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Purpose: Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model.Methods: Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods.Results: Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) μg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*μg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL).Conclusion: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited. [ABSTRACT FROM AUTHOR]

Treatment with fludarabine phosphate (9-β-D-arabinofuranosyl-2-F-adenine 5'-phosphate, F-araAMP) leads to regressions and cures of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (EcPNP). This occurs despite the fact that fludarabine (F-araA) is a relatively poor substrate for EcPNP, and is cleaved to liberate 2-fluoroadenine at a rate only 0.3% that of the natural E. coli PNP substrate, adenosine. In this study, we investigated a panel of naturally occurring PNPs to identify more efficient enzymes that may be suitable for metabolizing F-araA as part of experimental cancer therapy. We show that Trichomonas vaginalis PNP (TvPNP) cleaves F-araA with a catalytic efficiency 25-fold greater than the prototypic E. coli enzyme. Cellular extracts from human glioma cells (D54) transduced with lentivirus stably expressing TvPNP (D54/TvPNP) were found to cleave F-araA at a rate similar to extracts from D54 cells expressing EcPNP, although much less enzyme was expressed per cell in the TvPNP transduced condition. As a test of safety and efficacy using TvPNP, human head and neck squamous cell carcinoma (FaDu) xenografts expressing TvPNP were studied in nude mice and shown to exhibit robust tumor regressions, albeit with partial weight loss that resolved post-therapy. F-araAMP was also a very effective treatment for mice bearing D54/TvPNP xenografts in which approximately 10% of tumor cells expressed the enzyme, indicating pronounced ability to kill non-transduced tumor cells (high bystander activity). Moreover, F-araAMP demonstrated activity against D54 tumors injected with an E1, E3 deleted adenoviral vector encoding TvPNP. In that setting, despite higher F-araA cleavage activity using TvPNP, tumor responses were similar to those obtained with EcPNP, indicating factors other than F-Ade production may limit regressions of the D54 murine xenograft model. Our results establish that TvPNP is a favorable enzyme for activating F-araA, and support further studies in combination with F-araAMP for difficult-to-treat human cancers. [ABSTRACT FROM AUTHOR]

Purpose: Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.Methods: The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment.Results: We found that tumor growth was arrested only by the o-rMETase-AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change.Conclusion: This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma. [ABSTRACT FROM AUTHOR]

Purpose: Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy.Methods: As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated.Results: Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%).Conclusions: Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated. [ABSTRACT FROM AUTHOR]

Purpose: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ.Methods: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ.Results: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032).Conclusions: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response. [ABSTRACT FROM AUTHOR]

Purpose: GTI-2040 is a novel antisense oligonucleotide inhibitor of the R2 subunit of ribonucleotide reductase. This phase I study assessed safety and maximum tolerated dose (MTD) of GTI-2040 in combination with weekly gemcitabine in patients with advanced solid tumors.Methods: GTI-2040 was given as a 14-day continuous intravenous infusion, while gemcitabine was administered on days 1, 8, and 15. This combination was repeated every 4 weeks and study followed a modified 3 + 3 Fibonacci schema. Incidence, severity of adverse events, pharmacokinetics (PK), and pharmacodynamics (PD) was assessed. Responses were assessed using RECIST criteria version 1.0 with CT scans performed after every other cycle.Results: A total of 16 patients received at least one dose of GTI-2040/gemcitabine and were included in the safety analysis. The MTD of this regimen is 100 mg/m2/day of GTI-2040 over 14 days combined with 400 mg/m2/day of gemcitabine administered weekly on days 1, 8, and 15. The dose-limiting toxicities (DLTs) included grade 3 fatigue and thrombocytopenia with hematemesis (both at 100/600 mg/m2/day). The most common adverse events were grade 1/2 fatigue, nausea, vomiting, diarrhea, and anorexia. There was no evidence of alteration in gemcitabine PKs. PD modulation of R2mRNA expression in peripheral blood mononuclear cells was observed. No objective tumor response was observed although stable disease was seen in 25% patients.Conclusions: The combination of GTI-2040 and gemcitabine has an acceptable safety profile in a heavily pre-treated patient population with advanced solid tumors. No clear signal of anti-tumor activity was observed; however, several patients had prolonged stable disease. [ABSTRACT FROM AUTHOR]

Purpose: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors.Methods: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells.Results: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose.Conclusion: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published. [ABSTRACT FROM AUTHOR]

Purpose: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy.Methods: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen.Results: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373).Conclusion: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation.Clinical Trial Registration: JAPIC Clinical Trials Information; JapicCTI-121751. [ABSTRACT FROM AUTHOR]

