Clinicopathological analysis of biopsy-proven diabetic nephropathy based on the Japanese classification of diabetic nephropathy

Background

The Japanese classification of diabetic nephropathy reflects the risks of mortality, cardiovascular events and kidney prognosis and is clinically useful. Furthermore, pathological findings of diabetic nephropathy are useful for predicting prognoses. In this study, we evaluated the characteristics of pathological findings in relation to the Japanese classification of diabetic nephropathy and their ability to predict prognosis.

Methods

The clinical data of 600 biopsy-confirmed diabetic nephropathy patients were collected retrospectively from 13 centers across Japan. Composite kidney events, kidney death, cardiovascular events, all-cause mortality, and decreasing rate of estimated GFR (eGFR) were evaluated based on the Japanese classification of diabetic nephropathy.

Results

The median observation period was 70.4 (IQR 20.9–101.0) months. Each stage had specific characteristic pathological findings. Diffuse lesions, interstitial fibrosis and/or tubular atrophy (IFTA), interstitial cell infiltration, arteriolar hyalinosis, and intimal thickening were detected in more than half the cases, even in Stage 1. An analysis of the impacts on outcomes in all data showed that hazard ratios of diffuse lesions, widening of the subendothelial space, exudative lesions, mesangiolysis, IFTA, and interstitial cell infiltration were 2.7, 2.8, 2.7, 2.6, 3.5, and 3.7, respectively. Median declining speed of eGFR in all cases was 5.61 mL/min/1.73 m²/year, and the median rate of declining kidney function within 2 years after kidney biopsy was 24.0%.

Conclusions

This study indicated that pathological findings could categorize the high-risk group as well as the Japanese classification of diabetic nephropathy. Further study using biopsy specimens is required to clarify the pathogenesis of diabetic kidney disease.

     

The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis

Background

Sulforaphane (SUL), a kind of isothiocyanate, has recently been focused due to its strong pro-apoptotic effect on cancer cells as well as tumor vascular endothelial cells (ECs). And recently, we demonstrated the induction of autophagy by colon cancer cells as a protective mechanism against SUL. In the present study, we aimed to investigate the possible role of autophagy induction by ECs as a defense mechanism against SUL.

Methods

Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model of angiogenic ECs. The induction of autophagy was evaluated by the detection of acidic vesicular organelles (AVOs) by flow-cytometry, after the staining with acridine orange, as well as the detection of light chain 3(LC3) by Western blot. Finally, the functional implication of autophagy inhibition and SUL treatment in ECs was investigated by their ability to form vascular-like structures on Matrigel.

Results

Treatment of HUVECs with relatively low concentrations of SUL for 16 h resulted in the evident formation of AVOs and the recruitment of LC3 to autophagosomes, the pathognomonic features of autophagy. Co-treatment of cells with the specific autophagy inhibitor (3-methyladenine) potentiated the proapoptotic effect of SUL. And inhibition of autophagy potentiated the inhibitory effect of SUL on the ability of ECs to form capillary-like structures.

Conclusion

Similar to cancer cells, ECs induced autophagy in response to the pro-apoptotic agent, SUL, and the inhibition of autophagy potentiated the pro-apoptotic effect. These findings open premises for the use of autophagy inhibitors in combination with anti–angiogenic agents.     

Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study

Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer.     

Endoscopic Subtotal Thyroidectomy: The Procedure of Choice for Graves’ disease?

Background  The aim of this study was to evaluate the feasibility and outcomes of endoscopic subtotal thyroidectomy for Graves’ disease. Methods  From August 1998 to April 2008, a total of 100 patients with benign thyroid diseases underwent endoscopic thyroidectomy via the breast approach. Among these patients, 42 underwent subtotal thyroidectomy for Graves’ disease. Results  The resection was successfully completed endoscopically in 41 patients (98%). Overall, the mean operating time, mean blood loss, and mean resected thyroid weight were 277 minutes, 76 ml, and 49.9 g, respectively. As the resected thyroid weight increased, the operating time was significantly prolonged and the blood loss significantly increased. Morbidities included one permanent and one temporary case of recurrent laryngeal nerve palsy with hypocalcemia. A hypertrophic scar was seen in the right breast medial margin in three men. Thyroid function was classified as euthyroidism, hypothyroidism, and recurrent hyperthyroidism in 5, 34, and 3 patients, respectively. At 92 months of median follow-up, two patients had modest operation-associated symptoms: one with swallowing discomfort and another with paresthesia in the anterior chest wall at the time of discharge. However, both patients’ symptoms disappeared within 36 months after surgery. Young women were highly satisfied, with an overall mean satisfaction rating of 9.3 points. Conclusions  Although the endoscopic approach may be relatively contraindicated for large thyroid glands, endoscopic subtotal thyroidectomy via the breast approach is a safe, feasible procedure with excellent cosmetic benefits, and it may be the procedure of choice in carefully selected patients with Graves’ disease.     

