A large number of molecular-targeted drugs have been discovered, and we are facing diverse adverse effects that we have not experienced previously. In particular, dermatological toxicity is frequently caused by various molecular-targeted drugs, and this side effect often contributes to the interruption of therapy and decreases the quality of life (QOL) in patients. Especially, typical dermatitis induced by multi-targeted tyrosine kinase inhibitors (mTKI), hand-foot skin reaction (HFSR), is a serious adverse reaction that affects the therapeutic outcomes of mTKI, although pathological and molecular mechanisms of this reaction are unclear. This review summarizes our findings about the roles of the signal transducer and activator of transcription 3 (STAT3) in the mechanisms of mTKI-induced dermatitis, risk factors of HFSR, and mechanism-based prophylaxis of HFSR:

1) Molecular biological roles of STAT3 in the mTKI-induced keratinocyte toxicity

2) Association between mTKI-induced HFSR and STAT3 polymorphisms

3) A novel prophylaxis strategy based on maintaining STAT3 activity

These findings provide important perceptions on the mechanisms of HFSR and the identification of predictive factors for toxicity of mTKI, and it may lead to the realization of precision medicine in molecular-targeted therapy.

Sunitinib and sorafenib as well as interferon-α (IFN-α) are first-line therapies for advanced or recurrent renal cell carcinoma. Although the efficacy of molecular targeted drugs appears indisputable, some research suggests that they are not significantly effective compared to cytokine therapies in terms of progression-free survival. The therapeutic effects of new drugs depend on the decision of doctors and hospitals, which is partially based on the evaluation of cost-effectiveness of these therapies. The purpose of this study was to analyze the clinical decisions involved in selecting IFN-α, sunitinib, and sorafenib regimens and to identify the best regimen for the first-line treatment of advanced or recurrent renal cell carcinoma based on clinical and economic evidence.

The health outcomes of the therapies considered in this study were analyzed based on the literature on randomized controlled clinical trials of the drugs. The total costs of the regimens were calculated on the basis of direct costs obtained from medical records of patients diagnosed with advanced or recurrent renal cell carcinoma at Yamagata University Hospital. Cost-effectiveness was analyzed by the Markov chain Monte Carlo (MCMC) method. The study was designed from a social viewpoint.

The MCMC analysis revealed that the incremental cost per effectiveness ratios of sunitinib and sorafenib to IFN-α were 746,919 yen and 421,930 yen per life month, respectively. Molecular targeted drugs are superior to IFN-α in terms of health outcomes but are less cost-effective.

Paclitaxel (PTX) is a key drug used in the treatment of ovarian cancer. One well-known adverse effect is chemotherapy-induced peripheral neuropathy (CIPN), which can often lead to the discontinuation of chemotherapy or decreased quality of life. There are some pivotal clinical trial data for patients with ovarian cancer, which have shown the incidence of CIPN according to severity but have not shown detailed data. Therefore, we retrospectively investigated the incidence, timing, and severity of CIPN associated with PTX-containing regimens in 142 patients with ovarian cancer. Patients received dose-dense paclitaxel/carboplatin (TC) (n = 93, 65.5％), TC (n = 36, 5.4％), or weekly TC (n = 13, 9.1％). CIPN occurred in 130 patients (91.5％); 67 of 130 patients (51.5％) had CIPN of Grade 2 or higher. The median cumulative dose associated with the onset of CIPN was 320 mg/m². The median cumulative dose associated with the onset of CIPN was 400 mg/m² for Grade 1, 320 mg/m² for Grade 2, and 175 mg/m² for Grade 3. Patients with CIPN onset at lower doses of PTX developed more severe CIPN (P < 0.05). Further investigation of optimal timing to prevent and therapeutic strategy to treat CIPN is required.

