Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma

Sunitinib treatment with a 2-week-on/1-week-off schedule (Schedule 2/1) is a common alternative regimen with high relative dose intensity (RDI) and superior tolerability for patients with metastatic renal cell carcinoma (mRCC). The prognostic impact of RDI is reported only in 4-week-on/2-week-off or mixed regimens. Herein, we evaluated the prognostic impact of RDI during early-phase sunitinib treatment using Schedule 2/1. Seventy-four patients who received first-line sunitinib treatment using Schedule 2/1 were evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). We assessed RDI within the initial two cycles (2c-RDI), and its prognostic impact. Predictive factors for 2c-RDI deterioration were also evaluated. The cut-off value of 2c-RDI was set at 65%. Based on this cut-off, 31 patients (42.0%) were classified into the low 2c-RDI group (<?65%). PFS and OS were significantly shorter in the low-2c-RDI patients, compared with the high 2c-RDI patients (median PFS: 6.15 vs. 18.4 months, p?=?0.0005; OS 11.0 vs. 39.3 months, p?=?0.0002). Furthermore, multivariate analyses showed that the development of dose-limiting toxicities (DLTs) within the initial two cycles, as well as low initial dose, were independent factors for low 2c-RDI (DLTs: OR 18.6, 95% CI 3.27–105.30, p?=?0.0010; initial dose: OR 9.26, 95% CI 1.42–60.40, p?=?0.020). The most common adverse event was thrombocytopenia (any grade: 24.3%; grade?≥?3: 8.1%). More than 65% of 2c-RDI should be maintained for optimal therapeutic effect of sunitinib treatment using Schedule 2/1. To achieve the appropriate 2c-RDI, careful follow-up for patient tolerability is needed to avoid early DLT development.     

Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy

Objectives

The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear.

Adjuvant gemcitabine monotherapy for resectable perihilar cholangiocarcinoma with lymph node involvement: a propensity score matching analysis

Purpose

The aim of this study was to evaluate the efficacy of adjuvant gemcitabine monotherapy following resection for perihilar cholangiocarcinoma with lymph node involvement.

Methods

We performed a retrospective analysis of 180 patients undergoing resection for perihilar cholangiocarcinoma with lymph node involvement between 2001 and 2012. The patients were divided into two groups according to the presence (n = 67) or absence (n = 113) of adjuvant gemcitabine monotherapy. Univariate and multivariate analyses were performed followed by a propensity score matching analysis to adjust for the differences in the baseline characteristics of the groups.

Results

The overall survival rates after surgery and the median survival times in patients who were treated with adjuvant chemotherapy were significantly longer than those who were treated without adjuvant chemotherapy (32.9 vs. 15.0 % at 5 years, 37 vs. 20 months, P = 0.001). A multivariate analysis indicated that adjuvant chemotherapy, a residual microscopic tumor, and pathological T stage were independent prognostic factors for survival. After two new cohorts of 32 patients were generated following 1:1 propensity score matching, the overall survival rate in the adjuvant chemotherapy group was found to be significantly longer than that in the surgery alone group (43.2 vs. 15.6 % at 5 years, P = 0.001).

Conclusion

Adjuvant gemcitabine monotherapy may improve survival in node-positive perihilar cholangiocarcinoma patients.

     

Postoperative Pancreatic Fistula in Surgery for Perihilar Cholangiocarcinoma

There are numerous studies on postoperative pancreatic fistula (POPF) in pancreatic surgery but few studies on POPF in extrahepatic bile duct resection with or without hepatectomy for perihilar cholangiocarcinoma (PHCC). The aim of this study is to investigate the incidence of and risk factors for POPF in this challenging surgery. All consecutive patients who underwent surgical resection for presumed PHCC between January 2008 and December 2017 were retrospectively reviewed, with special attention paid to POPF. Among 416 patients, 90 patients showed a drain amylase level of > 3 times the normal limit on day 3 or after. The severity of POPF was biochemical leakage in 46 patients and grade B in 44 patients. No patient had grade C POPF; thus, the incidence of clinically relevant POPF was 10.6% (44/416). The resection line of the common bile duct was closely associated with POPF; 23 (27.7%) of the 83 patients who underwent intrapancreatic resection of the common bile duct developed POPF. The occurrence of intra-abdominal abscess and liver failure was significantly higher in patients with POPF, but the 90-day mortality was similar. The multivariate analysis identified a body mass index of ≥ 22 and intrapancreatic bile duct resection as independent risk factors for POPF. POPF occurs in approximately 10% of patients undergoing resection for PHCC. Careful postoperative management with attention to POPF is required, especially in patients who undergo intrapancreatic resection of the common bile duct and in those with a high body mass index.     

