Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity

Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.     

Pontine infarction manifesting as isolated cranial nerve palsies.

Isolated ipsilateral fifth, seventh, tenth and twelfth cranial nerve palsies in a 74-year-old woman were shown at autopsy to result from an inferior lateral pontine infarction. The clinical features and pathogenesis of this uncommon lesion are discussed.     

Oculoskeletal myopathy with abnormal mitochondria

A clinical, electrophysiological and pathological review of 14 patients having oculoskeletal myopathy with abnormal mitochondria was undertaken. These patients present with ophthalmoplegia, and mild skeletal muscle weakness. The clinical course is slowly progressive. Electromyographic examination shows myopathic changes. Serum enzymes are normal. The diagnosis is confirmed by skeletal muscle biopsy which shows abnormal mitochondria, including crystalloid inclusions on electron microscopy. These patients form a distinct clinical group in which the risk of sudden cardiac death is much less than it is in the Kearns-Sayre syndrome.     

DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular

The flavone acetic acid derivative DMXAA [5,6-dimethylXAA (xanthenone-4-acetic acid), Vadimezan, ASA404] is a drug that displayed vascular-disrupting activity and induced haemorrhagic necrosis and tumour regression in pre-clinical animal models. Both immune-mediated and non-immune-mediated effects contributed to the tumour regression. The vascular disruption was less in human tumours, with immune-mediated effects being less prominent, but nonetheless DMXAA showed promising effects in Phase II clinical trials in non-small-cell lung cancer. However, these effects were not replicated in Phase III clinical trials. It has been difficult to understand the differences between the pre-clinical findings and the later clinical trials as the molecular targets for the agent have never been clearly established. To investigate the mechanism of action, we sought to determine whether DMXAA might target protein kinases. We found that, at concentrations achieved in blood during clinical trials, DMXAA has inhibitory effects against several kinases, with most potent effects being on members of the VEGFR (vascular endothelial growth factor receptor) tyrosine kinase family. Some analogues of DMXAA were even more effective inhibitors of these kinases, in particular 2-MeXAA (2-methylXAA) and 6-MeXAA (6-methylXAA). The inhibitory effects were greatest against VEGFR2 and, consistent with this, we found that DMXAA, 2-MeXAA and 6-MeXAA were able to block angiogenesis in zebrafish embryos and also inhibit VEGFR2 signalling in HUVECs (human umbilical vein endothelial cells). Taken together, these results indicate that at least part of the effects of DMXAA are due to it acting as a multi-kinase inhibitor and that the anti-VEGFR activity in particular may contribute to the non-immune-mediated effects of DMXAA on the vasculature.     

Male circumcision for HIV prevention - a cross-sectional study on awareness among young people and adults in rural Uganda

Background  

Medical male circumcision is now part of a comprehensive approach to HIV prevention. It has been shown that awareness of the protective effect of male circumcision leads to high acceptability towards the introduction of medical male circumcision services within countries. The objective of this survey was to identify factors determining awareness of male circumcision for HIV prevention.     

A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer

BACKGROUND:

Localized prostate cancer can be treated several different ways, but head‐to‐head comparisons of treatments are infrequent. The authors of this report conducted a randomized, unblinded, noninferiority trial to compare cryoablation with external beam radiotherapy in these patients.

METHODS:

From December 1997 through February 2003, 244 men with newly diagnosed localized prostate cancer were assigned randomly to receive either cryoablation or radiotherapy (122 men in each arm). All received neoadjuvant antiandrogen therapy. The primary endpoint was disease progression at 36 months based on a trifecta definition: 1) radiologic evidence of metastatic disease, or 2) initiation of further antineoplastic therapy, or 3) biochemical failure. Two definitions of biochemical failure were used: 1) 2 consecutive rises in prostate‐specific antigen (PSA) with a final value >1.0 ng/mL, and 2) a rise above PSA nadir + 2 ng/mL. Secondary endpoints included overall survival, disease‐specific survival, and prostate biopsy at 36 months.

RESULTS:

The median follow‐up was 100 months. Disease progression at 36 months was observed in 23.9% (PSA nadir + 2 ng/mL, 17.1%) of men in the cryoablation arm and in 23.7% (PSA nadir + 2 ng/mL, 13.2%) of men in the radiotherapy arm. No difference in overall or disease‐specific survival were observed. At 36 months, more patients in the radiotherapy arm had a cancer‐positive biopsy (28.9%) compared with patients in the cryoablation arm (7.7%).

CONCLUSIONS:

The observed difference in disease progression at 36 months was small, 0.2%; however, because of the wide confidence interval, from ?10.8% to 11.2%, it was not possible to rule out inferiority (defined a priori as a 10% difference). With longer term follow‐up, the trend favors cryoablation. Significantly fewer positive biopsies were documented after cryoablation than after radiotherapy. Cancer 2010. © 2010 American Cancer Society.     

Methanol optic neuropathy: a histopathological study

The histopathologic effects of methanol on the optic nerve were studied in four patients. Circumscribed myelin damage occurred behind the lamina cribrosa in each nerve. Axons were preserved. Demyelination also occurred in cerebral hemispheric white matter in one patient. This selective myelinoclastic effect of methanol metabolism is probably caused by histotoxic anoxia in watershed areas of the cerebral and distal optic nerve circulations. Juxtabulbar demyelination may cause optic disk edema in methanol poisoning by compressive obstruction of orthograde axoplasmic flow. Visual loss may be due to disruption of saltatory conduction. Retrolaminar demyelinating optic neuropathy is an early morphologic correlate of visual loss in methanol intoxication.     

Biliary obstruction after cholecystectomy: diagnosis with quantitative cholescintigraphy

Fifty patients with recurrent post-cholecystectomy pain underwent hepatobiliary scintigraphy. Time-activity curves were generated from regions of interest over the liver, bile duct, duodenum, and bowel. Patients were divided into obstructed and unobstructed groups with endoscopic retrograde cholangiopancreatography criteria. Measurements from the liver, duodenum, and bowel curves contributed little to the analysis. The washout phase of the bile duct curve showed intermittent emptying in both obstructed and unobstructed groups. Less than one-third of peak activity remained in both groups at 90 minutes. Retention fell more rapidly in the later portion of the sequence in patients with obstruction. Quantification was essential, since differences were subtle and could not be appreciated visually. In the absence of hepatocellular disease, the most reliable criterion was the time at which maximal bile duct activity occurred. A cutoff level of 29 minutes or more was used in the diagnosis of obstruction. A sensitivity of 93% with an adequate specificity of 64% and an overall accuracy of 80% was achieved in the prediction of obstruction.