Molecular profiling of the “plexinome” in melanoma and pancreatic cancer

Plexins are transmembrane high‐affinity receptors for semaphorins, regulating cell guidance, motility, and invasion. Functional evidences implicate semaphorin signals in cancer progression and metastasis. Yet, it is largely unknown whether plexin genes are genetically altered in human tumors. We performed a comprehensive gene copy analysis and mutational profiling of all nine members of the plexin gene family (plexinome), in melanomas and pancreatic ductal adenocarcinomas (PDACs), which are characterized by high metastatic potential and poor prognosis. Gene copy analysis detected amplification of PLXNA4 in melanomas, whereas copy number losses of multiple plexin genes were seen in PDACs. Somatic mutations were detected in PLXNA4, PLXNB3, and PLXNC1; providing the first evidence that these plexins are mutated in human cancer. Functional assays in cellular models revealed that some of these missense mutations result in loss of plexin function. For instance, c.1613G>A, p.R538H mutation in the extracellular domain of PLXNB3 prevented binding of the ligand Sema5A. Moreover, although PLXNA4 signaling can inhibit tumor cell migration, the mutated c.5206C>T, p.H1736Y allele had lost this activity. Our study is the first systematic analysis of the “plexinome” in human tumors, and indicates that multiple mutated plexins may be involved in cancer progression. Hum Mutat 30,1–8, 2009. © 2009 Wiley‐Liss, Inc.     

Branch-duct intraductal papillary mucinous neoplasms of the pancreas: to operate or not to operate?

BACKGROUND: Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are reported to be less aggressive than the main-duct type. Hence, less aggressive treatment has been proposed for the former. AIM: To evaluate the effectiveness of a follow-up protocol for BD-IPMNs. DESIGN: Prospective study. SETTING: An academic tertiary referral centre. PATIENTS: From 2000 to 2003, 109 patients with BD-IPMNs underwent trans-abdominal ultrasound and magnetic resonance cholangiopancreatography with secretin. Patients who presented malignancy-related parameters (size >3.5 cm, nodules, thick walls, carbohydrate antigen 19.9 level >25 U/l, recent-onset or worsened diabetes) and/or complained of symptoms were submitted to surgery (arm A). All asymptomatic patients without suspicion of malignancy were followed up according to a 6-month clinical-radiological protocol (arm B). MAIN OUTCOME MEASURES: The effectiveness of conservative management of BD-IPMNs. RESULTS: 20 (18.3%) patients underwent surgery (arm A); pathological diagnosis of BD-IPMNs was always confirmed. 89 (81.7%) patients were followed up for a median of 32 months (arm B); of these, 57 (64%) patients had multifocal disease. After a mean follow-up of 18.2 months, 5 (5.6%) patients showed an increase in lesion size and underwent surgery. The pathological diagnosis was branch-duct adenoma in three patients and borderline adenoma in two. CONCLUSIONS: Surgery is indicated in <20% of cases of BD-IPMNs, and, in the absence of malignancy-related parameters, careful non-operative management seems to be safe and effective in asymptomatic patients. Although observation for a longer time is needed to confirm these results, our findings support the guidelines recently recommended by the International Association of Pancreatology.     

gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells

Multiple aspects of homocysteine metabolism were studied to understand the mechanism responsible for hyperhomocysteinemia toxicity in Alzheimer disease. Besides oxidative stress and vascular damage, homocysteine has also a great importance in regulating DNA methylation through S-adenosylmethionine, the main methyl donor in eukaryotes. Alterations of S-adenosylmethionine and methylation were evidenced in Alzheimer disease and in elderly. In order to clarify whether DNA methylation can provide the basis for amyloid-beta overproduction, we used human SK-N-BE neuroblastoma and A172 glioblastoma cell lines. We tested the effects of folate, B12 and B6 deprivation and S-adenosylmethionine addition on methylation metabolism. Our results indicate that homocysteine accumulation induced through vitamin B deprivation could impair the "Methylation Potential" with consequent presenilin 1, BACE and amyloid-beta upregulation. Moreover, we found that homocysteine alterations had an effect on neuroblastoma but not on glioblastoma cells; this suggests a possible differential role of the two cell types in Alzheimer disease.     

