Volumetric-modulated arc therapy for left-sided breast cancer and all regional nodes improves target volumes coverage and reduces treatment time and doses to the heart and left coronary artery,compared with a field-in-field technique

We compared two intensity-modulated radiotherapy techniques for left-sided breast treatment, involving lymph node irradiation including the internal mammary chain. Inverse planned arc-therapy (VMAT) was compared with a forward-planned multi-segment technique with a mono-isocenter (MONOISO). Ten files were planned per technique, delivering a 50-Gy dose to the breast and 46.95 Gy to nodes, within 25 fractions. Comparative endpoints were planning target volume (PTV) coverage, dose to surrounding structures, and treatment delivery time. PTV coverage, homogeneity and conformality were better for two arc VMAT plans; V95%^PTV-T was 96% for VMAT vs 89.2% for MONOISO. Homogeneity index (HI)^PTV-T was 0.1 and HI^PTV-N was 0.1 for VMAT vs 0.6 and 0.5 for MONOISO. Treatment delivery time was reduced by a factor of two using VMAT relative to MONOISO (84 s vs 180 s). High doses to organs at risk were reduced (V30^{left lung} = 14% using VMAT vs 24.4% with MONOISO; dose to 2% of the volume (D2%)^heart = 26.1 Gy vs 32 Gy), especially to the left coronary artery (LCA) (D2%^LCA = 34.4 Gy vs 40.3 Gy). However, VMAT delivered low doses to a larger volume, including contralateral organs (mean dose [Dmean]^{right lung} = 4 Gy and Dmean^{right breast} = 3.2 Gy). These were better protected using MONOISO plans (Dmean^{right lung} = 0.8 Gy and Dmean^{right breast} = 0.4 Gy). VMAT improved PTV coverage and dose homogeneity, but clinical benefits remain unclear. Decreased dose exposure to the LCA may be clinically relevant. VMAT could be used for complex treatments that are difficult with conventional techniques. Patient age should be considered because of uncertainties concerning secondary malignancies.     

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group

Annals of Surgical Oncology - Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly...     

Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation

Whereas alpidem is hepatotoxic, zolpidem is not. Despite closely related chemical structures, alpidem, but not zolpidem, is a peripheral benzodiazepine receptor (PBR) ligand, and is also more lipophilic than zolpidem. We compared their effects in isolated rat liver mitochondria and rat hepatocytes. Zolpidem did not affect calcium-induced mitochondrial permeability transition (MPT) in mitochondria, caused little glutathione depletion in hepatocytes, and was not toxic, even at 500 microM. At 250 to 500 microM, alpidem prevented calcium-induced MPT in isolated mitochondria, but caused severe glutathione depletion in hepatocytes that was increased by 3-methylcholanthrene, a cytochrome P4501A inducer, and decreased by cystine, a glutathione precursor. Although cell calcium increased, mitochondrial cytochrome c did not translocate to the cytosol and cells died of necrosis. Cell death was prevented by cystine, but not cyclosporin A, an MPT inhibitor. At low concentrations (25-50 microM), in contrast, alpidem accelerated calcium-induced MPT in mitochondria. It did not deplete glutathione in hepatocytes, but nevertheless caused some cell death that was prevented by cyclosporin A, but not by cystine. Alpidem (10 microM) also increased the toxicity of tumor necrosis factor-alpha (1 ng/ml) in hepatocytes. In conclusion, low concentrations of alpidem increase both calcium-induced MPT in mitochondria, and TNF-alpha toxicity in cells, like other PBR ligands. Like other lipophilic protonatable amines, however, alpidem inhibits calcium-induced MPT at high concentrations. At these high concentrations, toxicity involves cytochrome P4501A-mediated metabolic activation, glutathione depletion, and increased cell calcium, without MPT involvement. In contrast, zolpidem has no mitochondrial effects, causes little glutathione depletion, and is not toxic.     

Watch and Wait Approach for Re-excision After Unplanned Yet Macroscopically Complete Excision of Extremity and Superficial Truncal Soft Tissue Sarcoma is Safe and Does Not Affect Metastatic Risk or Amputation Rate

Annals of Surgical Oncology - The benefits of systematic re-excision (RE) after initial unplanned excision (UE) of soft tissue sarcoma (STS) are unknown. The aim of this study was to evaluate the...     