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.Methods: Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).Results: 24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (- 0.12 vs. - 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.Conclusions: Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.Impact: Combining metformin with sirolimus did not improve mTOR inhibition. [ABSTRACT FROM AUTHOR]

Purpose: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.Methods: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage.Results: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5β1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses.Conclusions: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study. [ABSTRACT FROM AUTHOR]

Purpose: AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet.Methods: Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and Cmax ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2).Results: In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and Cmax were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later tmax and lower Cmax after food versus overnight fast. Fed and fasted AUCτ and Cmax ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states.Conclusions: PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability. [ABSTRACT FROM AUTHOR]

Combining sorafenib and eribulin mesylate may provide synergistic antitumor activities with limited overlapping toxicities. This phase 1b, open-label, dose-escalation study evaluated safety, pharmacokinetics, maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), and preliminary efficacy of sorafenib plus standard-dose eribulin mesylate in patients with advanced, metastatic, or refractory tumors. Patients received sorafenib 200 mg twice daily (BID; n = 5), 600 mg/day (n = 8), and 400 mg BID (MTD; n = 27). Dose-limiting toxicities were increased alanine aminotransferase and acute coronary syndrome (both grade 3) in the 400-mg BID dose-escalation and expansion cohorts, respectively. No significant increase in mean QTcF duration was observed with eribulin plus sorafenib versus eribulin alone; there were no drug-drug interactions. Five patients achieved partial response; 16 achieved stable disease. The combination of sorafenib and eribulin mesylate presented no unexpected safety concerns and no significant impact on QT/QTc intervals or drug-drug interactions. Sorafenib 400 mg BID plus standard-dose eribulin is the RP2D. [ABSTRACT FROM AUTHOR]

Purpose: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.Method: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.Results: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.Conclusion: The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development. [ABSTRACT FROM AUTHOR]

Purpose: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.Methods: We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.Results: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n = 3) or 125 mg/m2 (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.Conclusions: The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated. [ABSTRACT FROM AUTHOR]

Purpose: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors.Method: This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability.Results: The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in Cmax and a modest increase (31%) in AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80-125%), the high-fat meal reached bioequivalence with dosing under fasting.Conclusion: In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect. [ABSTRACT FROM AUTHOR]

B7-H3 is a type I transmembrane co-stimulatory molecule of the B7 family. B7-H3 mRNA is widely distributed in most tissues; however, B7-H3 protein is not constitutively expressed. Few molecules have been shown to mediate the regulation of B7-H3 expression, and their regulatory mechanisms remain unexplored. Recently, TREM-like transcript 2 (TLT-2) has been identified as a potential receptor of B7-H3. However, TLT-2 may not be the only receptor of B7-H3, as B7-H3 has many contradictory roles. As a co-stimulatory molecule, B7-H3 increases the proliferation of both CD4+ and CD8+ T-cells and enhances cytotoxic T-cell activity. However, greatly increased T-cell proliferation and IL-2 levels have been observed in the absence of B7-H3. Thus far, it has been shown that various tumors test positive for B7-H3 expression and that B7-H3 levels correlate with tumor growth, invasion, metastasis, malignant stage, and recurrence rate. Furthermore, transfection of cells with a B7-H3 plasmid and treatment with monoclonal antibodies to block B7-H3 are the main immunotherapeutic strategies for cancer treatment. Several groups have generated anti-B7-H3 antibodies and observed tumor growth suppression in vitro and in vivo. Therefore, it is likely that B7-H3 plays an important role in cancer diagnosis and treatment, aside from its role as a co-stimulatory molecule. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to clarify the efficacy and safety of sunitinib in Japanese patients with pancreatic neuroendocrine tumors (PNET), especially by focusing on dose and schedule modification.Methods: Sixteen patients with advanced PNET treated with sunitinib were reviewed retrospectively. Efficacy was evaluated by progression-free survival (PFS) and objective tumor response. Toxicity profile was assessed regularly. Correlation between relative dose intensity (RDI) and treatment period was also evaluated.Results: The median PFS was 25.8 months, and the probability of PFS at 1-year was 92%. The objective response rate and clinical benefit rate were 44% and 69%, respectively. The common adverse drug reactions (ADRs) were hand-foot syndrome (88%), neutropenia (75%), leucopenia (75%), and diarrhea (63%). Due to the development of severe ADRs, 81% required dose reduction and 31% discontinued sunitinib treatment, respectively. Prolonged treatment period was significantly correlated with decreased RDI (Spearman r = - 0.57, P = 0.022). The median RDI among 9 patients whom continued sunitinib more than 1 year was 49%.Conclusions: Sunitinib showed significant clinical benefit in Japanese patients with advanced PNET in the real-world clinical setting. Successful management of ADRs with appropriate dose reduction and interruption can enable long-term continuation of sunitinib. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the optimal starting time point of sorafenib therapy in suppressing the tumor-promoting effects of VEGF up-regulation, which is frequently found after local therapy in clinical practice. Methods: VEGF was intravenously injected to imitate the evaluated expression after local tumor therapy, such as TACE. A total of 40 SD rats bearing hepatic tumors were randomly divided into four groups and sorafenib was administered at different timepoints: (A) control group: VEGF injection only; (B) initiating sorafenib 72 h prior to VEGF injection; (C) initiating sorafenib simultaneously with VEGF injection; (D) initiating sorafenib 72 h post-VEGF injection. The rate of tumor growth, median survival time, expression of VEGF, and microvessel density (MVD), as determined by immunohistochemical (IHC) examination, were compared. Results: The results revealed that the tumor size and median survival time were significantly different between the three sorafenib groups compared to the control group ( p < 0.05). Median survival times were 19.6 ± 1.78, 31.2 ± 6.99, 27.4 ± 4.9, and 26.5 ± 4.6 days in group A, B, C, and D, respectively. Furthermore, there was a difference in statistical significance between the two sorafenib groups B and D ( p = 0.04). Tumors were collected for HE staining and IHC examination. The expression levels of VEGF in B, C, and D were 42.8 ± 7.96, 71.9 ± 15.73, and 73.6 ± 13.73, and all of them were significantly lower than that in the control group (88.3 ± 13.61). Furthermore, the level of MVD was 109.2 ± 8.98 in the control group, which was significantly higher than in the three sorafenib groups (45.7 ± 16.92, 77.1 ± 16.29, and 93.6 ± 12.87, all p < 0.05). Conclusions: According to our results, the most suitable regimen for the administration of sorafenib is before the increased expression of VEGF, which showed a potential advantage for controlling the tumor growth and prolonging the survival time of test animal via inhibiting VEGF-receptor expression through the bifunction of VEGF, and the reduction of tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment. [ABSTRACT FROM AUTHOR]

