Efficacy and safety of bevacizumab in glioblastomas.

Glioblastoma multiforme (GBM) is a common and malignant primary brain tumor arising from glial precursors the survival of which is estimated to be about 14 months after diagnosis despite current standard care with radiotherapy, surgery, and chemotherapies. Therapeutic approaches were greatly improved in the last years; however, GBM still represents the most lethal subtype of glioma. Actually, it has been estimated that only about 3.4% of patients will survive at the most five years when obtaining the best outcome from treatment; however, this depends on tumor resistance, which is generally related to repairing radiation injury, and self- improving cell growth repair and survival. All GBMs recur after initial therapy, limiting patients � survival at 20-25% within 1 year after diagnosis of recurrent disease. Moreover, for recurrent GBM response rates are less than 10% (ranging from 5% to 9%), and progression free survival at 6-month (PFS-6) rates ranges between 9% and 28% (median 15%). The development of targeted therapy based on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching its receptors (VEGFR1 and VEGFR2) on endothelium, resulting in an inhibition of cells proliferation and vessels sprouting. The aim of this review is to address bevacizumab mode of action in malignant gliomas and provide a summary on currently available data on efficacy and safety.

Jaw osteonecrosis in patients treated with bisphosphonates: an ultrastructural study.

Osteonecrosis of the jaw is a severe bone disorder traditionally associated with periodontal disease, local malignancy, chemotherapy, glucocorticoid therapy, or trauma. Recently a growing number of publications reported the occurrence of osteonecrosis of the jaw in patients undergoing treatment with bisphosphonates. The mechanism by which bisphosphonates might contribute to the development of osteonecrosis of the jaw is far from being fully elucidated. Suppression of bone turnover, infection, tissue hypoxia and cellular toxicity were proposed as possible mechanisms by which bisphosphonates may exert adverse effects on bone metabolism. Here, we studied 25 consecutive patients treated with bisphosphonates for osteoporosis or tumoral pathologies. We provide good evidence of hyperactive osteoclastic bone resorption and suggest a direct cytotoxic effect of bisphosphonates on bone tissue through induction of osteocyte cell death. We also demonstrate that bisphosphonates only have limited adverse effects on bone vascular network.

Anticholinergic drug-induced delirium in an elderly Alzheimer's dementia patient.

Drug-induced delirium is a common matter in the elderly and anticholinergics, together with a number of different drugs, may significantly contribute to the delirium onset, especially in demented people. We report a case of a probable anticholinergic drug-induced delirium in an elderly patient. An 80-year-old man with Alzheimer's dementia presented with wandering, depressed mood with crying, somatic worries, anedonism and suicide recurrent ideas. A first external psychiatric assessment led to the diagnosis of melancholic depression and therapy with haloperidol 2mg/day, orphenadrine 100mg daily, amitriptyline 40 mg/day, lorazepam 2mg/day was started. Two weeks later patient suddenly developed delirium, characterized by nocturnal agitation, severe insomnia, daytime sedation, confusion, hallucinations and persecutory delusions. These symptoms progressively worsened, with the consequent caregiver's stress. A geriatric consultation excluded the main causes of delirium, therefore both Operative Units of Pharmacovigilance and Psychiatry were activated, for a clinical pharmacological and psychiatric assessment. Haloperidol, amitriptyline and orphenadrine were promptly dismissed. The patient began a treatment with quetiapine 25mg/day for two days, then twice a day, and infusion of saline 1000 ml/day for two days; psychiatric symptoms gradually diminished and therapy with galantamine was begun. We postulate that this clinical report is suggestive for an anticholinergic drug- induced delirium since the Naranjo probability scale indicated a probable relationship between delirium and drug therapy. In conclusion, a complete geriatric, pharmacological, and psychiatric evaluation might be necessary in order to reduce the adverse drug reactions in older patients treated with many drugs.

Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs.

BACKGROUND AND OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs, and their use can be complicated by the development of adverse drug reactions (ADRs). The aim of this study was to assess the frequency of NSAID-induced ADRs in hospitalised patients in the Clinical Divisions of the Catanzaro and Cosenza hospitals. METHODS: We retrospectively analysed NSAID-induced ADRs after evaluating all ADRs recorded by the Clinical Divisions of the Catanzaro and Cosenza hospitals over a 10-year period, from January 1995 to December 2004. RESULTS: NSAIDs were found to be responsible for 55.2% of the episodes of ADRs overall. Diclofenac and aspirin (acetylsalicylic acid) were the drugs most frequently involved in the development of ADRs, while the skin was the body system most susceptible to NSAID-induced ADRs (43%). We determined that the drug-ADR relationship was probable in 62% of the reports; withdrawal of NSAID therapy led to a resolution of the clinical features of ADRs in 86% of episodes. CONCLUSION: NSAID therapy represents a common cause of ADRs in hospitalised patients. Their use should be carefully considered, especially in the presence of polydrug therapy.

