Jan J. Koornstra

To investigate whether altered megakaryocyte morphology contributes to reduced platelet production in idiopathic thrombocytopenic purpura (ITP), ultrastructural analysis of megakaryocytes was performed in 11 ITP patients. Ultrastructural abnormalities compatible with (para-)apoptosis were present in 78% +/- 14% of ITP megakaryocytes, which could be reversed by in vivo treatment with prednisone and intravenous immunoglobulin. Immunohistochemistry of bone marrow biopsies of ITP patients with extensive apoptosis showed an increased number of megakaryocytes with activated caspase-3 compared with normal (28% +/- 4% versus 0%). No difference, however, was observed in the number of bone marrow megakaryocyte colony-forming units (ITP, 118 +/- 93/105 bone marrow cells; versus controls, 128 +/- 101/105 bone marrow cells; P =.7). To demonstrate that circulating antibodies might affect megakaryocytes, suspension cultures of CD34+ cells were performed with ITP or normal plasma. Morphology compatible with (para-)apoptosis could be induced in cultured megakaryocytes with ITP plasma (2 of 10 samples positive for antiplatelet autoantibodies). Finally, the plasma glycocalicin index, a parameter of platelet and megakaryocyte destruction, was increased in ITP (57 +/- 70 versus 0.7 +/- 0.2; P =.009) and correlated with the proportion of megakaryocytes showing (para-) apoptotic ultrastructure (P =.02; r = 0.7). In conclusion, most ITP megakaryocytes show ultrastructural features of (para-) apoptosis, probably due to action of factors present in ITP plasma.

BACKGROUND: It is controversial whether proton pump inhibitor use leads to fundic gland polyp development. AIM: To determine whether fundic gland polyp development is due to proton pump inhibitor use and to investigate mechanisms involved. METHODS: Proton pump inhibitor use and the presence of fundic gland polyps were assessed in consecutive patients undergoing oesophagogastroduodenoscopy. Biopsies from fundic gland polyps and gastric mucosa were taken. Dysplasia was graded as negative, low or high grade. Prevalence of parietal cell hyperplasia and parietal cell protrusions and the proportional cystic area were assessed. RESULTS: 599 patients participated, 322 used proton pump inhibitors, 107 had fundic gland polyps. Long-term proton pump inhibitor use was associated with an increased risk of fundic gland polyps (1-4.9 years use: OR 2.2, 95% CI: 1.3-3.8; > or =5 years: OR 3.8, 95% CI: 2.2-6.7) while short-term therapy (<1 year) was not (OR 1.0, 95% CI: 0.5-1.8). Low-grade dysplasia was found in one fundic gland polyp. Fundic gland polyps associated with long-term proton pump inhibitor use had a larger proportional cystic area and higher frequency of parietal cell hyperplasia and parietal cell protrusion. CONCLUSIONS: Long-term proton pump inhibitor use is associated with an up to fourfold increase in the risk of fundic gland polyps. Risk of dysplasia is negligible. Aetiologically, these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression.

BACKGROUND: The Stent-In 2 trial randomized patients with malignant colonic obstruction to emergency surgery or stent placement as a bridge to elective surgery. The aim of this study was to compare the oncological outcomes. METHODS: Disease recurrence, and disease-free, disease-specific and overall survival were evaluated, including a subgroup analysis of patients with a stent- or guidewire-related perforation. RESULTS: Of 98 patients included in the original Stent-In 2 trial, patients with benign (16) or incurable (23) disease were excluded from this study, along with a patient who had withdrawn from the trial. Of the remaining 58 patients, 32 were randomized to emergency surgery (31 resection, 1 stoma only) and 26 to stenting. Unsuccessful stenting required emergency surgery in six patients owing to wire or stent perforation. Locoregional or distant disease recurrence developed in nine of 32 patients in the emergency surgery group and 13 of 26 in the stent group. Disease-free survival was worse in the subgroup with stent- or guidewire-related perforation. Five of six patients in this subgroup developed a recurrence, compared with nine of 32 in the emergency surgery group and eight of 20 who had unperforated stenting. CONCLUSION: Stent placement for malignant colonic obstruction was associated with a risk of recurrence in this trial, but the numbers are small. There is not enough evidence to refute the approach strongly. REGISTRATION NUMBER: ISRCTN46462267 ( http://www.controlled-trials.com).

BACKGROUND AND AIMS: Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance. METHODS: Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC). RESULTS: In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5-26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4-16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence. CONCLUSIONS: HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a 'serrated pathway' to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.

Recombinant human (rh) TNF-related apoptosis-inducing ligand (TRAIL) harbors potential as an anticancer agent. RhTRAIL induces apoptosis via the TRAIL receptors TRAIL-R1 and TRAIL-R2 in tumors and is non-toxic to nonhuman primates. Because limited data are available about TRAIL receptor distribution, we performed an immunohistochemical (IHC) analysis of the expression of TRAIL-R1, TRAIL-R2, the anti-apoptotic TRAIL receptor TRAIL-R3, and TRAIL in normal human and chimpanzee tissues. In humans, hepatocytes stained positive for TRAIL and TRAIL receptors and bile duct epithelium for TRAIL, TRAIL-R1, and TRAIL-R3. In brains, neurons expressed TRAIL-R1, TRAIL-R2, TRAIL-R3 but no TRAIL. In kidneys, TRAIL-R3 was negative, tubuli contorti expressed TRAIL-R1, TRAIL-R2, and TRAIL, and cells in Henle's loop expressed only TRAIL-R2. Heart myocytes showed positivity for all proteins studied. In colon, TRAIL-R1, TRAIL-R2, and TRAIL were present. Germ and Leydig cells were positive for all proteins studied. Endothelium in liver, heart, kidney, and testis lacked TRAIL-R1 and TRAIL-R2. In alveolar septa and bronchial epithelium TRAIL-R2 was expressed, brain vascular endothelium expressed TRAIL-R2 and TRAIL-R3, and in heart vascular endothelium only TRAIL-R3 was present. Only a few differences were observed between human and chimpanzee liver, brain, and kidney. In contrast to human, chimpanzee bile duct epithelium lacked TRAIL, TRAIL-R1, and TRAIL-R3, lung and colon showed no TRAIL or its receptors, TRAIL-R3 was absent in germ and Leydig cells, and vascular endothelium showed only TRAIL-R2 expression in the brain. In conclusion, comparable expression of TRAIL and TRAIL receptors was observed in human and chimpanzee tissues. Lack of liver toxicity in chimpanzees after rhTRAIL administration despite TRAIL-R1 and TRAIL-R2 expression is reassuring for rhTRAIL application in humans.