Increased delivery of erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using intracarotid pentylglycerol in rats

BACKGROUND: Erucylphosphocholine (ErPC) has been shown to exert strong antineoplastic effects against various brain tumor cell lines in vitro. Since ErPC only enters the brain after long-term treatment, ineffective drug delivery to the tumor is considered to be the reason for the moderate responses to chemotherapy with ErPC observed in animal brain tumor models. We investigated a recently described method for chemically opening the blood-brain barrier (BBB) using intraarterial administration of alkylglycerols to increase the transfer of ErPC into the brain. METHODS: ErPC (40 mg/kg) was given to C6 glioma-bearing rats either as a single intracarotid bolus injection in the presence or absence of 1- O-pentylglycerol (300 m M) or as an intracarotid infusion in conjunction with bradykinin. Brain tissue concentrations were analyzed and compared to values obtained after intravenous ErPC treatment over 14 and 30 days (cumulative ErPC doses of 210 and 350 mg/kg, respectively). RESULTS: Pentylglycerol-induced BBB opening resulted in a significant increase in ErPC delivery to the tumor (17-fold) and, to a lesser extent, to the surrounding ipsilateral brain (7-fold) compared to intraarterial ErPC administration without alkylglycerol ( P<0.05). Furthermore, the resulting ErPC concentrations in the brain tumor exceeded those obtained in tumor and tumor-free brain after long-term intravenous ErPC administration. In contrast to this, intracarotid bradykinin did not increase the transfer of ErPC to the tumor or tumor-free brain. CONCLUSIONS: The intracarotid administration of pentylglycerol represents a novel and nontoxic method of overcoming the limited access of ErPC to both brain tumors and brain tissue adjacent to tumors. The present results provide further evidence that chemical opening of the BBB by intraarterial alkylglycerols is a promising new concept for improving delivery of chemotherapeutic agents to brain tumors.     

The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity.     

Adrenocortical carcinoma with Ectopic LH production

This report concerns a 3 1/4-year-old boy, in whom a left-sided adrenocortical adenocarcinoma of predominantly androgenic potency caused isosexual precocious development with enlargement of the testicles and, probably, predominantly testicular testosterone secretion. It was possible to identify an increase in LH production as the cause of this phenomenon; the seat of origin was the tumor. Ectopic LH production was proved upon extraction of the tumor and by the decline of gonadotropic activity after its removal.     

Carcinoma of the Ampulla of Vater: Determinants of Long-term Survival in 94 Resected Patients

This retrospective study details 94 patients after surgical resection of carcinoma of the ampulla of Vater to determine prognostic factors. The tumour was limited to the ampulla of Vater in 32%, invaded the duodenal wall in 34%, infiltrated 2cm or less into the pancreas in 22%, and invaded more than 2cm into the pancreas and/or other adjacent structures in 11%. Curative resection was accomplished in 97% of cases. After exclusion of perioperative deaths the 1-, 5- and 10-year survival rates were 79.6%, 38.2%, and 31.6%, respectively with a median survival of 3.68 years. 26 patients survived more than five and 15 patients more than ten years. In an univariate analysis advanced tumour size, poor tumour grading, lymph node metastases and advanced UICC stage significantly decreased survival. Comparison of short and long survivors confirmed tumour size, lymph node status and UICC stage as significant prognostic factors. In a multivariate analysis (Cox model), only tumour size was a statistically independent predictor of prognosis. The survival probability increased with each year a patient survived after resection. When a patient had already survived five years after resection, the probability to survive another five years was 83%. Careful clinicopathologic staging is important for the prognosis after resection.     