Purpose: There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.Methods: We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).Results: ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.Conclusion: These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: Everolimus is a standard treatment option for advanced pancreatic neuroendocrine tumors (pNETs). This multicenter study evaluated the efficacy and safety of everolimus in low and intermediate grade advanced pNETs.Methods: Tumors were graded according to the World Health Organization 2010 classification system. Patients with low or intermediate grade pNETs who received everolimus as first- or second-line chemotherapy between 2002 and 2014 were included.Results: A total of 40 patients with metastatic or recurrent pNETs were included in this study. The median age was 54.5 years (range 19-83 years). Twelve patients (30%) experienced recurrence. There were 11 patients (27.5%) with low grade pNETs and 29 (72.5%) with intermediate. Everolimus was administered as first-line therapy in 30 patients (75%) and as second-line therapy in 10 patients (25%). The median progression-free survival (PFS) of patients with low and intermediate grade pNETs was significantly different (median not reached vs. 11 months, P = 0.015). On multivariate analysis, tumor grade (intermediate grade; HR 6.52, 95% CI 1.31-32.27, P = 0.022) was the only independent prognostic factor for PFS in pNETs. The most common adverse events were stomatitis, skin rash, and anemia.Conclusions: World Health Organization 2010 grade is the most important determinant for PFS in patients undergoing everolimus treatment for pNETs with an acceptable incidence of adverse events. [ABSTRACT FROM AUTHOR]

Purpose: To determine the efficacy and safety of sunitinib in Chinese patients with unresectable or metastatic pancreatic neuroendocrine tumors (pNETs) and the clinical significance of steady-state sunitinib serum concentrations.Methods: We conducted a multicenter retrospective study including six centers from across China. A total of 60 patients with unresectable or metastatic pNETs who were treated with sunitinib were evaluated retrospectively.Results: The median overall survival (OS) was 47.5 months and the median time to progression (TTP) was 15.3 months. The objective response rate was 5.0%, and the stable disease (SD) rate was 81.7%. About 35.2% of patients required a dosage decrease from 37.5 to 25 mg/day due to adverse events, which in most cases were alleviated or disappeared with the dosage reduction. In 14 patients who experienced sunitinib-related hypertension, 2 achieved a partial response (PR) and 11 had SD. The median OS and TTP of these 14 patients experienced hypertension were both not reached. The median Css of sunitinib was similar between patients treated with sunitinib 37.5 and 25 mg/day (P = 0.955), but higher in patients who had PR than in those who achieved SD or progressive disease, although no statistically significant difference was found (P = 0.173).Conclusions: Sunitinib had similar treatment efficacy to western patients with pNET in China. A 25 mg/day dosage was better tolerated than 37.5 mg/day in Chinese patients, and there were no significant differences in sunitinib Css between the two dosage groups. Patients with higher sunitinib Css seem to have better efficacy. Sunitinib-related hypertension may be a predictor of a better treatment effect. [ABSTRACT FROM AUTHOR]