High hepatic glutathione stores alleviate Fas-induced apoptosis in mice

BACKGROUND/AIMS: The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis. METHODS: We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2. RESULTS: The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet. CONCLUSIONS: The SAA(+) diet preserves GSSG/GSH ratios, and prevents PKCzeta and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, mitochondrial permeabilization, and hepatic apoptosis after Fas stimulation. GSH monoethyl ester is also protective, suggesting possible clinical applications.     

Prolonged, but not acute, glutathione depletion promotes Fas-mediated mitochondrial permeability transition and apoptosis in mice

Glutathione depletion either decreased or increased death-receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death-receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared the effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA(-)) diet and the acute depletion caused by a single dose of phorone on hepatic apoptosis triggered by the administration of an agonistic anti-Fas antibody. The chronic SAA(-) diet did not affect hepatic Fas or Bcl-XL, but increased p53 and Bax, and exacerbated Fas-mediated mitochondrial membrane depolarization, electron-microscopy-proven outer mitochondrial membrane rupture, cytochrome c translocation to the cytosol, and caspase 3 activation. These effects were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. The SAA(-) diet increased internucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, serum alanine transaminase (ALT) activity, and mortality after Fas stimulation. Despite a similar decrease in hepatic glutathione, administration of a single dose of phorone 1 hour before the anti-Fas antibody did not change p53 or Bax, and did not enhance Fas-induced mitochondrial permeability transition and toxicity. However, 4 repeated doses of phorone (causing more prolonged glutathione depletion) increased Bax and Fas-mediated toxicity. In conclusion, a chronic SAA(-) diet, but not acute phorone administration, increases p53 and Bax, and enhances Fas-induced mitochondrial permeability transition and apoptosis. Thiol depletion could cause oxidative stress that requires several hours to increase p53; the latter induces Bax, which translocates to mitochondria after Fas stimulation.     

Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice

Although Fas stimulation has been reported to cause outer mitochondrial membrane rupture in Jurkat cells, the mechanism of this effect is debated, and it is not known if outer membrane rupture also occurs in hepatocyte mitochondria. We studied the in vivo effects of Fas stimulation on ultrastructural lesions and mitochondrial function in mice. Four hours after administration of an agonistic anti-Fas antibody (8 microg/animal), caspase activity increased 5.4-fold. Nuclear DNA showed internucleosomal fragmentation, whereas supercoiled mitochondrial DNA was replaced by circular and linear forms. Mitochondrial cytochrome c was partly released into the cytosol. Ultrastructurally, mitochondrial lesions were observed in both apoptotic hepatocytes (with nuclear chromatin condensation/fragmentation) and nonapoptotic hepatocytes (without nuclear changes). In nonapoptotic cells, outer mitochondrial membrane rupture allowed herniation of the inner membrane and matrix through the outer membrane gap. In apoptotic hepatocytes, the matrix became electron-lucent and no longer protruded through the outer membrane gap. Mitochondria clustered around the nucleus, whereas rough endoplasmic reticulum cisternae became peripheral. In liver mitochondria isolated after Fas stimulation, the membrane potential decreased, whereas basal respiration increased. Pretreatment with either z-VAD-fmk (an inhibitor of caspases) or cyclosporin A (a permeability transition inhibitor) totally or mostly prevented mitochondrial outer membrane rupture, membrane potential decrease, cytochrome c release, and apoptosis. In conclusion, in vivo Fas stimulation causes caspase activation, mitochondrial permeability transition (decreasing the membrane potential and increasing basal respiration), mitochondrial matrix expansion (as shown by matrix herniation), outer mitochondrial membrane rupture, and cytochrome c release.     

Treatment of pain in patients with renal insufficiency: the World Health Organization three-step ladder adapted.

The World Health Organization established official recommendations for managing pain in cancer patients. Since then, this stepladder approach has been widely adopted as a conceptual framework to treat all types of pain. However, those guidelines have not been critically evaluated for use in patients with renal insufficiency. In these patients, the questions of drug dosage adjustment and renal toxicity must be considered. This article reviews the pharmacokinetics of major analgesic drugs and data on their use and/or behavior in renal failure and considers their potential nephrotoxicity. Finally, according to available data in the international literature on pharmacokinetics, recommendations for dosage adjustment in patients with renal failure, and their potential nephrotoxicity, the World Health Organization three-step ladder for the treatment of pain was modified and adapted for patients with impaired renal function. Perspective This well-known treatment strategy now adapted for use in patients with renal insufficiency should secure and rationalize pain treatment in those patients.