Colonic rupture in a patient on combination chemotherapy for metastasized carcinoma of the esophagogastric junction. Case report and review of the literature

BACKGROUND: Cecal perforation due to neutropenic colitis is a known and described side effect of many chemotherapy regimens. We present a case of a patient with gastric adenocarcinoma who developed spontaneous cecal perforation during chemotherapy without the classic pattern of typhlitis. CASE REPORT: A 58-year-old woman was on chemotherapy for an adenocarcinoma of the gastric junction, when she developed a cecal perforation. There was neither evidence for leucopenia nor for typhlitis. Laparotomy was performed and cecostomy was established using the perforated bowel. Postoperative course was uneventful. The patient died from tumor progression 8 months after the diagnosis was made. CONCLUSION: There is no evidence for a connection between this event and chemotherapy treatment but neither can it be excluded. Even if unusual, colon toxicity could be a potential life-threatening complication associated with more drugs than usually thought.     

Blood-brain barrier opening with alkylglycerols: Biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats

Short-chain alkylglycerols have been described to increase the penetration of drugs and macromolecules across the blood-brain barrier (BBB) into the central nervous system (CNS) and were considered to be of potential value in the pharmaceutical treatment of CNS disorders. Due to the lack of information on the pharmacological behavior of these compounds in vivo, pharmacokinetics and biodistribution of [14C]- and [3H]-labeled 1-O-pentylglycerol (49 mg/kg, 100 mM) was investigated in normal male Wistar rats after intravenous as well as intracarotid administration. There was a rapid and predominant renal elimination of 1-O-pentylglycerol and more than 70% of administered dose was found in the urine within 270 min. Analysis of the pharmacokinetic parameters after a single i.v. bolus injection of 1-O-pentylglycerol resulted in a peak blood concentration of 0.58+/-0.06 micromol/ml, an initial half life of 23+/-7 min and a terminal half life of 18.8+/-4.1 h. No accumulation of 1-O-pentylglycerol was observed in the brain or other organs while highest concentrations were found in liver and thymus. This was confirmed by autoradiographic studies. Five minutes after intracarotid administration, high radioactivity was found in the ipsilateral brain, whereas after 30 min radioactivity in the brain has dramatically decreased. Autoradiographic images gave evidence of biliary excretion in addition to the renal elimination. There were no signs of cleavage of the O-alkyl bond in vivo as demonstrated by HPLC analysis.In conclusion, 1-O-pentylglycerol is characterized by pharmacological properties appearing very favorable for in vivo use as a permeabilizing drug for increased drug delivery to the brain.     

Botulinum A toxin injections into the detrusor: An effective treatment in idiopathic and neurogenic detrusor overactivity?

AIMS: To assess and compare the effect of botulinum A toxin (BTX-A) injections into the detrusor in idiopathic and neurogenic detrusor overactivity resistant to anticholinergic treatment. PATIENTS AND METHODS: In a prospective study, 11 patients with idiopathic and 11 with neurogenic detrusor overactivity resistant to anticholinergic treatment were injected with 300 U of BTX-A (Botox) into the detrusor. Clinical and urodynamic parameters were assessed before and after BTX-A injections. RESULTS: In idiopathic as well as in neurogenic detrusor overactivity, median daytime frequency decreased significantly from 11 to 4 (P = 0.004) and 12 to 5 (P = 0.001), median nocturia from 3 to 1 (P = 0.004) and 3 to 1 (P = 0.001), and median number of used pads from 5 to 0 (P = 0.001) and 5 to 0 (P = 0.002), respectively. There was a significant increase in median maximum cystometric capacity from 220 to 340 ml (P = 0.001) and 190 to 410 ml (to instead of) (P = 0.001), median bladder compliance from 20 to 55 ml/cm H(2)O (P = 0.001) and 23 to 60 ml/cm H(2)O (P = 0.004) and median post void residual from 10 to 140 ml (P = 0.002) and 30 to 240 ml (P = 0.002), respectively. Median maximum detrusor pressure decreased significantly from 45 to 29 cm H(2)O (P = 0.002) and 40 to 24 cm H(2)O (P = 0.002), and median detrusor pressure at maximum flow rate from 30 to 14 ml/sec (P = 0.001) and 38 to 21 ml/sec (P = 0.016), respectively. Due to post void residuals >150 ml following BTX-A injections, de novo clean intermittent self-catheterization was necessary in nine patients (four with idiopathic and five with neurogenic detrusor overactivity) and in one patient (with idiopathic detrusor overactivity) a suprapubic catheter was placed. The effect of BTX-A injections lasted for a median time of 5 months in both idiopathic and neurogenic detrusor overactivity. There was no significant difference in idiopathic compared to neurogenic detrusor overactivity in regard to clinical and urodynamic parameters assessed before and after BTX-A injections. CONCLUSIONS: BTX-A injections into the detrusor have a significant and comparable but temporally limited effect in idiopathic and neurogenic detrusor overactivity resistant to anticholinergic treatment.     

