Evaluation of Efficacy and Safety of Upfront Weekly Nanoparticle Albumin-bound Paclitaxel for HER2-negative Breast Cancer.

BACKGROUND: Taxanes are among the key drugs for breast cancer treatment. This study aimed to evaluate the efficacy of upfront weekly nanoparticle albumin-bound paclitaxel (Nab-PTX; 100 mg/m2) for human epidermal growth factor 2 (HER2)-negative breast cancer. PATIENTS AND METHODS: Patients with stage II to IV breast cancer received 12 cycles of weekly 100 mg/m2 Nab-PTX as first-line treatment. Preoperative chemotherapy with anthracyclines after Nab-PTX was recommended. RESULTS: From 2012 to 2014, we enrolled 66 patients. The overall response rate after Nab-PTX was 59.1% [95% confidence interval(CI)=47.2% to 71.0%), 63.6% in those with hormone receptor-positive tumors, and 36.4% in those with triple-negative tumors. The pathological complete response rate at surgery was 15% (95% CI=6.1% to 24.4%). Toxicity analysis showed grade 2 peripheral neuropathy in 38 patients (57.6%), grade 2/3 leukocytopenia in 29 (43.9%) and grade 2/3 liver dysfunction in five (7.5%). CONCLUSION: Weekly neoadjuvant Nab-PTX at 100 mg/m2 led to good response rates (59.1%) and was well tolerated.

Predicting operational tolerance in pediatric living-donor liver transplantation by absence of HLA antibodies.

BACKGROUND: The role of anti-human leukocyte antigen (HLA) antibodies in operational tolerance (OT) after pediatric living-donor liver transplantation (LDLT) remains inconclusive. We investigated whether the presence of HLA antibodies impeded the development of OT. METHODS: We retrospectively examined the prevalence of anti-HLA antibodies in pediatric LDLT recipients before transplantation and at 3 weeks after transplantation and analyzed the significance of those antibodies in relation to later OT. Forty pediatric LDLTs were performed between April 1996 and December 2000 and followed up through July 2011, with sera available for measurement of HLA antibodies. Seventeen patients achieved OT (mean follow-up, 4571.9±544.7 days) and 23 patients did not achieve OT (mean follow-up, 4532.0±425.4 days). Protocol liver biopsy was done for 14 OT patients and 16 non-OT patients. Their sera were tested for anti-HLA class I and II antibodies using the LABScreen single antigen beads test, in which a 1000 mean fluorescence value was considered positive. RESULTS: The prevalence of antibodies after transplantation in non-OT patients was higher than in OT patients (95.2% vs. 73.3%; P<0.001). The highest mean fluorescence intensity of antibodies was significantly higher in non-OT patients than in OT patients. The prevalence of HLA-B, HLA-C, HLA-DQ, and HLA-DR antibodies was significantly higher in non-OT patients than in OT patients. The highest mean fluorescence intensity of HLA-A, HLA-B, and HLA-DQ observed in non-OT patients was significantly higher than those in OT patients. CONCLUSIONS: In our study, posttransplantation HLA antibodies were associated with the future absence of OT. A prospective study with more patients is necessary to confirm the predictive value of HLA antibodies for OT.

Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer.

PURPOSE: Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5'-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC). MATERIALS AND METHODS: Patients received capecitabine 828 mg/m(2) twice daily with cyclophosphamide 33 mg/m(2) twice daily, days 1-14 every 3 weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1 months. ORR was 44.4% and stable disease (≥24 weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3 months (95% confidence interval: 8.9-18.9 months). Median PFS was 10.7 months in triple-negative disease and 13.2 months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome. CONCLUSIONS: Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.

Hydrolysis of Al3+ from constrained molecular dynamics.

We investigated the hydrolysis reactions of Al(3+) in AlCl(3) aqueous solution using the constrained molecular dynamics based on the Car-Parrinello molecular-dynamics method. By employing the proton-aluminum coordination number as a reaction coordinate in the constrained molecular dynamics the deprotonation as well as dehydration processes are successfully realized. From our free-energy difference of DeltaG(0) approximately 8.0 kcal mol(-1) the hydrolysis constant pK(a1) is roughly estimated as 5.8, comparable to the literature value of 5.07. We show that the free-energy difference for the hydrolysis of Al(3+) in acidic conditions is at least 4 kcal mol(-1) higher than that in neutral condition, indicating that the hydrolysis reaction is inhibited by the presence of excess protons located around the hydrated ion, in agreement with the change of the predominant species by pH.

Hydration structure of Y3+ and La3+ compared: an application of metadynamics.

We studied the hydration structures of Y(3+) and La(3+) in aqueous solutions by applying the metadynamics method recently introduced as a tool to explore reaction pathways based on the Car-Parrinello molecular dynamics. By employing the metal-water oxygen coordination number as a collective variable of the metadynamics a couple of aqua and chloroaqua complexes are successfully generated within the time scale of 10 ps. The reconstructed free-energy surface captures the characteristics of the hydration of the light and heavy trivalent rare-earth ions. The present study demonstrates that the metadynamics based on the Car-Parrinello molecular dynamics is a promising tool for exploring the free-energy surface of complicated systems such as solutions.