Generalised urticaria in a young woman treated with clomipramine and after ingestion of codfish.

We report a case of generalized dermatitis and itch induced by a possible drug-food interaction in a young woman who was consuming clomipramine for Obsessive Compulsive Disorder (OCD). A 33-year-old woman affected by anxiety symptoms presented to our observation for a clinical evaluation. After psychiatric evaluation, the diagnosis of OCD was performed according to DSM-IV-TR and a pharmacological treatment with clomipramine (75-100 mg/day) plus alprazolam (0.5 mg/day) was started. About one month later, the patient developed a severe generalized urticaria with intense itch. A new anamnesis revealed that on the day before the development of the skin rash, no other drug was consumed and the patient had eaten codfish; clomipramine was then gradually discontinued and changed into paroxetine (30 mg/day). At the moment the patient does not show any OCD related symptom and any adverse event to paroxetine treatment has been recorded. We postulate a possible interaction between clomipramine and codfish ingestion. Allergic potential of clomipramine was investigated, while clomipramine de-challenge induced a decrease of the skin rash, the drug re-challenge performed one month later did not induce any adverse event. In contrast, when the combined re-challenge of codfish and clomipramine was performed urticaria was newly observed. The Naranjo Probability Scale Score suggested a probable causal relationship between drug-food interaction and the skin rash. In conclusion, we suggest evaluating also the complete risk of drug-food interaction occurring on clomipramine treatment.

[Typology of defunctioning colostomy and state of art in the treatment of bowel emergencies]. / Indicazioni attuali e tipologia della colostomia di protezione nelle urgenze coliche.

BACKGROUND: A trend toward avoidance of a defunctioning colostomy at emergency large-bowel surgery has been placed in recent years. The surgical management of patients with acute colonic disease has been evolving from multiple to single operations with a reduced use of colostomy. METHODS AND RESULTS: One hundred four consecutive non-selected patients underwent surgery for left-sided large bowel emergencies between 1980-2003. Defunctioning colostomy was performed in 10 out of 58 resection-anastomosis procedures. Thirty-seven patients underwent Hartmann procedure, 9 received only diverting colostomy. Postoperative morbidity was 28.8%. Postoperative mortality 8.2%. Anastomotic leak occurred in 1 and 6 patients with and without defunctioning colostomy respectively. Four out of the 6 patients without colostomy needed reintervention, while patient with covering colostomy underwent conservative treatment. Six (10.5%) out 56 patients with colostomy experienced major stoma related complications and underwent reintervention. DISCUSSION: Although there is general acceptance of one-stage surgery for right-sided colon emergencies, the surgical management of left-side large bowel obstruction and peritonitis remains controversal. Risk of anastomotic dehiscence associated with large-bowel anastomosis in unfavourable circumstance must be balanced against the high complications and low closure rates of a temporary colostomy. CONCLUSION: Primary resection and anastomosis without diverting colostomy for left-sided acute obstruction and peritonitis may be performed in selected patients. Diffuse purulent and faecal peritonitis are contraindications to one-stage surgery being necessary a two- stage procedure with loop or end colostomy. Colostomy remain a valid surgical option when high risk of dehiscence is suspected.

[Surgical treatment of carotid chemodectoma: our experience]. / II trattamento chirurgico del chemodectoma carotideo: nostra esperienza.

Carotid chemodectoma is a tumor that affects the bifurcation of the carotids. It is not a frequent event, but it has great importance for surgical and diagnostic problems involved. In this article three cases of chemodectoma observed and surgically treated are reported.

Development of a chromatographic bioreactor based on immobilized beta-glucuronidase on monolithic support for the determination of dextromethorphan and dextrorphan in human urine.

