Characterization of acute and chronic neuropathies induced by oxaliplatin in mice and differential effects of a novel mitochondria-targeted antioxidant on the neuropathies.

BACKGROUND: Oxaliplatin, a chemotherapeutic agent used for the treatment of colorectal cancer, induces dose-limiting neuropathy that compromises quality of life. This study aimed to reproduce, in mice, patients' symptoms of oxaliplatin-induced neuropathy and to observe effects of SS-31, a mitochondria-targeted antioxidant on the neuropathy. METHODS: Neuropathy was induced by single or repeated injections of oxaliplatin. Cold and mechanical hypersensitivities were assessed by 15°C-cold plate, temperature preference, and von Frey tests. Morphology of peripheral nerves and dorsal root ganglions, expression of spinal cord c-Fos, density of intraepidermal nerve fibers, and levels of dorsal root ganglion-reactive oxygen/nitrogen species were examined. SS-31 was administered concomitantly or after oxaliplatin injections. RESULTS: Single injection of oxaliplatin induced cold hypersensitivity in forepaws but not in hind paws which resolved within days (maximal forepaw shakes: 28 ± 1.5 vs. 9.3 ± 1.6/150 s, mean ± SEM, P < 0.001, n = 6 per group). Oxaliplatin-administered mice disfavored 10° and 15°C plates more than control. Paw stimulation at 15°C induced c-Fos-positive cells within superficial laminae of the dorsal horn in C7-T1 segments. Weekly administrations induced gradual development of persistent mechanical allodynia in the hind paws (minimal mechanical threshold: 0.19 ± 0.08 vs. 0.93 ± 0.11 g, P < 0.001, n = 10 per group). Microscopy revealed no overt morphological changes in peripheral nerves and dorsal root ganglions. Concomitant SS-31 administration with repeated oxaliplatin administration attenuated both cold and mechanical hypersensitivity. Decrease in intraepidermal nerve fibers and increase in dorsal root ganglion-reactive oxygen/nitrogen species were also attenuated. Acute SS-31 administration after symptoms were established reversed only cold hypersensitivity. CONCLUSION: This model of oxaliplatin-induced neuropathy mimicked patients' conditions. SS-31 has potentials to prevent both acute and chronic neuropathies but is only helpful in treatment of acute neuropathy. (Anesthesiology 2014; 120:459-73).

Brush cytology of acinar cell carcinoma of the pancreas with intraductal growth: a case report.

We describe a rare case of pancreatic acinar cell carcinoma (ACC) with intraductal growth in a 77-year-old man, which was diagnosed by endoscopic brush cytology. Preoperative imaging revealed an ill-defined mass involving the main pancreatic duct of the body, which was suspected to be an invasive ductal carcinoma. Endoscopic brush cytology showed several thick, small to large clusters of tumor cells. However, a loosely cohesive or individual cell arrangement was more prominent. Singly dispersed naked nuclei, occasionally with crush artifact, were frequently observed. The nuclear contour was smooth and chromatin was finely clumped. The cytoplasm contained many coarse D-PAS-positive granules. Histologically, the tumor expansively invaded to parenchyma and expanded to fill the pancreatic ducts. Ultrastructurally, the tumor cells were less cohesive with scarce tight junctions, and their cytoplasm contained numerous zymogen granules and filamentous inclusions. Although ACCs usually show expansive growth, the incidence of intraductal extension may be higher than previously considered. A few of the characteristic cytomorphological features described here may be useful for differential diagnosis of this tumor from malignant epithelioid neoplasms involving the large pancreatic ducts.