Hydration of Y3+ ion: a Car-Parrinello molecular dynamics study.

The solvation shell structure of Y3+ and the dynamics of the hydrated ion in an aqueous solution of 0.8 M YCl3 are studied in two conditions with and without an excess proton by using first principles molecular dynamics method. We find that the first solvation shell around Y3+ contains eight water molecules forming a square antiprism as expected from x-ray absorption near edge structure in both the conditions we examined. A detailed analysis relying upon localized orbitals reveals that the complexation of water molecules with yttrium cation leads to a substantial amount of charge redistribution particularly on the oxygen atoms, giving rise to the chemical shifts of approximately -20 ppm in 17O nuclear magnetic resonance relative to the computed nuclear shieldings of the bulk water.

Fluoride complexation of element 104, rutherfordium.

Fluoride complexation of element 104, rutherfordium (Rf), produced in the 248Cm(18O,5n)261Rf reaction has been studied by anion-exchange chromatography on an atom-at-a-time scale. The anion-exchange chromatographic behavior of Rf was investigated in 1.9-13.9 M hydrofluoric acid together with those of the group-4 elements Zr and Hf produced in the 18O-induced reactions on Ge and Gd targets, respectively. It was found that the adsorption behavior of Rf on anion-exchange resin is quite different from those of Zr and Hf, suggesting the influence of relativistic effects on the fluoride complexation of Rf.

Gastrointestinal bleeding after living-related liver transplantation.

We examined the prevalence of gastrointestinal bleeding in patients undergoing living-related liver transplantation (LRLT). Seventy-seven patients (37 male and 40 female) underwent LRLT at the University of Tokyo Hospital from January 1996 through December 1999. Forty-nine patients were children or adolescents and 28 patients were adults. The mean follow-up period was 21.3 +/- 12.8 months. Nine of the 77 recipients had gastrointestinal bleeding after transplantation. The incidence of posttransplant bleeding was significantly higher in adult recipients than in pediatric recipients (25% vs 4%, P < 0.05). The ratio of graft volume to standard liver volume was significantly lower in adult recipients than in pediatric recipients (41 +/- 6% vs 86 +/- 26%, P < 0.05). Portal vein thrombosis (PVT) developed after LRLT in 8 patients. Variceal bleeding subsequently occurred in all 4 adult patients with PVT but in only 1 of 4 pediatric patients. Small-for-size grafts may cause transient portal hypertension, which increases the risk of gastrointestinal bleeding.

Immunosuppressive effect of chenodeoxycholic acid on natural killer cell activity in patients with biliary atresia and hepatitis C virus-related liver cirrhosis.

Patients with severe liver diseases, such as liver cirrhosis and biliary atresia, have low natural killer (NK) cell activity. The relations between NK activity and measures of liver function, including serum levels of total bilirubin, total bile acids, bile acid components, aspartate aminotransferase, and alanine aminotransferase, and platelet count were examined in patients with biliary atresia (6 boys and 6 girls; mean age, 4.8+/-5.7 years) and patients with liver cirrhosis due to hepatitis C virus infection (10 men and 2 women; mean age, 54.3+/-13.8 years). Univariate analysis showed that platelet count was positively correlated with NK activity in patients with biliary atresia (r = 0.611, P < 0.05). Serum levels of free chenodeoxycholic acid were negatively correlated with NK activity both in patients with biliary atresia (r = -0.647, P < 0.05) and in patients with hepatitis C virus-related liver cirrhosis (r = -0.876, P < 0.01). None of the other free bile acids or conjugated bile acids or other indicators of liver function were correlated with NK activity. Multiple stepwise regression analysis showed that only levels of free chenodeoxycholic acid were independently correlated with NK activity. All patients with biliary atresia underwent liver transplantation from living related donors. NK activity had increased significantly two months after transplantation (from 24.1+/-20.2% to 49.2+/-12.5%, P < 0.01). In contrast, levels of free chenodeoxycholic acid in transplant recipients had decreased significantly two months after transplantation (from 1.22+/-1.16 to 0.26+/-0.21 micromol/l, P < 0.05). In conclusion, in patients with biliary atresia or liver cirrhosis, NK activity in peripheral blood decreases, mostly because of free chenodeoxycholic acid.

Living-donor liver transplantation at Tokyo University.

One hundred fourteen living-donor liver transplants were performed at Tokyo University hospital from 1996-2000, including 66 children and 48 adults. Most (86%) of the children were transplanted for biliary atresia, whereas adults were more often transplanted for primary biliary cirrhosis (40%) or liver cirrhosis (23%) due to hepatitis or other unknown causes. Among children, 52% received the left lobe lateral segment, 23% an extended lateral segment and 21% the left lobe. The graft volume to standard liver ratio averaged 84%. Among adults, 79% received a left lobe; however, we have used the right lobe for most recent cases (21%) to provide sufficient volume. Parents donated to the pediatric recipients about 95% of the time, but a variety of family members donated for the adult transplants. The actual overall 3- and 5-year patient survival rates were 88.6% and 87.7%, respectively, and were slightly higher in children than adults. The results are comparable to those achieved with cadaver livers.