We here reported the development and application of an immobilized enzyme reactor (IMER) based on beta-glucuronidase to the on-line determination of urinary molar ratios of dextromethorphan (DOMe)/dextrorphan (DOH) for the assessment of the metabolic activity of CYP2D6, a genetically variable isoform of cytochrome P-450 (CYP). beta-Glucuronidase was immobilized on an HPLC monolithic aminopropyl silica support. Catalytic activity and stability of the chromatographic reactor were evaluated using 8-hydroxyquinoline glucuronide (8-HQG) as substrate. The IMER was coupled through a switching valve to a reversed-phase column (C8) for the simultaneous determination of dextromethorphan and its main metabolite dextrorphan. On purpose a selective reversed-phase ion pair HPLC method coupled with fluorescence detection was developed. Urine samples were first centrifuged to remove insoluble materials and then aliquots of the supernatants were injected into the coupled-column analyser. Linearity, precision and accuracy of the method were established. The method reliability was verified by comparing our data with previous data of a phenotyping study carried out by the Poison Control Centre of Pavia-Clinical Toxicology Division.

[Pancreatic metastasis of renal cell carcinoma: a case report and review of the literature]. / Metastasi pancreatica di carcinoma renale a cellule chiare: presentazione di un caso clinico e revisione della letteratura.

The pancreas is an uncommon site of metastases from renal cell carcinoma; however in the literature late pancreatic metastases are described. In this report a 74 years-old asymptomatic man was referred for evaluation of a mass in the distal portion of the pancreas, found on CT 4 years after right nephrectomy for a renal cell carcinoma. A distal pancreatectomy and splenectomy were performed and histopathological analysis revealed to be a metastases from renal cell carcinoma. A postoperative pancreatic fistula was treated in a conservative way. The patient is alive and doing well 3 years after pancreatic surgery. This clinical report suggests that late pancreatic metastases are rare but not impossible and should be taken into consideration during a careful long-term follow-up for renal carcinoma. In addition, as it is also desumed by the Literature on survival, pancreatic metastases should be treated when possible with radical resection.

Genetics and imaging to assess oocyte and preimplantation embryo health.

Two major criteria are currently used in human assisted reproductive technologies (ART) to evaluate oocyte and preimplantation embryo health: (1) rate of preimplantation embryonic development; and (2) overall morphology. A major gene that regulates the rate of preimplantation development is the preimplantation embryo development (Ped) gene, discovered in our laboratory. In mice, presence of the Ped gene product, Qa-2 protein, results in a fast rate of preimplantation embryonic development, compared with a slow rate of preimplantation embryonic development for embryos that are lacking Qa-2 protein. Moreover, mice that express Qa-2 protein have an overall reproductive advantage that extends beyond the preimplantation period, including higher survival to birth, higher birthweight, and higher survival to weaning. Data are presented that suggest that Qa-2 increases the rate of development of early embryos by acting as a cell-signalling molecule and that phosphatidylinositol-32 kinase is involved in the cell-signalling pathway. The most likely human homologue of Qa-2 has recently been identified as human leukocyte antigen (HLA)-G. Data are presented which show that HLA-G, like Qa-2, is located in lipid rafts, implying that HLA-G also acts as a signalling molecule. In order to better evaluate the second criterion used in ART (i.e. overall morphology), a unique and innovative imaging microscope has been constructed, the Keck 3-D fusion microscope (Keck 3DFM). The Keck 3DFM combines five different microscopic modes into a single platform, allowing multi-modal imaging of the specimen. One of the modes, the quadrature tomographic microscope (QTM), creates digital images of non-stained transparent cells by measuring changes in the index of refraction. Quadrature tomographic microscope images of oocytes and preimplantation mouse embryos are presented for the first time. The digital information from the QTM images should allow the number of cells in a preimplantation embryo to be counted non-invasively. The Keck 3DFM is also being used to assess mitochondrial distribution in mouse oocytes and embryos by using the k-means clustering algorithm. Both the number of cells in preimplantation embryos and mitochondrial distribution are related to oocyte and embryo health. New imaging data obtained from the Keck 3DFM, combined with genetic and biochemical approaches, have the promise of being able to distinguish healthy from unhealthy oocytes and embryos in a non-invasive manner. The goal is to apply the information from our mouse model system to the clinic in order to identify one and only one healthy embryo for transfer back to the mother undergoing an ART procedure. This approach has the potential to increase the success rate of ART and to decrease the high, and undesirable, multiple birth rate presently associated with ART.

Role of graft interleukin-10 expression in the tolerogenicity of neonatal skin allografts.