The phosphorus content of the drug was reported in the United States, and attention was paid to pharmaceutical additives. However, papers surveying the phosphorus content of drugs in Japan have not been reported. We calculated the phosphorous content in dibasic calcium phosphate hydrate (DCPH) or dibasic calcium phosphate (DCP) in amlodipine (AML) and compared the phosphorus content for each formulation. DCPH or DCP was found in all the 104 AML tablets and in 15 of the 78 AML OD tablets. On request, the pharmaceutical company revealed the amounts of DCPH or DCP in 78 of the 104 AML tablets (75.0％) and 9 of the 15 AML OD tablets (60％). The phosphorus content in AML tablets varied among the pharmaceutical companies and it tended to increase with an increase in dose. On the other hand, 63 of the 78 AML OD tablets did not contain DCPH or DCP. Furthermore, the phosphorus content in 9 of the 15 AML OD tablets containing DCPH or DCP was lower than that in AML tablets. Therefore, unnecessary phosphorus load can be avoided in dialysis patients by opting for AML OD tablets rather than AML tablets or opting for low phosphorus content AML tablets.

This study demonstrates that the stability of insulin is affected by the components in the preparation. The stability of human insulin was measured using high-performance liquid chromatography (HPLC) at various concentrations and temperatures (37.0℃, 30.0℃ or 22.0℃) in the presence and absence of sodium hydrogen sulfite. Insulin in physiological saline at 37℃ was stable for at least 24 hours. In the presence of sodium hydrogen sulfite, however, it was degraded, presumably due to cleavage of S-S bonds in the insulin molecules. Higher degradation rate constants were observed with increases in temperature. The degradation rate constant (k, observed value hr^-1) was 0.00619 at 22℃, 0.01649 at 30℃, and 0.03308 at 37℃. The activation energy of insulin (Arrhenius equation) calculated from these values was 20.3 kcal/mol. The daytime room temperature in hospitals is maintained at 22.0-27.0℃, and this study showed that, in this temperature range, the stability of insulin in physiological saline containing sodium hydrogen sulfite decreases. The residual percentage of insulin after 24 hours at 22.0℃ and 25.0℃ was 85.9％ and 80.7％, respectively, based on the Arrhenius equation. These results indicate the importance of proper handling of insulin at medical facilities. They also show that appropriate temperature control is necessary for insulin dissolved in solutions containing sodium hydrogen sulfite.

To investigate the efficacy and safety of tolvaptan (TLV) in patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH)at Kyoto-Katsura Hospital, a retrospective chart review of TLV dosage, duration, change in serum sodium concentration from baseline to Day 14 after the initial TLV administration, and side effects was performed. In 27 patients (mean age: 75.4 years), the main causes of SIADH were drugs (33.3％) and small cell lung cancer (SCLC) (33.3％). Patients administered TLV received a mean starting dose of 3.97 mg (SD 1.45) and mean daily dose of 4.10 mg (SD 1.65). The maximum TLV dosage did not exceed 7.5 mg. The treatment duration of TLV required for serum sodium improvement (Na ≥ 135 mEq/L) was 5.91 days (SD 3.33) in all patients. TLV was administrated for 13.44 days (SD 1.57) to maintain the serum sodium in SCLC patients. Concomitant sodium load (≥ 100 mEq orally or intravenously) did not significantly affect the duration of improvement in hyponatremia [sodium load vs load-free: 7.1 days (SD 3.4) vs 5.3 days (SD 3.1), P = 0.24]. The side effects were dry mouth (11.1％) and hypernatremia (3.7％). In conclusion, we confirmed the effectiveness and safety of TLV for hyponatremia of SIADH at low doses for 14 days. TLV may improve the quality of life in patients with loaded sodium intake, and could be used in the longer run to treat SCLC with a permanent antidiuretic hormone production.

The number of cases of Clostridium difficile infection (CDI) had increased in our hospital since November 2013. As the outbreak of horizontal infection of CDI was strongly suspected, we introduced potassium peroxymonosulfate cleaner (RST) in May 2014. The incidence of CDI was significantly reduced after beginning to use RST (May 2014 - December 2015) compared to the pre-introduction period (January 2012 to April 2014). The results of this study suggest that environmental improvement using RST is a useful approach for suppressing horizontal infection of Clostridium difficile.