oral, and oropharyngeal phases of deglutition were visible in all cases. No aspiration, reflux, or abnormal residue was observed. Spatial resolution allowed for anatomical measurements of laryngeal elevation, oropharyngeal diameter, and tongue base and velum displacement in all cases. SSFSE dynamic MRI is pertinent for evaluation of the anatomical and physiological characteristics of swallow. The temporal parameters, however, cannot be studied using this technique. Motion artifacts preclude its use in the study of mastication. It remains complementary to videofluoroscopy and other techniques in swallow evaluation.     

Neck recurrence from thyroid carcinoma: serum thyroglobulin and high-dose total body scan are not reliable criteria for cure after radioiodine treatment

BACKGROUND: Local and regional recurrences occur in up to 20% of patients with papillary and follicular thyroid carcinoma. Diagnostic work-up and treatment modalities are still controversial, because nodal control is difficult to ascertain. We assessed the value of serum thyroglobulin (Tg) determination and of high-dose 131I total body scan (TBS) for ascertaining the absence of disease in patients who had already been treated with radioiodine and who subsequently underwent surgery. METHODS: Between 1990 and 2000, 105 patients who had been treated with radioiodine for lymph node recurrence with initial 131I uptake were included in a standardized protocol performed after withdrawal of thyroid hormone treatment: on day 1, serum Tg determination and administration of 3.7 GBq 131I; on day 4, 131I TBS; on day 5, surgery; on day 8, 131I TBS. RESULTS: In 25 patients the serum Tg obtained following thyroid hormone withdrawal was undetectable: for these patients, the 131I TBS showed uptake foci in 21 and pathology disclosed neoplastic foci in 19. In 32 patients the serum Tg ranged from 1 to 10 ng/ml: for these patients, the 131I TBS showed uptake foci in 26 and pathology disclosed neoplastic foci in 28. In 48 patients the serum Tg level was above 10 ng/ml: for these patients, the 131I TBS showed uptake foci in 38 and pathology disclosed neoplastic foci in 46. Thus, no uptake was found preoperatively in 20 patients, among whom pathology disclosed lymph node metastases in 16. However, both tests were negative in only two of the 93 patients in whom pathology disclosed neoplastic foci. CONCLUSION: Serum Tg levels and 131I TBS cannot be considered as reliable indicators for the absence of disease in patients already treated with 131I. However, when both tests are negative, the risk of persistent disease is minimal.     

Use of the molecular adsorbent recycling system in the treatment of postoperative hepatic failure and septic multiple organ dysfunction--preliminary results.

PURPOSE OF THE STUDY: Molecular adsorbent recycling system (MARS) has been applied successfully in patients with a variety of liver diseases. However, preliminary results in patients with multiple organ failure (MOF) and sepsis were disappointing, possibly because the number of applied MARS cycles was too low. To determine potential effects of prolonged MARS treatment in patients with postsurgical MOF we evaluated five postoperative patients with acute liver failure and septic multiple organ dysfunction in a retrospective observational study. METHODS: MARS cycles (13.4+/-1.9) were applied during an average time period of 17.2+/-5.2 days. Fresh frozen plasma, thrombocyte units and blood units were transfused to maintain pre-MARS Quick values and thrombocyte counts, and to keep the hemoglobin concentration above 8 g/dl. MAIN FINDINGS: Plasma bilirubin concentrations declined significantly during treatment. In contrast, ammonia concentration remained constant, and parameters of the clotting system (Quick value) did not get better or even worsened (partial thromboplastin time) despite significantly increasing the substitution frequency of coagulatory factors. Due to poor clotting, we observed significant bleeding complications during MARS therapy causing a simultaneous rise in the number of transfused blood units. All patients demonstrated persistent, severe abdominal infection during MARS therapy. After discontinuing MARS treatment because of insufficient efficiency, all patients died of progressive septic organ malfunction. CONCLUSION: Our preliminary findings do not support use of MARS in patients with postoperative hepatic failure and progressive septic multiple organ dysfunction, particularly if the septic focus cannot be eliminated. If MARS is still applied, special attention should be paid to simultaneous clotting disorders and bleeding complications.     