BACKGROUND: Allografts of skin from neonatal donors survive longer than those from adult donors and can induce tolerance in mice that are treated with short-term immunosuppression. Neonatal (< or =24 hr old) epidermal cells (EPC) secrete high levels of interleukin-(IL) 10 and include abundant class II- immature Langerhans cells (LC). In this study, the role of IL-10 in the tolerogenicity of neonatal skin grafts was examined. METHODS: After a preliminary experiment established that tolerogenesis by neonatal grafts could be supported by monoclonal antilymphocyte antibodies, B10.A(5R) recipients were immunosuppressed with anti-CD4 plus anti-CD8 (days 0, +2) and adult C57B1/6 bone marrow cells (day +7). Recipients were grafted with adult or neonatal C57B1/6 skin from wild-type or IL-10 deficient ("knockout" donors). EPC from wild-type and knockout neonatal skin were compared by flow cytometry, before and after 48 hr culture, to adult cells in terms of class II and costimulatory molecule expression. RESULTS: Grafts from knockout neonates survived longer than those from adult donors (median survival, MST=81 vs. 61 days), but not as long as those from wild-type neonates (MST=100 days; P<0.05). As with normal neonatal EPC, neonatal knockout EPC expressed little class II antigen. Both types of neonatal EPC acquired class II in culture, and up-regulated CD80 and CD86 in an adult pattern, but failed to up-regulate class II antigen to the high level seen among cultured adult cells. CONCLUSIONS: The tolerogenicity of neonatal skin grafts derives in part from natural expression of IL-10 by the graft. Another possible contribution to tolerogenicity may be the inability of neonatal antigen presenting cells to up-regulate class II fully. Low expression of class II by neonatal cells is not attributable to epidermal IL-10 secretion.

Requirement for early donor cell chimerism during prolonged survival of murine skin allografts.

BACKGROUND: Posttransplantation infusion of donor bone marrow cells (BMC) can prolong allograft survival in antilymphocyte antibody- (ALA) treated recipients. This study examined the hypothesis that chimerism of donor BMC origin contributes to allograft unresponsiveness. METHODS: Survival of day 0 skin grafts from C3H (H2k) donors was prolonged on ALA-treated B6AF1 mice by day +7 infusion of BMC from C3H or C3H-H2o2 (H2K(d)I(d)D(k)) mice. To test for functional chimerism, depletional anti-H2Kd antibody was injected at intervals after C3H-H2o2 BMC infusion. To confirm the persistence of active cells in the recipients, cells harvested from bone marrow of ALA- and C3H BMC-treated primary recipients were transferred to secondary ALA-treated recipients. Other recipients were infused on day +21 with additional donor BMC or light-density BMC that had been cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) to promote the differentiation of dendritic cells (DC). RESULTS: Injection of depletional antibody targeting infused BMC interrupted skin graft survival, whether the injection was made on day +7, 2 hr after BMC injection, or as late as day +28. Prolonged graft survival was transferred to secondary recipients with cells recovered from primary recipient marrow as long as 4 weeks after initial donor BMC treatment. Graft survival prolonged by day +7 BMC was further enhanced by infusion on day +21 of light density cultured BMC, although a second dose of unfractionated BMC was inactive. Repeated injection of cultured BMC at 2-week intervals after day +21 prolonged graft survival even further. CONCLUSIONS: These data directly demonstrate that at least short-term donor BMC-derived microchimerism is required for prolonged allograft survival. The data further suggest that the active chimeric cells persist in recipient marrow. Finally, the beneficial effect of late infusion of cultured cells containing partially differentiated DC suggest that DC may be the active chimeric cells.

Modified Hill operation vs. Nissen fundoplication in the surgical treatment of gastro-esophageal reflux disease.

BACKGROUND/AIMS: The authors compared the results of the Nissen fundoplication technique with the results of the Hill procedure, by using a 10-year history of patients with gastro-esophageal reflux disease. MATERIALS AND METHODS: Seventy two consecutive patients entered the study, 32 of whom underwent a 360 degrees fundoplication according to Nissen and 40 with a modified Hill operation. In the Nissen Group, intraoperative manometry (IOM) was carried out in all patients; in the Hill Group, the patients were randomized in two sub-groups (A and B), before operation; in 20 of them (group A), the procedure was randomly associated to IOM. RESULTS: The overall complications were low in both groups (15.6% in the Nissen Group and 5% in the Hill Group, p = 0.1), and there was no mortality rate. The clinical results were excellent or good in 28 patients (87.6%) of the Nissen Group and in 36 patients (90%) of the Hill Group (p = 0.5); in particular, an excellent outcome was observed in 16 patients (80%) with IOM (sub-group A), while 12 patients (60%) without it (sub-group B) showed similar results. The manometric studies carried out six months after surgical treatment showed a decrease of the lower esophageal sphincter pressures in all patients if compared to the pressure recorded intra-operatively. In comparison to the pre-operative values, both the lower esophageal sphincter length and its intra-abdominal portion were markedly increased in the Nissen Group and in the sub-group A of the Hill patients. CONCLUSIONS: These results support the conclusions that modified posterior gastropexy and 360 degrees fundoplication are effective, well tolerated, and can be properly used in the treatment of Gastro-esophageal reflux disease (GERD), since both techniques showed good clinical results. A favorable clinical outcome depends mostly on adequate lower esophageal sphincter length (LESL) and LESIA extension, which could be more efficiently achieved by the use of intraoperative manometry (IOM).

