Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Rapid on-site evaluation during endoscopic ultrasound-guided fine-needle aspiration of lymph nodes does not increase diagnostic yield: A randomized, multicenter trial.

OBJECTIVES: Studies on the impact of rapid on-site evaluation (ROSE) during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of lymph nodes are retrospective and have shown conflicting results. We aimed to compare the diagnostic yield of EUS-FNA of lymph nodes with ROSE (ROSE+) and without ROSE (ROSE-). METHODS: This was a multicenter, randomized controlled trial. Consecutive patients who were scheduled to undergo EUS-FNA of mediastinal or abdominal lymph nodes were randomized to ROSE+ or ROSE-. In the ROSE+ group, the number of passes was dictated by the on-site cytotechnician. In the ROSE- group, five passes were performed without interference from the cytotechnician. All samples were reviewed by a single-expert cytopathologist, blinded to group allocation. Primary endpoint was diagnostic yield with and without ROSE. RESULTS: After inclusion of 90 patients, interim analysis showed futility of study continuation since diagnostic yield of ROSE+ and ROSE- were comparable. A total of 91 patients were randomized to ROSE+ (N = 45) or ROSE- (N = 46). Diagnostic yield of ROSE+ and ROSE- and diagnostic accuracy were comparable: 93.3% vs. 95.7% (P = 0.68) and 97.6% vs. 93.2% (P = 0.62), respectively. Two major complications (one per group) occurred (p = 0.99). ROSE- patients more often reported self-limiting post-procedural pain (p < 0.001). Median procedure time for ROSE+ (20 min) and ROSE- (23 min) was comparable (P = 0.06). Median time to review slides in the ROSE- group (12:47 min) was longer than with ROSE+ (7:52 min) (P < 0.001). Mean costs of ROSE- and ROSE+ were comparable: €938.29 (±172.70) vs. €945.98 (±223.38) (P = 0.91), respectively. CONCLUSIONS: Diagnostic yield and accuracy of EUS-FNA of mediastinal and abdominal lymph nodes with and without ROSE are comparable. Time needed to review slides was shorter and post-procedural pain was less often reported in the ROSE+ group. Based on the primary outcome, the implementation of ROSE during EUS-FNA of mediastinal and abdominal lymph nodes cannot be advised. (Dutch Trial Register: NTR4876).

[Recurrent, itching and creeping skin lesions in (former) travellers to the tropics: strongyloidiasis]. / Recidiverende, jeukende en zich verplaatsende huidafwijkingen bij (voormalige) tropenreizigers: strongyloidiasis.

Two patients, a woman aged 24 and a man aged 86, had suffered from recurrent, itchy, linear, creeping skin lesions, notably on the thighs, buttocks and lower abdomen, for 9 months and more than 50 years, respectively. The woman had been in South America, and the man had worked on the Burma railway as a prisoner of war during World War II. In both patients 'larva currens' was observed. The clinical diagnosis of 'strongyloidiasis' was supported by eosinophilia and raised antibody titres against Strongyloides stercoralis in the blood. No larvae could be detected in either patient. Treatment with albendazole, and ivermectin, respectively, resulted in disappearance of the complaints. S. stercoralis is found in many parts of the world. In the Netherlands the major risk groups in which strongyloidiasis should be considered are people from, and visitors to, South-America (Surinam) and South-East Asia (Indonesia, former prisoners of war).

[Malaise after a trip to Africa: amoebic liver abscess]. / Malaise na een Afrika-reis: amoebenabces van de lever.

During a flight to Kenya, a 42-year-old man took a therapeutic dose of chloroquine because of fever. He regularly travelled to Africa and always took chloroquine and proguanil for malaria prophylaxis. The fever disappeared but he did not fully recover. He complained of malaise and weight loss. Fourteen years previously he had suffered from amoebic dysentery. One month after the onset of the patient's complaints, an amoebic liver abscess was suspected on the basis of his medical history, an elevated ESR and a slight leukocytosis. The diagnosis was confirmed by ultrasonography and serology.