IS NEWER ALWAYS BETTER? A COMPARATIVE STUDY OF 3 LITHOTRIPTOR GENERATIONS

PURPOSE: At a single center we compared the efficacy of 3 generations of lithotriptors using identical protocol inclusion and followup criteria but with different modes of anesthesia. MATERIALS AND METHODS: We compared stone disintegration and dilatation of the pyelocaliceal system achieved in a prospective, randomized trial comparing the original HM3 (Dornier Medtech, Kennesaw, Georgia) and Lithostar Plus (LSP) lithotriptors, and a matched, consecutive series of 107 treatments with the Modulith SLX. Stone disintegration and dilatation of the pyelocaliceal system were evaluated by abdominal plain x-ray and renal ultrasonography 1 day and 3 months after treatment. RESULTS: A total of 82 treatments with the HM3, 75 with the LSP and 107 with the SLX were analyzed, matched for stone burden and location within the pyelocaliceal system. On postoperative day 1, 91%, 65% and 48% patients treated with the HM3, LSP and SLX, respectively, were stone-free or had fragments that were 2 mm or less (HM3 vs LSP p <0.001, HM3 vs SLX p <0.001 and LSP vs SLX p = 0.015). Three to 5 mm fragments were found in 7%, 21% and 35% of patients (p = 0.006, <0.001 and 0.06), and fragments 6 mm or greater were found in 1%, 14% and 15% (p = 0.002, <0.001 and 0.1, respectively). The re-treatment rate was 4% in the HM3 group, 13% in the LSP group and 38% in the SLX group (HM3 vs LSP p = 0.05, HM3 vs SLX p <0.001 and LSP vs SLX p <0.001). Obstructive pyelonephritis occurred in 1% of the HM3 group, 8% of the LSP group and 5% of the SLX group (HM3 vs LSP p = 0.02, HM3 vs SLX p = 0.12 and LSP vs SLX p = 0.4). All re-treatments except those in 5 patients were performed with the HM3. Therefore, the 3-month stone-free rate was comparable in all 3 groups (HM3 87%, LSP 80% and SLX 81%). CONCLUSIONS: This study indicates that the HM3 lithotriptor disintegrates caliceal and renal pelvic stones better than the LSP and SLX machines, resulting in fewer complications and re-treatments. Disintegration with the LSP machine was also superior to that of the SLX with a need for fewer re-treatments.     

Legionella pneumophila mediated activation of dendritic cells involves CD14 and TLR2

In this study, we analyzed the activation of bone-marrow derived dendritic cells (BMDCs) from mice lacking the cd14-gene with purified Legionella pneumophila lipopolysaccharide and with viable or formalin-killed L. pneumophila. We found that low concentrations of LPS and doses of L. pneumophila that are relevant to infection are dependent on CD14 to activate BMDCs. Higher concentrations of LPS are able to overcome the lack of CD14 indicating that other receptors areinvolved. We, therefore, included studies using BMDCs from mice lacking functional TLR2 and/or TLR4 molecules. We found that purified L. pneumophila LPS as well as L. pneumophila either viable or formalin-killed are able to activate BMDCs from TLR4-deficient C3H/HeJ mice but fail to activate BMDCs from TLR2-knockout mice. Our data show that not only purified LPS from L. pneumophila but also the microorganism itself stimulate BMDCs via TLR2 and that this stimulation is dependent on CD14 in this mouse model.