Mouse models in liver cancer research： A review of current literature

Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma （HCC）, as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases.     

Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: a prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy

PURPOSE: Our purpose was to compare the sensitivity of whole body (WB) magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) for the diagnosis of bone metastases (BMs) in patients with well-differentiated gastro-entero-pancreatic endocrine cancer (WD-GEP-EC) and to determine predictive factors of BM. PATIENTS AND METHODS: WB-MRI and SRS were prospectively performed in 79 patients with bronchial (11), thymic (five), gastric (two), duodeno-pancreatic (24), ileal (26), colic (one), or unknown primary (10) WD-GEP-EC. RESULTS: A total of 36 patients (46%) had 333 BMs involving 119 skeletal segments. WB-MRI and SRS were equally sensitive for detecting patients with BM (86 vs. 81%; P = 0.56), with 33% of the patients diagnosed with only one procedure. WB-MRI detected more BMs than SRS (80 vs. 57%; P = 0.017). Compared with SRS, WB-MRI detected more spine BMs (96 vs. 45%; P < 0.001) and tended to detect more pelvic and lower limb BMs (P = 0.054 and P = 0.06, respectively). Compared with WB-MRI, SRS detected more skull BMs (100 vs. 0%; P < 0.001) and tended to detect more rib BMs (P = 0.08). Sternal and upper-limb BMs were equally detected with WB-MRI and SRS (P = 0.32 and P = 0.46, respectively). Bone staging with SRS and spine MRI rather than WB-MRI would have detected 92% of the patients with BMs and 83% of all BMs. The extent of liver involvement and bronchial-thymic primary tumors were independent predictive factors for BM. CONCLUSIONS: We recommend bone staging with SRS and spine MRI in all patients with bronchial-thymic or unknown primary WD-GEP-EC. In case of duodeno-pancreatic or ileal primary, bone imaging may be restricted to patients with liver metastases.     

Mortality and rate of stroke or embolism in atrial fibrillation during long-term follow-up in the embolism in left atrial thrombi (ELAT) study

BACKGROUND: Patients with atrial fibrillation (AF) have a higher mortality and risk of stroke/embolism than patients with sinus rhythm. HYPOTHESIS: The aim of the study was to assess the association of clinical and echocardiographic characteristics with mortality and stroke/embolism and the use of antithrombotic medication in the year 2000 in patients who participated 1990-1995 in the Embolism in Left Atrial Thrombi (ELAT) study. METHODS: The study included 409 outpatients with nonrheumatic AF (62 +/- 12 years, 36% women, 39% intermittent AF). Patients with thrombi received anticoagulation, patients without thrombi aspirin until follow-up in 1995; thereafter, anticoagulation according to clinical risk factors was recommended. Primary events were death and secondary events were stroke/embolism. All patients were contacted during the year 2000. RESULTS: Mean follow-up was 102 months. Mortality was 4%/year; the cause of death was cardiac (n = 84), fatal stroke (n = 26), malignancy (n = 23), sepsis (n = 5), and unknown (n = 24). Multivariate analysis identified age (p < 0.0001), heart failure (p = 0.0013), and reduced left ventricular systolic function (p = 0.0353) as predictors of mortality. Stroke/embolism occurred in 83 patients, with a rate of 3%/year. Multivariate analysis identified age (p = 0.0006) and previous stroke (p = 0.0454) as predictors of stroke/embolism. In the year 2000, 51 (21%) of the 247 surviving patients received no antithrombotic medication, 88 received (36%) oral anticoagulants, 102 (41%) acetylsalicylic acid, and 6 (2%) low-molecular heparin. CONCLUSIONS: Therapy for heart failure and oral anticoagulation in AF should be seriously considered, especially in elderly patients and in those with previous stroke.