It is suggested that the bioavailability of CYP3A4 substrates might be low due to first-pass metabolism in the small intestine, and it is possible that P-glycoprotein (P-gp) may influence first-pass metabolism in a co-operative manner. We have collected information of the pharmacokinetics of CYP3A4 substrates to evaluate the fraction absorbed (Fa), intestinal availability (Fg) and hepatic availability (Fh) and have investigated the intestinal first-pass metabolism and the effect of P-gp on this. The pharmacokinetic data involved ten compounds metabolized by CYP3A4 in humans, with and without an inhibitor or inducer. FaFg, which is the product of Fa and Fg, and Fh were calculated using three liver blood flow rates (17.1, 21.4, 25.5 mL/min/kg) in consideration of variations in the liver flow rate. Co-administration with an inhibitor of CYP3A4 and treatment of an inducer of CYP3A4 caused an increase and decrease in the FaFg of CYP3A4 substrates, regardless of the liver blood flow, indicating that CYP3A4 substrates exhibit a first-pass effect in their metabolism. This holds true regardless of whether the compounds are P-gp substrates or not. No relationship was observed between FaFg and Fh, regardless of the hepatic blood flow rate and the P-gp substrates. The FaFg of both P-gp and non P-gp substrates decreased as the hepatic intrinsic clearance increased. FaFg was markedly reduced when the hepatic intrinsic clearance was more than 100 mL/min/kg. This in vivo intrinsic clearance corresponds to an in vitro intrinsic clearance of 78 muL/min/mg human hepatic microsomal protein, equivalent to a half-life of 8.9 min for the substrate in a commonly used metabolic stability test with human microsomes (1 mgMs protein/mL). This phenomenon was not observed in substrates of CYP isoforms other than CYP3A4. In conclusion, it is suggested that CYP3A4 substrates which have a hepatic intrinsic clearance of 100 mL/min/kg exhibit a low bioavailability due to intestinal first-pass metabolism, regardless of whether they are substrates of P-gp or not.

When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I] u /K i ratio, where [I] u is the unbound concentration around the enzyme and K i is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I] u /K i ratio using literature data.The maximum concentration of the inhibitor in the circulating blood ([I] max ), its maximum unbound concentration in the circulating blood ([I] max,u ), and its maximum unbound concentration at the inlet to the liver ([I] in,max,u ) were used as [I] u , and the results were compared with each other. In order to calculate the [I] u /K i ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported K i values determined in in vitro studies using human liver microsomes.For most of the drugs with a calculated [I] in,max,u /K i ratio less than 0.25, which applied to about half of the drugs investigated, no in vivo interactions had been reported or "no interaction" was reported in clinical studies. In contrast, the [I] max,u /K i and [I] max /K i ratio was calculated to be less than 0.25 for about 90% and 65% of the drugs, respectively, and more than a 1.25-fold increase was reported in the area under the concentration-time curve of the co-administered drug for about 30% of such drugs. These findings indicate that the possibility of underestimation of in vivo interactions (possibility of false-negative prediction) is greater when [I]

Compared with SPS, CPS may be safer for the treatment of hyperkalemia in pre-dialysis patients, because it did not induce hyperparathyroidism or volume overload.

Aim: Considering the dramatic increase in average life expectancy during the 20th century throughout the world, the management of elderly patients with cancer has become a global issue. We herein investigated the clinical characteristics and outcomes of super-elderly hepatocellular carcinoma (HCC) patients over 80 years old not indicated for surgical resection. Methods:We retrospectively evaluated 206 newly diagnosed HCC patients. The patients were divided into two groups according to their age at inclusion; a super-elderly group (n = 37, ≥80 years) and a younger group (n = 169, <80 years). We compared the clinical characteristics, overall survival (OS) and disease-specific survival (DSS) rates among the two groups. Both univariate and multivariate analyses were performed to identify the factors associated with the OS and DSS.Results: The proportion of women was higher in the superelderly group than in the younger group (P = 0.017). There were no significant differences in the OS (P = 0.171) or DSS (P = 0.176) between the two groups. The multivariate analysis revealed that only the Cancer Liver Italian Program score (hazard ratio [HR], 2.972; P < 0.0001; HR, 3.694; P < 0.0001) was independently associated with the OS and DSS. Age was not found to be associated with the OS or DSS according to either the univariate or multivariate analysis.Conclusion: There were no significant differences in the OS and DSS rates among the super-elderly HCC patients and younger HCC patients not indicated for surgical resection. An advanced age itself does not restrict the therapeutic approach, even in super-elderly HCC patients not indicated for surgical resection.

Routine EBL is not recommended in the duodenum because the risk of perforation is unacceptably high.