Purpose: In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects.Methods: In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs.Results: Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary.Conclusion: HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far. [ABSTRACT FROM AUTHOR]

Purpose: The renal safety of cisplatin-based chemotherapy has not been investigated in patients with urothelial carcinoma of the upper urinary tract (UUT-UC) who retain a solitary kidney after nephroureterectomy. This study aimed to assess and compare the renal safety and efficacy of gemcitabine-cisplatin (GP) and gemcitabine-carboplatin (GC) in these patients.Methods: The medical records of patients diagnosed with urothelial carcinoma at the Sun Yat-Sen University Cancer Center between January 2005 and December 2015 were retrospectively reviewed. The creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR) were used to assess renal function and were calculated using different formulas.Results: A total of 71 patients were enrolled in this study; 48 patients were on GP, and 23 were on GC. The renal function indicators (CrCl and eGFR) were all significantly lower after GP chemotherapy than at baseline, a phenomenon that was not observed in the GC group. Severe nephrotoxicities (SNTs) were reported in 12 patients on GP (25%) and zero on GC. SNT risk factors included a more than 20% decrease in eGFR after one GP cycle and the presence of diabetes (all p < 0.05). Among patients treated with first-line palliative chemotherapy (n = 32), GC (n = 13) patients had an ORR of 46.2%, which was not significantly different from GP patients (36.8%, n = 19), whereas GC patients tended to have a shorter OS than GP patients (9.2 vs. 29 months, p = 0.200).Conclusions: Our results confirm that GP has an adverse impact on the renal function of patients with UUT-UC who retain a solitary kidney, but it can be safely administered to the majority of these patients without inducing SNT. In specific patients, GC is an alternative to GP that has comparable efficacy and favourable renal toxicity. [ABSTRACT FROM AUTHOR]

Purpose: To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin.Patients and Methods: The eligibility criteria required stage III-IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy.Results: Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed.Conclusion: Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients. [ABSTRACT FROM AUTHOR]

Purpose: S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed.Methods: The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m2 on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1-14 and 22-35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1-4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival.Results: A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild.Conclusions: This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies. Clinical trials information: UMIN000006332. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and toxicity of induction chemotherapy followed by concurrent chemoradiotherapy vs. concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma (NPC).Methods: We reviewed data of locoregionally advanced NPC patients who underwent 2 different treatment plans, 1 with induction chemotherapy followed by concurrent chemoradiotherapy (IC + CCRT) and the other with only concurrent chemoradiotherapy (CCRT). All patients received cisplatin 80 mg/m2 3 weeks one cycle concurrently with intensity-modulated radiation therapy, and three IC protocols were included for the IC + CCRT group.Results: Data of 262 patients treated from May 2011 to November 2014 were found eligible for our study. With a median follow-up of 29.02 months, no significant differences were detected between the two groups on the 2-year overall survival or OS rates (96.63 vs. 92.86%, P = 0.169), 2-year distant metastasis-free survival or DMFS rates (91.57 vs. 86.90%, P = 0.246) and 3-year DMFS rates (90.45 vs. 82.14%, P = 0.093). However, they were statistically different on 2-year locoregional failure-free survival or LFFS rates (94.94 vs. 86.90%, P = 0.020), 3-year OS rates (95.51 vs. 82.14%, P = 0.002) and 3-year LFFS rates (93.82 vs. 79.76%, P = 0.001). The most common severe (grade 3-4) adverse events we recorded were Nausea/vomiting (36.52 vs. 33.33%), leukopenia (14.04 vs. 4.76%), thrombocytopenia (3.93 vs. 3.57%) and hepatic toxicity (3.37 vs. 2.38%).Conclusion: Compared with CCRT, the treatment plan IC + CCRT produced significantly encouraging outcomes in locoregionally advanced NPC patients on local progression-free survival and 3-year overall survival position, but might raise the risk of certain adverse reactions. [ABSTRACT FROM AUTHOR]

