Yoshiyuki Kadokura

Involvement of alpha-klotho and fibroblast growth factor receptor in the development of secondary hyperparathyroidism.

Background/Aims: Fibroblast growth factor 23 (FGF23) has been shown to suppress parathyroid hormone (PTH) secretion. α-Klotho has been demonstrated to function as a fibroblast growth factor receptor (FGFR) cofactor for FGF23. Thus, both α-Klotho and FGFR may play roles in PTH synthesis and/or secretion. Functions of α-Klotho and FGFR in secondary hyperparathyroidism (SHPT) remain to be studied. The present studies explore the role of α-Klotho and FGFR in SHPT. Methods: Hyperplastic parathyroid glands (n = 44) were obtained from patients with SHPT. Results: Immunohistochemical study showed that both α-Klotho and FGFR1c expression in hyperplastic glands was significantly decreased compared with that in normal glands (Klotho p < 0.01, and FGFR1c p < 0.05). A significant positive correlation was observed between α-Klotho and FGFR1c (r2 = 0.375, p < 0.01) indicating a cooperative system. Both α-Klotho (r2 = 0.235, p < 0.05) and FGFR1c (r2 = 0.181, p < 0.05) correlated positively with the calcium-sensing receptor (CaR), which plays an important role in the development of SHPT. In addition, expression of α-Klotho correlated negatively with parathyroid cell proliferation, as confirmed by Ki67 staining (r2 = 0.148, p < 0.05). Conclusion: Decreased expression of α-Klotho and FGFR1c in parallel with CaR expression and parathyroid cell growth may be involved in the pathogenesis of SHPT.

Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

Effects of preoperative cinacalcet hydrochloride treatment on the operative course of parathyroidectomy and pathological changes in resected parathyroid glands

BackgroundSecondary hyperparathyroidism (SHPT) is associated with higher cardiovascular risk and mortality in patients undergoing dialysis. Cinacalcet hydrochloride (CH), which has been clinically available in Japan since 2008, could effectively reduce parathyroid hormone (PTH) levels even in patients with severe SHPT. However, parathyroidectomy (PTx) is performed in patients with severe SHPT refractory to CH. This study investigated the effects of preoperative CH treatment on the operative course and pathological findings of resected parathyroid glands (PTGs) in patients undergoing PTx.MethodsWe retrospectively analyzed 194 PTx cases for SHPT in long-term hemodialysis patients at Showa University Northern Yokohama Hospital from April 2002 to March 2014.ResultsA total of 45 patients were administered CH before PTx (CH group), and 149 patients never received CH (non-CH group). No significant difference was seen in intact PTH levels, the number of resected PTGs, or operative time between the two groups. However, the total volume of all PTGs and the volume of the largest PTG were significantly lower in the CH than in the non-CH group. Patients with PTG adhesion to surrounding tissues were significantly more prevalent in the CH than in the non-CH group. In addition, cystic changes or hemorrhagic necrosis in the resected PTGs was observed more frequently in the CH group than in the non-CH group.ConclusionsThe results of the present study suggest that preoperative CH treatment might introduce pathological changes in resected PTGs in PTx for severe SHPT, but it does not affect the operative time.

Surgical Treatment for Superior Advanced Maxillary Carcinoma and Reconstruction of the Zygomaticoorbital Floor

In cases of superior advanced maxillary carcinoma, the zygomaticoorbital floor is reconstructed using a rectus abdominis muscle flap or a osteocutaneous scapular flap after a radical maxillectomy including the zygomaticoorbital floor bone. In cases with residual disease in the zygomaticoorbital floor without an invading palatine process after radiotherapy and chemotherapy, we made an effort to keep the palatine process intact and reconstruct the zygomaticoorbital floor using a collagen plate. On the other hand, in cases with residual disease in both the zygomaticoorbital floor and palatine process, we performed a radical maxillectomy and carried out the reconstruction using an osteocutaneous scapular flap combined with a collagen plate. We performed a partial or radical maxillectomy for 8 patients with superior advanced maxillary carcinoma and reconstructed the zygomaticoorbital floor defects using a collagen plate. One was reconstructed by combining a collagen plate with an osteocutaneous scapular flap. By this method we succeeded in preventing eye ball sinking.

A Case of Leukoencephalopathy after Drip Infusion of 5-Fluorouracil (5-FU)

A 42-year-old man was admitted due to advanced nasopharynx cancer and administered a total dose of 19250 mg 5-fluorouracil (5-FU). On the fifth day, he exhibited acute consciousness disturbance, and the 5-FU administration was immediately stopped. An MRI revealed a high intensity lesion on the T2weighed image. The brain disease improved gradually. We do not have an effective cure for this disease but it must be detected early.