Late adjunctive therapy with single doses of rapamycin in skin-allografted mice treated with antilymphocyte serum and donor bone marrow cells.

Temporary donor-specific unresponsiveness induced by treatment of skin allografted mice with antilymphocyte serum (ALS) and donor bone marrow cells (BMC) can be converted to long-term graft survival and tolerance by adding adjunctive immunosuppressive agents, including rapamycin (Rapa). Rapa was given in a suboptimal dosing schedule to probe several aspects of its use in the promotion of tolerization. Single doses were given at 2 weeks post-transplantation to recipients prepared with ALS and donor BMC. Graft survival was markedly prolonged in a dose-dependent fashion by day +14, Rapa doses ranging from 0.75 to 6.0 mg/kg. Indefinite (> 300 day) graft survival was observed in 26% of recipients given the highest Rapa dose. Short-term treatment with cyclosporin A (CsA) or deoxyspergualin (DSG) was ineffective when injected at this time. Rapa augmented the tolerizing effect of grafting with skin from newborn mice but had no significant additive or synergistic effects with the short course of CsA or with DSG given on days +1 to +3, even though the latter prolonged graft survival when added to the ALS/BMC protocol. Single doses of Rapa on day +1 also prolonged graft survival, but without any of the grafts surviving indefinitely. Later dosing on day +28 resulted in > 70% of grafts surviving > 300 days. Challenge grafting of these mice after day +300 resulted in delayed rejection of donor strain, but not third-party skin grafts. Rapa was very effective when given as widely spaced doses on days +14 and +49. Also, grafts showing the earliest signs of rejection could be rescued with a single Rapa dose in recipients treated with ALS and BMC but not ALS alone. Transfer of prolonged graft survival with spleen cells from ALS plus BMC treated recipients was not adversely affected by Rapa given to the suppressor-like spleen cell donors approximately 1 week before cell harvest. We conclude that the use of Rapa as an adjunctive agent in allograft recipients treated with ALS plus donor BMC is very flexible in terms of timing of administration, and that the drug can be effectively given as widely spaced doses or as a rescue agent after ALS/BMC treatment. Additionally, an active immunoregulatory mechanism induced by ALS/BMC treatment appears to be spared by Rapa.

Effect of monoclonal anti-CD4 and anti-CD8 on skin allograft survival in mice treated with donor bone marrow cells.

Allograft unresponsiveness can be induced by donor bone marrow cells (BMC) in antilymphocyte serum (ALS)-treated recipients. The effect of administering monoclonal anti-CD4 and -CD8 at several points has been examined in a mouse skin allograft model of this protocol. Brief peritransplant administration of anti-CD4 and -CD8 was used to replace ALS. Anti-CD4 treatment prolonged graft survival only slightly and conditioned recipients poorly for the effect of posttransplantation donor BMC infusion. Anti-CD8 was ineffective in both capacities. A mixture of anti-CD4 and anti-CD8 was at least as effective as ALS in prolonging graft survival and in promoting the beneficial effects of donor BMC. Like the monoclonal antibodies, ALS also depleted splenic and lymph node CD4+ and CD8+ cells. Injection of ALS, but not the monoclonal antibodies, altered the CD4/CD8 phenotype of thymocytes, although persistent binding of both types of antibody to thymocytes was demonstrated. Abrogation of the positive effect of BMC by reconstitution of normal spleen cells on day +3 after ALS treatment confirmed that cell depletion is a requirement of this system. Monoclonal antibodies were also given to ALS/BMC-treated recipients after their grafts had become established. Anti-CD8 injection at either 2 or 4 weeks after transplantation further prolonged graft survival. In contrast, anti-CD4 injection at 2 or 6 weeks after grafting precipitated rejection, which suggests that continued allograft survival following ALS and donor BMC treatment is due to the activity of a CD4+ cell population.