Objective To compare intra-arterial chemotherapy combined with intravesical chemotherapy with intravesical chemotherapy alone in the treatment of high-risk non-muscle invasive bladder cancer (HRBC) after thulium laser resection of a bladder tumor (TmLRBT).Materials and Methods: From January 2009 to December 2013, 283 patients with HRBC were randomly assigned to the combined group (group A, n = 141) or intravesical chemotherapy-alone group (group B, n = 142) after TmLRBT. Intra-arterial chemotherapy was administered after initial TmLRBT, with 3 courses at 4-week intervals. Each course consisted of cisplatin (50 mg/m2) and epirubicin (30 mg/m2). Intravesical chemotherapy was administered in both groups, including an immediate 50 mg of epirubicin instillation after TmLRBT and weekly maintenance for 8 weeks, followed by monthly maintenance for 1 year.Results: The recurrence rate was 29.1% (41/141) in group A and 42.9% (61/142) in group B, with a significant difference (p = 0.01). The progression rate was 15.6% (22/141) in group A and 25.3% (36/142) in group B, with a significant difference (p = 0.039). Patients with concomitant carcinoma in situ (CIS) also had a lower recurrence rate and progression rate in group A compared to those in group B (p = 0.006 and p = 0.03, respectively). On univariate and multivariate logistic regression analyses, patients with low-grade histology had a higher reccurrence-free rate. Multivariate COX analysis of tumor-related factors suggested that concomitant CIS was the only significant prognostic factor associated with poorer recurrence-free survival and progression-free survival.Conclusions: Intra-arterial chemotherapy combined with intravesical chemotherapy could reduce the risk of recurrence and progression compared to intravesical chemotherapy alone in HRBC. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to present the clinical outcomes of adjuvant concurrent chemoradiotherapy (CCRT) with low-dose daily cisplatin regimen compared to the conventional 5-fluorouracil (5-FU)-based regimen for extrahepatic bile duct cancer (EHBDC).Methods: From October 1994 to April 2013, 41 patients received adjuvant CCRT with low-dose daily regimen or 5-FU-based regimens. Nineteen patients received low-dose of cisplatin just before every delivery of radiation therapy, and 21 patients received two cycles of 5-FU-based regimen during radiotherapy. We compared the clinical outcomes between two adjuvant CCRT regimens.Results: Adjuvant CCRT with low-dose daily cisplatin showed comparable toxicity profiles compared with that of a 5-FU-based regimen. The median follow-up time was 33 months (range, 5-205), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were 34.2, 50.8, and 49.7%, respectively. Univariable analyses showed no significant differences in OS, LRRFS, and DMFS between the groups with two regimens. In multivariable analyses, chemotherapeutic regimen was a significant prognostic factor for OS, favoring the low-dose daily cisplatin regimen (HR = 2.491, p = 0.036) over 5-FU-based regimen, though not for LRRFS (p = 0.642) and DMFS (p = 0.756).Conclusions: Adjuvant CCRT with low-dose daily cisplatin regimen showed acceptable toxicities and survivals compared to those of the 5-FU-based regimen. Low-dose daily cisplatin can be one of the feasible regimens for adjuvant CCRT for EHBDC. [ABSTRACT FROM AUTHOR]

Purpose: ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727).Methods: Data from patients who received ABT-414 monotherapy at a dose of 1-4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia's formula (QTcF).Results: Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses ≥2 mg/kg, the estimated mean ∆QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure-response analysis showed no statistically significant relationship between ΔQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ∆QTcF value >30 ms.Conclusions: ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors. [ABSTRACT FROM AUTHOR]

Purpose: Gene therapy has shown extensive potential to treat human diseases occurring from the defection of genes like various types of cancers. The cationic polymers, as non-viral gene carriers, offer the ability to engineer carrier systems having customized features that can be adapted to suit any system. Upon polymeric micelle systems' core-shell structure, micelles can create the capacity to load genes/gene-drugs into the different micelle compartments, respectively.Methods: The search will be managed in Pubmed, Medline, Cochrane library, Embase and Proquest for articles related to polymeric micelle-based gene delivery in order to cancer gene therapy using the accommodative search terms. A database of the first search of all search engines results will be made and repeated articles will be removed. After that, the related articles will be selected, and also the references of selected articles will be searched in order to find any other articles to complete the search database.Results: This study reviews kinds of polymeric nanomicelles, which have been used in gene therapy, critical parameters for micelle-based gene delivery, challenges and advantages/disadvantages as well as biosafety of nanomicelles in gene delivery systems. Furthermore, the discussion has focused on stimuli-responsive polymers and strategy and mechanisms regarding tumor-selective gene delivery.Conclusions: This study provides an overview of the advantages/disadvantages of polymeric-based nanocarriers for cancer gene therapy. [ABSTRACT FROM AUTHOR]