High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes.

The regenerating liver after partial hepatectomy is one of the few physiologic models of cellular proliferation in the adult animal. During hepatic regeneration, the animal is able to maintain metabolic homeostasis despite the acute loss of two thirds of hepatic tissue. In examining the molecular mechanisms regulating hepatic regeneration, we isolated novel immediate-early genes that are rapidly induced as the remnant liver undergoes the transition from its normal quiescent state into the G1 phase of the cell cycle. One of the most rapidly and highly induced genes which we initially termed RL-1, encodes rat glucose-6-phosphatase (rG6Pase). G6Pase mRNA peaks at 30 min and 36-48 h after hepatectomy correlating with the first and second rounds of cell division. This finding is compatible with studies that showed that G6Pase enzyme activity increases during liver regeneration. However, the increase in G6Pase mRNA is much more dramatic, indicating that it is a more sensitive indicator of this regulation. G6Pase gene expression peaks in the perinatal time period in the liver and remains elevated during the first month of life. The expression of the G6Pase gene is also dramatically elevated in BB diabetic rats, again higher than the enzyme elevation, and its relative induction after partial hepatectomy is blunted in these animals. Insulin treatment of partially hepatectomized diabetic animals downregulates the expression of G6Pase mRNA. Using specific antibodies against G6Pase, we detect a 36-kD G6Pase protein, and its level is elevated in regenerating and diabetic livers. The pattern of G6Pase mRNA expression appears to reflect similar changes in insulin and glucagon levels which accompany diabetes and hepatic proliferation. The elevation of G6Pase expression in these conditions is indicative of its importance as a regulator of glucose homeostasis in normal and abnormal physiologic states.

Protein tyrosine kinase activity and its substrates in rat intestinal microvillus membranes.

Tyrosine phosphorylation has recently been recognized as a unique system involved in the regulation of cellular growth and differentiation. The role of tyrosine kinase activity in regulating intestinal proliferation has received little attention. The aim of this study was to document the presence of tyrosine kinase activity in intestinal microvillus membranes and to characterize the major endogenous tyrosine kinase substrates in microvillus membranes. Microvillus membranes, prepared from 21-day gestation fetal and adult CD rats by the calcium precipitation method, were solubilized in 0.1% Triton X-100 and incubated with [32P]adenosine triphosphate and (Glu80Tyr20)n, which is a heterogeneous population of synthetic peptides containing glutamate and tyrosine. Fetal, and to a lesser extent adult, microvillus membranes were shown to phosphorylate (Glu80Tyr20)n assayed by trichloroacetic acid-precipitable 32P incorporation as well as autoradiography of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Preliminary identification of the endogenous substrates of microvillus membrane tyrosine kinase activity was determined by three techniques. First, phosphorylated microvillus membrane proteins were solubilized in sodium dodecyl sulfate and separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the resultant gel was incubated in 1 mol/L KOH at 55 degrees C to selectively retain phosphotyrosine proteins. The patterns of tyrosine phosphorylation were dissimiliar in fetal and adult microvillus membranes; specifically, two major bands, 80 and 190 kilodaltons, were present in fetal microvillus membranes and were not prominent in adult microvillus membranes. These proteins were both phosphorylated on tyrosine residues as determined by phosphoamino acid analysis. Second, a specific antiphosphotyrosine monoclonal antibody was used to immunoprecipitate phosphotyrosine proteins from solubilized phosphorylated microvillus membranes. This antibody specifically immunoprecipitated proteins of molecular weights 36 and 68 from fetal and 33, 54, and 68 from adult microvillus membranes. Third, using a polyclonal antiphosphotyrosine antibody, Western blot analysis showed that the 68-kilodalton protein is the most abundant phosphotyrosine protein in fetal and adult microvillus membranes. These data will focus new investigations into the cellular mechanisms of the regulation of intestinal growth, particularly the role of luminal factors that may modulate microvillus membrane tyrosine kinase, and thus modulate enterocyte proliferation, differentiation, and function.