Ruptured aneurysms of the abdominal aorta: from the First Aid to the Operating Room. Changing concepts

Worldwide literature review from PubMed indicate that progress has been made in first aid assistance, diagnosis and treatment of ruptured abdominal aortic aneurysms, which led to a reduced operative mortality. Nevertheless, ruptured aneurysms may present atipically in about half of the cases, thus leading to an initially uncorrect diagnosis up to 25% of cases. Mean survival interval from onset of symptoms and death is 10-14 hours, thus indicating that time exists to consider the new imaging techniques in 80% of patients, particularly the TC multislice. This, when is strategically located close to the emergency or the operative room, can rapidly allow a correct diagnosis and provide an accurate morphological evaluation, thus enabling the surgeon to plan the most adequate treatment with open or endovascular repair.     

Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation

Generation of new neurons in the adult brain, a process that is likely to be essential for learning, memory, and mood regulation, is impaired by radiation. Therefore, radiation exposure might have not only such previously expected consequences as increased probability of developing cancer, but might also impair cognitive function and emotional stability. Radiation exposure is encountered in settings ranging from cancer therapy to space travel; evaluating the neurogenic risks of radiation requires identifying the at-risk populations of stem and progenitor cells in the adult brain. Here we have used a novel reporter mouse line to find that early neural progenitors are selectively affected by conditions simulating the space radiation environment. This is reflected both in a decrease in the number of these progenitors in the neurogenic regions and in an increase in the number of dying cells in these regions. Unexpectedly, we found that quiescent neural stem cells, rather than their rapidly dividing progeny, are most sensitive to radiation. Since these stem cells are responsible for adult neurogenesis, their death would have a profound impact on the production of new neurons in the irradiated adult brain. Our finding raises an important concern about cognitive and emotional risks associated with radiation exposure.     

Double contrast small-bowel radiography in the preoperative assessment of Crohn’s disease: Is it still useful?

PURPOSE: To evaluate the usefulness of double contrast small-bowel radiography (SBR) in the preoperative assessment of patients with Crohn's disease (CD). METHODS: Thirty-nine consecutive patients who underwent surgery for CD between 2000 and 2004, preceded by a preoperative small-bowel series evaluation, were enrolled in our study. The radiologic findings were compared with the intraoperative findings. RESULTS: Small-bowel radiography was associated with good specificity and sensitivity for the detection of stenosis. Although its main limitation was a remarkable overestimation of stenosis, the main indications for surgery were always confirmed. Sensitivity and specificity were lower for the detection of internal fistulas and the correlation was significant only for SBR performed within 3 months of the operation; however, the concordance between radiological and operative findings was greater. No correlation was observed for the detection of an abdominal mass. CONCLUSIONS: Small-bowel radiography is still reliable for evaluating stenoses and internal fistulas. However, magnetic resonance imaging or computed tomography is mandatory to evaluate an abdominal mass.     

The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells

Investigational New Drugs - Our group recently demonstrated that K858, an inhibitor of motor kinesin Eg5, has important antiproliferative and apoptotic effects on breast cancer, prostatic cancer,...     

Assessment of Risk Factors for Complications of Laparoscopic Partial Nephrectomy

Objective

Laparoscopic partial nephrectomy (LPN) is a technique that is emerging as an attractive option for the treatment of renal tumors ≤4 cm. We retrospectively analyzed our experience with LPN to identify patient and tumor features that correlate with a higher risk of complications.

Material and methods

From January 2001 to May 2007, 90 patients underwent LPN at our institution for a clinically localized renal tumor. A retrospective chart review was carried out. Clinical and pathological information were collected for each patient, including patient age and body mass index, tumor size, location and pattern of growth (cortical vs. corticomedullar), surgical approach (transperitoneal vs. retroperitoneal), warm ischemia time, technique that was used to achieve hemostasis, maximum thickness of the margin of resection, and histology. Statistical analysis (chi-square test, Fisher exact test, Mann-Whitney U test, linear regression model) was performed to test the correlation between the above-mentioned variables and the occurrence of complications.

Results

Twenty-two patients (24.4%) had surgical and/or medical complications in our series. The only variable that was found to significantly correlate with a higher number of complications was a corticomedullar tumor growth pattern as opposed to a cortical growth pattern (p = 0.02).

Conclusions

LPN is an attractive alternative to open partial nephrectomy for the treatment of small renal tumors. On the basis of our experience, the selection of patients with cortical renal lesions seems to be required to reduce the risk of complications and therefore maximize the advantages of this minimally invasive but challenging procedure.