Purpose: The survival benefit of neoadjuvant therapy for patients with borderline resectable pancreatic carcinoma has been reported recently. However, prognostic factors for this strategy have not been clearly elucidated. The aim of this study was to clarify prognostic factors for patients with borderline resectable pancreatic carcinoma who received neoadjuvant chemotherapy.Methods: Medical records of 66 patients with pancreatic carcinoma with arterial contact who intended to undergo tumor resection following neoadjuvant chemotherapy were analyzed retrospectively. Prognostic factors were investigated by analyzing the clinicopathological factors with univariate and multivariate survival analyses.Results: Gemcitabine plus S-1 was generally used as neoadjuvant chemotherapy. The objective response rate was 24%, and normalization of serum tumor markers following neoadjuvant chemotherapy was achieved in 29 patients (44%). Of the 66 patients, 60 patients underwent tumor resection and the remaining six patients did not due to distant metastases following neoadjuvant chemotherapy. For all 66 patients, overall 1-, 2-, and 5-year survival rates were 87.8, 54.5, and 20.5%, respectively (median survival time, 27.1 months) and multivariate analysis revealed that normalization of serum tumor markers was found to be an independent prognostic factor of better overall survival (P = 0.023). Moreover, for 60 patients who undergo tumor resection, normalization of serum tumor markers (P = 0.005) was independently associated with better overall survival by multivariate analysis.Conclusions: Patients with pancreatic carcinoma with arterial contact who undergo neoadjuvant chemotherapy and experience normalization of serum tumor markers thereafter may be good candidates for tumor resection. [ABSTRACT FROM AUTHOR]

Purpose: The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.Methods: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks.Results: Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2 and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug-drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease.Conclusions: The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2 (Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety, tolerability, pharmacokinetics, and efficacy of the intravenously administered pan-PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors.Methods: A Phase I open-label study in Japanese patients with advanced or refractory solid tumors was carried out. Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle. Safety was monitored throughout the study. Plasma copanlisib levels were measured for pharmacokinetic analysis.Results: Ten patients were enrolled and treated; three received copanlisib 0.4 mg/kg and seven received copanlisib 0.8 mg/kg. Overall, median duration of treatment was 6.2 weeks. No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity, and the maximum tolerated dose in Japanese patients was determined to be 0.8 mg/kg. Adverse events were recorded in all ten patients; the most common were hyperglycemia, hypertension, and constipation. Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation. No patients achieved a complete or partial response, and disease control rate was 40.0%.Conclusions: Copanlisib was well tolerated in Japanese patients with advanced or refractory solid tumors, and the maximum tolerated dose was determined to be 0.8 mg/kg. Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.Clinical Trial Registration Number: NCT01404390. [ABSTRACT FROM AUTHOR]

Purpose: Transcatheter arterial chemoembolization (TACE) is the treatment of choice for intermediate-stage hepatocellular carcinoma (HCC). The absence of an early response to TACE might indicate alternative therapeutic strategies early in the course of the disease, thus improving outcomes. Therefore, our purpose was to identify the relationship between treatment response after two sessions of TACE and the time to the development of extrahepatic metastasis and overall survival.Methods: In total, 108 treatment-naïve intermediate-stage HCC patients who received at least two consecutive sessions of TACE as the first-line treatment were analyzed.Results: The median follow-up duration was 28.5 months. Extrahepatic metastasis developed in 32 patients (29.6%). Patient age >60 years (P = 0.027), alpha-fetoprotein (AFP) >200 ng/ml (P = 0.039), and objective response after two TACE treatments (P = 0.001) were the predictive factors for time to the development of metastasis. The median survival time for the patients who achieved objective response after two sessions of TACE was 45.9 and 14.4 months for the patients who failed to achieve objective response (P = 0.0001). Objective response after two TACE treatments (P = 0.0001) and the occurrence of extrahepatic metastasis (P = 0.002) were associated with overall survival.Conclusions: Early objective tumor response after two sessions of TACE was associated with prolonged time to metastasis and improved survival. Therefore, surveillance for metastasis should be performed more frequently when an objective response is not obtained after two sessions of TACE and in younger intermediate-stage HCC patients with high AFP levels. [ABSTRACT FROM AUTHOR]

Purpose: There is still debated regarding the optimal treatment strategy for cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CCs.Methods: We retrospectively reviewed the patients who underwent R0 resection for intrahepatic and perihilar CCs between January 2001 and December 2013 at six tertiary medical centers; adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS).Results: We included a total of 137 consecutive patients in the analysis; 58.4% of them had intrahepatic CCs, and 25.5% had lymph node (LN) involvement. Seventy-three patients (53.3%) had received adjuvant therapy (CT, CRT, RT: 48, 13, 12, respectively), and most patients who had received adjuvant therapy had stage III or IVA, T3 or 4 tumors, and positive LNs. Multivariable analysis identified positive LN [hazard ratio (HR) 3.47; P < 0.001] and high baseline CA 19-9 level (HR 1.82; P = 0.027) as predictors of decreased OS. The effects of adjuvant therapy varied according to the treatment modality; adjuvant CRT showed significantly longer RFS than surgery only (HR 0.44; P = 0.036), with a nonsignificant trend for better OS (HR 0.46; P = 0.115).Conclusions: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CCs. CRT appears to be appropriate treatment after complete resection. [ABSTRACT FROM AUTHOR]