A case of acute vascular rejection after overseas deceased kidney transplantation

Abstract:  A 54-yr-old Japanese male received overseas deceased kidney transplantation in January 2006. His allograft functioned immediately and he received immunosuppression with cyclosporine A (CyA), mycophenolate mofetil (MMF), and prednisone (PR). On day 24 after transplantation, he came back to Japan. His serum creatinine level (s-Cr) was 1.39 mg/dL at two months after transplantation when he was admitted into Toda Central General Hospital on March 2006, for follow-up his renal allograft. He had taken only two immunosuppressive drugs, MMF and PR, and had not taken CyA at that time. His serum creatinine gradually rose after hospitalization. Allograft biopsy performed on April 6, 2006, showed acute vascular rejection (Banff 97 acute/active cellular rejection Grade III), together with suspicious for acute humoral rejection (Banff 97 antibody-mediated rejection Grade II). After treatment of two courses of steroid pulses and five d of gusperimus, acute vascular rejection and acute humoral rejection were relieved, which had been proven by the third allograft biopsy. In conclusion, this was a case of acute vascular rejection after overseas deceased kidney transplantation, resulted from non-compliance with immunosuppressive therapy.     

Nutritional screening with Subjective Global Assessment predicts hospital stay in patients with digestive diseases

OBJECTIVE: Nutritional status is an important factor that determines hospital stay, and the Subjective Global Assessment (SGA) is a candidate tool for nutritional screening on admission. However, the significance of the SGA has not been evaluated well in the ward for digestive diseases. We conducted the present study to test whether the SGA predicts hospital stay of these patients. METHODS: Two hundred sixty-two patients with digestive diseases were consecutively enrolled between July 2004 and April 2005. They consisted of 145 males and 117 females and included 110 patients with cancer. Disease category was gastrointestinal in 94, hepatic in 111, and biliary/pancreatic in 57. The SGA was performed by a certified dietician. Effects of SGA and other nutritional parameters on hospital stay were examined by simple and multiple regression analysis. RESULTS: Among tested variables, simple regression analysis identified the SGA, disease category, presence of malignancy, serum albumin level, percent triceps skinfold thickness, and percent arm muscle circumference as significant predictive parameters for hospital stay. Multiple regression analysis revealed that the SGA had the best predictive power, followed by the presence of malignancy and disease category. CONCLUSION: The SGA is a simple and reliable predictor for hospital stay in patients with digestive diseases.     

Neutrophil-derived epoxide, 9,10-epoxy-12-octadecenoate,induces pulmonary edema

We have observed that neutrophils biosynthesize linoleate epoxide, 9,10-epoxy-12-octadecenoate, and have named it leukotoxin because of its cytotoxic effect. In this experiment, the effect of leukotoxin on the lung was investigated. Acute effect of leukotoxin: Using Wistar rats, leukotoxin (100μmol/kg) was injected intravenously for the leukotoxin group, and linoleate (100μmol/kg) for the linoleate group. Physiological saline was injected as the control. Ten min after injection, rats were divided into 3 groups: (1) lungs were isolated, and lung wet weight, and dry weight were measured; (2) lung lavages were performed, and albumin concentration and activity of angiotensin converting enzyme (ACE) were measured; (3) morphological changes were studied by light and electron microscope. After administration of leukotoxin, lung wet weight/body weight ratios and dry weight/wet weight ratios were increased. Albumin concentration and ACE activity in lung lavages were also increased. Pulmonary edema was also confirmed by light microscopic findings. Alveolar epithelial cell damage and endothelium damage were also observed. Linoleate had no significant effect on these biochemical parameters and morphological findings. Subacute effect of leukotoxin: Twelve hr after administration of leukotoxin (50μmol/kg) or linoleate (50μmol/kg), the same studies were performed as in the acute experiments. Immediately after administration of leukotoxin, no significant effect was observed. However, 12 hr later similar changes were observed as in the acute experiments. Linoleate did not show any significant effect 12 hr after injection. These results indicate that leukotoxin biosynthesized by neutrophils might be closely related to the genesis of inflammatory edema.     

An official JRS statement: The principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.