Surgical Strategy for Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus Based on Prognostic Factors

Rationale  Surgical strategy for patients with hepatocellular carcinoma and portal vein tumor thrombus (PVTT) remains to be established. Methods  From 1990 to 2008, 48 hepatocellular carcinoma patients with PVTT detected by preoperative imaging underwent hepatic resection, and their clinical data were retrospectively analyzed. Possible prognostic factors for survival were analyzed with postoperative survival curves, and significant factors were determined by univariate and multivariate analysis. The frequency of postoperative severe complications was investigated for each prognostic factor. Results  Significant prognostic factors included patient age <60 years, serum total bilirubin (T-Bil) >0.8 mg/dl, serum aspartate aminotransferase >30 IU/L, serum alkaline phosphatase (ALP) >300 IU/L, tumor size >4 cm, PVTT in the main trunk (Vp4), and a surgical margin <1 mm by univariate analysis, and independent prognostic factors were serum T-Bil, ALP, and Vp4. No patient with Vp4 survived for more than 400 days after surgery, and frequency of postoperative severe complications in these Vp4 patients was significantly higher than in other Vp1–3 patients. Conclusion  Hepatic resection as a first-choice treatment should be carefully selected in patients with Vp4 unless emergent removal of the PVTT is required.     

Altered sensitivities to morphine and cocaine in scaffold protein tamalin knockout mice

Tamalin is a scaffold protein that interacts with metabotropic glutamate receptors and the kinase-deficient neurotrophin TrkCT1 receptor and forms a protein complex with multiple protein-trafficking and intracellular signaling molecules. In culture, tamalin promotes intracellular trafficking of group 1 metabotropic glutamate receptors through its interaction with guanine nucleotide exchange factor cytohesins and causes actin reorganization and membrane ruffling via the TrkCT1/cytohesin-2 signaling mechanism. However, how tamalin serves its physiological function in vivo has remained elusive. In this study, we generated tamalin knockout (Tam(-/-) KO) mice and investigated behavioral alterations resulting from their deficiency in functional tamalin. Targeted deletion of functional tamalin altered neither the overall brain architecture nor the general behavior of the mice under ordinary conditions. However, Tam(-/-) KO mice showed a decrease in sensitivity to acute morphine-induced hyperlocomotion and morphine analgesic effects in the hot-plate test. Furthermore, tamalin deficiency impaired the ability of the animals to show conditioned place preference after repeated morphine administration and to display locomotor sensitization by chronic cocaine treatment. Upon in vivo microdialysis analysis of the nucleus accumbens, Tam(-/-) KO and wild-type mice showed no genotypic differences in their response patterns of extracellular dopamine and glutamate before or after morphine administration. These results demonstrate that the tamalin scaffold protein plays a unique role in both acute and adaptive behavioral responses to morphine and cocaine and could regulate common neural substrates implicated in drugs of abuse.     

A case report-highly advanced gastric cancer leading to perforation during neoadjuvant chemotherapy with docetaxel, cisplatin and S-1

A 70-year-old man was found to have advanced gastric cancer with a deep ulcer and multiple lymph-node metastases. Although the tumor was resectable, we predicted that the patient would have a poor outcome. We therefore administered neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 to improve the prognosis before curative resection. On day 15 of chemotherapy, sudden abdominal pain occurred, and we performed an emergency surgery for a diagnosis of panperitonitis due to gastric cancer perforation. The defect in the gastric wall was about 2 cm in diameter and was located in the anterior wall of the antrum, consistent with the center of the tumor. The operative findings suggested that the perforation was caused by chemotherapy-induced necrosis of gastric cancer cells. We saved the patient's life, but intensive care with high-dose catecholamine therapy was needed for several days after the surgery. Gastric cancer perforation induced by neoadjuvant chemotherapy appeared to be more severe than perforation caused by other factors. The adverse effects of chemotherapy apparently increased the severity. Our findings suggest that the risk of gastric cancer perforation should be borne in mind when we administer neoadjuvant chemotherapy to patients who have advanced gastric cancer with a deep ulcer.