Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402)

BackgroundThis study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)).MethodsWe conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed.ResultsOf the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS.ConclusionsThis multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence

Nitrosonifedipine Ameliorates the Progression of Type 2 Diabetic Nephropathy by Exerting Antioxidative Effects

<div><p>Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.</p></div

Effects of NO-NIF on DN in KKAy mice.

<p>Changes in urinary total protein excretion (A) and urinary albumin excretion (B) of the C57BL/6 and KKAy mice with or without NO-NIF at 0, 2, and 4 weeks after the commencement of NO-NIF administration. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. C57BL/6 mice at 0 weeks, #p<0.05 vs. vehicle-treated KKAy mice at 4 weeks. (C) Histopathological analysis of diabetic kidneys at 0 and 4 weeks after the commencement of NO-NIF administration. Representative histological images of PAS staining. Quantitative analysis of the glomerular diameter (D) and glomerular tuft area (E) in the C57BL/6 and KKAy mice. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. C57BL/6 mice at 0 weeks, #p<0.05 vs. vehicle-treated C57BL/6 mice at 4 weeks, and †p<0.05 vs. vehicle-treated KKAy mice at 4 weeks. (F) The effect of NO-NIF on insulin-induced HMC proliferation. HMCs were treated with 10 μM NO-NIF for 6 h prior to treatment with 100 nM insulin for 48 h. Cell proliferation was determined using the MTT assay according to the manufacturer's instructions. *p<0.05 vs. control, #p<0.05 vs. insulin alone.</p

NO-NIF suppressed oxidative stress in a diabetic and endothelial injury model.

<p>(A) Kidney superoxide production was evaluated by DHE staining. Representative images of DHE stained sections from the kidney of the C57BL/6, KKAy and eNOS knockout mice. Scale bar; 100 μm. (B) Changes in urinary 8-OHdG of the C57BL/6 and KKAy mice with or without NO-NIF at 0 and 4 weeks after the commencement of NO-NIF administration. The levels of urinary 8-OHdG were measured by enzyme-linked immunosorbent assay. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice, #p<0.05 vs. vehicle-treated KKAy mice. (C) Change in SOD activity in the kidney of the C57BL/6 and KKAy mice with or without NO-NIF 4 weeks after the commencement of NO-NIF administration. SOD activity was measured by competitive inhibition assay using a SOD assay kit-WST. Values are expressed as the means ± S.E., n = 8–10. (D) The effect of NO-NIF on HG-induced mitochondrial ROS production using MitoSOX red in HGECs. HGECs were preincubated with 10 μM of NO-NIF for 6 h, and then exposed to 30 mM HG for 18 h. Representative images are shown. Scale bar, 100 μm.</p

NO-NIF had no effect on glucose metabolism.

<p>(A) Changes in the blood glucose level during IPGTT. (B) The area under the blood concentration versus time curve for glucose during IPGTT. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice. (C) Changes in the blood glucose level during ITT. Values are expressed as a percentage of the initial value. (D) Levels of serum insulin. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice. (E) Representative images showing hematoxylin-eosin staining of adipocytes in epididymal fat of the C57BL/6 and KKAy mice with or without NO-NIF. (F) Average of the epididymal adipocyte size. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice.</p

Physiological effects in C57BL/6 and KKAy mice 4 weeks after nitrosonifedipine (NO-NIF) administration.

<p>Values are expressed as mean ± SEM, n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice, #p<0.05 vs. vehicle-treated KKAy mice.</p

NO-NIF improved endothelial dysfunction and renal tubular injury in DN.

<p>Immunoblotting (A) and immunohistochemistry (B and C) for ICAM-1 expression in the diabetic kidney of the C57BL/6 and KKAy mice with or without NO-NIF 4 weeks after the commencement of NO-NIF (30 mg/kg) administration. (A) Representative blot of ICAM-1 and β-actin. Equal amounts of protein in each sample were separated by SDS-PAGE and analysis for ICAM-1 by western blotting. (B) Representative immunohistochemical staining of ICAM-1 in glomeruli. (C) Quantitative analysis for staining of ICAM-1 in glomeruli. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice, #p<0.05 vs. vehicle-treated KKAy mice. (D) Changes in the urinary albumin excretion of eNOS knockout mice with or without NO-NIF (30 mg/kg) at 0, 2, and 4 weeks after the commencement of NO-NIF administration. Values are expressed as the means ± S.E., n = 8. *p<0.05 vs. vehicle-treated KKAy mice at 4 weeks. (E) Quantitative analysis for mRNA expression of ICAM-1. The cDNA was synthesized from the thoracic aorta tissues of eNOS knockout mice, and quantitative real-time PCR was performed using primers for ICAM-1. The mRNA expression level was normalized to that of the β-actin gene. (F) Representative blot of ICAM-1 and β-actin in the thoracic aorta of eNOS knockout mice. (G) Changes in the urinary NAG excretion in the C57BL/6 and KKAy mice with or without NO-NIF treatment (30 mg/kg) 4 weeks after the commencement of NO-NIF administration. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice, #p<0.05 vs. vehicle-treated KKAy mice. (H) HK-2 cells were preincubated with 10 μM of NO-NIF for 6 h and then exposed to 100 μM H₂O₂ for 24 h. The cell viability was assessed using an MTT assay according to the manufacturer's instructions. *p<0.05 vs. control, #p<0.05 vs. H₂O₂ alone. (I) Representative immunohistochemical staining of desmin in glomeruli. (J) Quantitative analysis for the staining of desmin in glomeruli. Values are expressed as the means ± S.E., n = 8–10. *p<0.05 vs. vehicle-treated C57BL/6 mice.</p