Purpose: Characterize the pharmacokinetics of oral crizotinib in children with cancer.Methods: Sixty-four children with solid tumors or anaplastic large-cell lymphoma (ALCL) enrolled on a phase 1/2 trial of the ALK, MET and ROS1 inhibitor, crizotinib, had pharmacokinetic sampling after the first dose (n = 15) or at steady state (n = 49). Dose levels studied were 100, 130, 165, 215, 280 and 365 mg/m2/dose administered twice daily. Two capsule and two oral liquid formulations were used over the course of the trial. Crizotinib was quantified with a validated HPLC/tandem mass spectrometry method with a lower limit of detection of 0.2 ng/mL. Pharmacokinetic parameters were derived using non-compartmental analysis.Results: Time to peak plasma concentration was 4 h. At 280 mg/m2 (MTD), mean (±SD) steady-state peak plasma concentration was 717 ± 201 ng/mL, and steady-state trough plasma concentration was 480 ± 176 ng/mL. At steady state, AUC0-τ was proportional to dose over the dose range of 215-365 mg/m2/dose. Apparent clearance of crizotinib was 731 ± 241 mL/min/m2. Steady-state AUC0-τ at 280 mg/m2/dose was 2.5-fold higher than the AUC0-∞ in adults receiving 250 mg (~140 mg/m2). Age, sex and drug formulation do not account for the inter-subject variability in AUC0-τ at steady state. The accumulation index was 4.9, and the half-life estimated from the accumulation index was 36 h.Conclusions: The pharmacokinetics of oral crizotinib in children is similar to that in adults. Steady-state trough-free crizotinib concentrations in plasma at the MTD exceed inhibitory concentrations of crizotinib in ALCL cell lines. CLINICALTRIALS.Gov Identifier: NCT00939770. [ABSTRACT FROM AUTHOR]

Purpose: Efficacy of targeted agents, such as everolimus and sunitinib, has been demonstrated in prospective trials on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Considering the heterogeneous clinicopathological characteristics of neuroendocrine tumors (NETs), evaluation of treatment outcomes in a real-world setting is necessary.Methods: Clinical records of 44 patients with GEP-NET who were treated with everolimus or sunitinib between March 2007 and October 2014 were retrospectively reviewed. Considering the distinct characteristics of pancreatic NETs (pNETs) and non-pancreatic gastrointestinal NETs (GI-NETs), efficacy analysis was performed separately.Results: Pancreas was the most common primary site (n = 28, 64%), followed by rectum (n = 10, 23%) and stomach (n = 3, 7%). Sunitinib and everolimus were administered in 27 (61%) and 17 (39%) patients, respectively. In patients with pNET, median progression-free survival (PFS) with everolimus and sunitinib was 16.6 months (95% CI 8.0-25.1) and 8.0 months (95% CI 0.0-17.4), respectively (p = 0.51). Among non-pancreatic GI-NET patients, median PFS with everolimus and sunitinib was 14.7 months (95% CI 2.4-27.0) and 1.7 months (95% CI 0.5-3.0), respectively (p = 0.001). Compared to patients treated with everolimus, tumor grade 3 (30 vs. 0%) and history of prior cytotoxic chemotherapy (70 vs. 50%) were more common in patients treated with sunitinib.Conclusions: Both everolimus and sunitinib were effective in GEP-NET patients. Outcomes of everolimus therapy in GEP-NETs were consistent with those reported elsewhere. Poor efficacy of sunitinib in non-pancreatic GI-NETs may be attributable to the baseline characteristics associated with poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Concurrent chemoradiotherapy (CRT) is the current standard of treatment for anal squamous carcinoma. However, local or metastatic recurrences remain significant after CRT with 5-fluorouracil (5-FU) and mitomycin C (MMC). Therefore, the present study evaluated the feasibility and efficacy of adding cisplatin to the classic CRT (5-FU, MMC, and radiotherapy).Methods: Twenty patients with histologically confirmed squamous cell carcinoma of the anus without metastatic disease were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between January 2005 and December 2014. The CRT comprised of two cycles of 5-FU 750 mg/m2 days 1-4, MMC 10 mg/m2 day 1, and cisplatin 60 mg/m2 day 1 every 4 weeks and radiotherapy (59.6 Gy in 33 daily fractions). The primary endpoint was to determine the feasibility of FMC, while the secondary endpoints were the pathologic complete response (pCR) rate at 8 weeks following the completion of CRT, progression-free survival (PFS), and overall survival (OS).Results: The treatment was generally well tolerated, and all patients received two cycles of FMC chemotherapy. Among the 20 patients, 17 were assessed for their pathologic response and 12 patients (70.6%) achieved pCR. The most common grade 3 or 4 hematologic toxicity was neutropenia (n = 3), while the most frequent severe non-hematologic toxicity was radiation dermatitis (n = 6, 30%). After a median follow-up duration of 45.5 months, the estimated 5-year PFS and overall survival rates were 88.9 and 88.1%, respectively.Conclusion: CRT with two cycles of a FMC regimen was found to be feasible for patients with anal squamous carcinoma. Further study is warranted to evaluate the efficacy of CRT with a FMC regimen. [ABSTRACT FROM AUTHOR]