Background/Aim: We aimed to investigate the association between The Geriatric Nutritional Risk Index (GNRI) and the tolerability of lenvatinib in patients with hepatocellular carcinoma (HCC). Patients and Methods: We retrospectively evaluated 61 HCC patients treated with lenvatinib and compared those with low GNRI (≤98, n=26) to those with high GNRI (>98, n=35). Results: The discontinuation of lenvatinib due to adverse events was more frequent in the low GNRI group (46.2%) than in the high GNRI group (17.1%) (p=0.014). Multivariate analysis revealed that low GNRI (p=0.014), hypothyroidism (model 1 p=0.021, model 2 p=0.013), and advanced age (p=0.026) were independently associated with the discontinuation of lenvatinib. The progression-free survival in the low GNRI group was significantly shorter than that in the high GNRI group (p=0.047). Conclusion: The GNRI might be independently associated with the tolerability of lenvatinib in patients with HCC.Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a major health concern worldwide, and its incidence is rising in Western countries (1). In 2017, there were 953,000 incident cases of liver cancer and 819,000 deaths globally (2), indicating the poor outcomes of this disease despite recent advances in treatment modalities.Since the REFLECT study showed the non-inferiority of lenvatinib to sorafenib regarding the overall survival of patients with untreated advanced HCC (3), many investigators have reported the efficacy and feasibility of lenvatinib in patients with advanced HCC (4, 5).However, several investigators showed that an advanced age, poor liver functional reserve, and some adverse events, such as fatigue and appetite loss, were associated with dose reduction or discontinuation of lenvatinib (6-8), leading to a lower dose intensity and reduced objective response of lenvatinib, followed ultimately by a poor survival outcome. Thus, predicting the tolerability of lenvatinib before the initiation of treatment is crucial for achieving favorable survival outcomes in patients with HCC.The Geriatric Nutritional Risk Index (GNRI) (9), based on the serum albumin level, present body weight, and ideal body weight, was first reported to predict prognosis among elderly patients with acute ill, hemodialysis, and heart failure. Recently, this index was also found to be useful to predict postoperative complications or survival outcomes in cancer patients, including those with HCC (10,11).We herein focus on predictive markers for HCC, and report our investigation of the association between the GNRI and the tolerability of lenvatinib in patients with HCC.

BackgroundA solitary fibrous tumor (SFT) is a rare mesenchymal tumor that occurs mostly in pleural sites, and an SFT occurring in the ischiorectal fossa is extremely rare. Because of the rarity, there are few reports detailing an SFT in the ischiorectal fossa.Case presentationA pararectal tumor was incidentally found in a 42-year-old man during a routine medical examination. The patient had no symptoms and no previous medical history. In the physical examination, a smooth-margined and hard elastic mass was felt, and in a digital rectal examination, the rectal mucosa appeared normal. A computed tomography (CT) scan showed a 5-cm, well-defined, solid mass in the left ischiorectal fossa. Contrast-enhanced CT in the early phase showed intense heterogeneous enhancement that persisted during the delayed phase. T2-weighted images of magnetic resonance imaging yielded heterogeneous intermediate and low signal intensity. Intense arterial enhancement suggested a hypervascular nature, and persistent delayed enhancement and low signal bands on T2-weighted images suggested a fibrous component of the mass. An SFT was suspected. Most SFTs are benign but have malignant potential. Our patient did not hope for surgery if the tumor was benign; therefore, an ultrasound-guided transperineal core needle biopsy was performed to decide on a treatment strategy. Microscopic examination showed tumor cells appearing as spindle and fibroblast-like cells within a collagenous stroma. Immunohistochemistry identified CD34 and vimentin, supporting the diagnosis of an SFT. The patient consented to excision of the mass. He was placed in a prone jackknife position, and the tumor was removed transperineally using a posterior approach (modified Kraske procedure). The levator ani muscle, external sphincter muscles, and rectum were not involved and separated from the tumor. The tumor was successfully resected en bloc with no complications. Five uneventful days post surgery, the patient was discharged. There was no local recurrence during the year following surgery.ConclusionImaging findings reflect the tissue characterization such as hypervascularity and fibrous nature of SFTs. We have presented a rare case of an SFT in the ischiorectal fossa with useful imaging findings for diagnosis, treatment strategy, and successful surgical removal using a posterior approach.

We developed a small portable sensor device using a p-type semiconductor cuprous bromide (CuBr) thin film to measure breath ammonia in real time with highsensitivity and selectivity. Breath ammonia is reportedly associated with chronic liver disease (CLD). We aimed to assess the practical utility of the novel CuBr sensor device for exhaled breath ammonia and the correlation between breath and blood ammonia in CLD patients. This was a feasibility and pilot clinical study of 21 CLD patients and 18 healthy volunteers. Breath ammonia was directly and quickly measured using the novel CuBr sensor device and compared with blood ammonia measured at the same time. CLD patients had significantly higher breath ammonia levels than healthy subjects (p = 1.51 × 10−3), with the level of significance being similar to that for blood ammonia levels (p= 0.024). Significant differences were found in breath and blood ammonia between the healthy and cirrhosis groups (p = 2.97 × 10−3 and 3.76 × 10−3, respectively). Significant, positive correlations between breath and blood ammonia were noted in the CLD group (R = 0.747, p = 1.00 × 10−4), healthy/CLD group (R = 0.741, p = 6.75 × 10−8), and cirrhosis group (R = 0.744, p = 9.52 × 10−4). In conclusion, the newly developed, easy-to-use, and small portable CuBr sensor device was able to non-invasively measure breath ammonia in real time. Breath ammonia measured using the device was correlated with blood ammonia and the presence of liver cirrhosis, and might be an alternative surrogate biomarker to blood ammonia.