Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Preclinical studies have shown that nitric oxide (NO)-donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.     

Adenocarcinoma of the appendix. A case report and review of the literature

Primary adenocarcinoma of the appendix is a rare malignancy that constitutes less than 0.5% of all gastrointestinal neoplasms. Usually the diagnosis is made only after histological examination of surgically removed inflamed appendix. Alternatively represent an unexpected finding, confirmed by frozen section, during surgery performed for acute appendicitis or other non appendiceal pathologies. Natural history is strongly influenced by anatomic peculiarities of the appendix that predispose to early spread and perforation. Frequently is associated with synchronous and metachronous colorectal or extraintestinal cancers. The correct management is the right hemicolectomy as a primary procedure in the case of preoperatively or intraoperatively diagnosis or as secondary procedure, after two-three weeks from appendectomy, when the microscopic examination of specimen reveals the presence of adenocarcinoma. Right hemicolectomy is the best treatment for all histologic types (colonic, mucinous, adenocarcinoid), in presence of perforation and even in Dukes A tumors. A careful intraoperative search for synchronous lesions and a life-long program of surveillance for the detection of early stage metachronous carcinomas are recommended. The Authors report a case of primary adenocarcinoma of the appendix occurred in a 78 year-old female patient, diagnosed incidentally during surgery performed for ileus from suspected cecal neoplasm.     

Risk Assessment for Honeybees from Pesticide-Exposed Pollen

A method for assessing the risk for honeybees from pesticide exposure via pollen is proposed. Four pesticides, selected as markers, were monitored in pollen samples collected in two sampling areas, one located in an intensive agricultural area and the other far from direct pesticide impact. Analytical results were consistent with use patterns of the chemicals and their physico-chemical and persistence properties. For a preliminary estimate of bee exposure via pollen, both by ingestion and by contact, an exposure index was developed, based on physico-chemical properties, persistence and application rates. On the basis of the exposure estimates and acute toxicological data (ingestion and contact LD₅₀), Toxicity Exposure Ratios (TERs) were calculated as indicators of the risk for honeybees due to this particular exposure route. TER values were compared to Hazard Quotient (HQ), calculated as the ratio between application rate and the LC₅₀ value, according to European guidelines, showing a satisfactory agreement. The advantage of the above described procedures is that the environmental fate of the chemicals, and not only application rates, are taken into account. This approach may represent a preliminary tool for a comparative screening of the risk for pollinator insects due to this particular exposure route.     

Radiation‐induced glioblastoma in a medulloblastoma patient: A case report with molecular features

We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15‐year‐old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation‐induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6‐methylguanine‐DNA methyl‐transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation‐induced MGMT hyper‐methylation and p53 mutations may have a role in the development of a subgroup of radio‐induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post‐irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.     

CHILDHOOD LIPOSARCOMA: A Single-Institutional Twenty-Year Experience

A retrospective observational study was performed on a series of 12 consecutive pediatric patients treated over a 20-year period at the Istituto Nazionale Tumori, Milano. Conservative surgery was the treatment of choice in all patients; radical excision was obtained at diagnosis in 9 cases and after primary chemotherapy in 1 case. Five patients were subjected to surgery alone, and one to postoperative radiotherapy. After a median follow-up of 11 years (range 1-20), all the patients were alive without evidence of disease, 11 in first complete remisson, and 1 after local relapse. In agreement with other reports, the authors underline the unquestionable pivotal role of radical surgery in the treatment of liposarcoma. The high proportion of resectable tumors accounts for the excellent survival of the patients in this study. The role of both adjuvant chemotherapy and radiotherapy is uncertain and awaits multicentric cooperative prospective studies.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D₂ receptor agonist, SKF 38393, a selective D₁ receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed byl-sulpiride, a D₂ antagonist, and by a combination of reserpine with α-methyltyrosine (α-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D₁ antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D₂ receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D₁ receptor level.     

EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses.

Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.