Purpose: KML-001 (sodium metaarsenite) displaces hTERT from the nucleus and is synergistic with cisplatin. This phase I trial tested the tolerability, activity and pharmacology of this combination.Methods: Patients with advanced solid tumors that were "platinum sensitive," PS 0-1, normal renal and hepatic function were eligible. Treatment was with cisplatin 75 mg/m2 day 1 and KML-001 p.o. daily days 1-14 on a 21-day cycle. A standard 3 + 3 design was employed. Blood specimens for arsenic and platinum pharmacokinetics were obtained at 0, 1, 2, 3, 4, 5, 6, 24 h and days 8, 15 and 22.Results: Eighteen patients (7 M, 11 F) were evaluable for the primary endpoint of toxicity. Patients were heavily pretreated for a variety of malignancies (mean number of prior regimens = 3). Sixteen had prior platinum therapy. The dose-limiting toxicity was prolongation of the QTc interval, seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A documented response was seen in a patient with heavily pretreated SCLC in cohort one. Several other patients had reduction in tumor burden. In addition to the dose-limiting toxicity of QTc prolongation, the most common toxicities observed were nausea and vomiting and cytopenias. Myelosuppression was primarily seen in patients who had undergone prior radiotherapy.Conclusions: The combination of KML-001 and cisplatin was technically feasible and active. However, the occurrence of significant QTc prolongation led to discontinuation of the trial. This prolongation was likely a result of electrolyte abnormalities resulting from cisplatin superimposed on the known risks of arsenicals and QTc prolongation. Combinations with other platinum agents (e.g., carboplatin) should be considered. This is the first fully reported human trial of KML-001. [ABSTRACT FROM AUTHOR]

Purpose: A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.Methods: In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.Results: A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUClast, 0.95 (90 % CI 0.88-1.01); C max, 0.98 (90 % CI 0.91-1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.Conclusions: Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors. [ABSTRACT FROM AUTHOR]

Purpose: To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available.Methods: In this phase I study, patients aged ≥20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0-1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed.Results: Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1-4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations >40 µg/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients.Conclusions: Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle. [ABSTRACT FROM AUTHOR]

Purpose: Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia's formula (QTcF).Methods: Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points. Absence of clinically relevant QTcF effect was shown if the 95 % upper confidence bound (UCB) for the mean ∆∆QTcF was <10 ms for all time points. An exposure-response analysis was also performed.Results: Forty-seven patients were enrolled. Maximum mean ∆∆QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean ∆∆QTcF was 3.6 ms, with a 95 % UCB of 6.1 ms. No patient had a QTcF value >480 ms or change from baseline in QTcF interval >30 ms. Treatment-emergent adverse events (TEAEs) were experienced by 36.2, 48.9, and 47.8 % of patients while receiving veliparib 200 mg, veliparib 400 mg, and placebo, respectively. Most common TEAEs were nausea (12.8 %) and myalgia (8.5 %) after veliparib 200 mg, nausea (8.5 %) and vomiting (8.5 %) after veliparib 400 mg, and nausea (6.5 %) after placebo.Conclusions: Single-dose veliparib (200 mg or 400 mg) did not result in clinically significant QTc prolongation and was well tolerated in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Purpose: Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine.Methods: This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m2. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference.Results: A total of nine patients with advanced solid tumors were treated. Median t max for belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t 1/2 of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related.Conclusions: Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug-drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI).Methods: Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis.Results: Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83-1.05) for AUC(0-∞) and 1.04 (90 % CI 0.97-1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88-1.04) for AUC(0-∞) and 0.97 (90 % CI 0.85-1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients.Conclusions: There was no PK drug-drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this pilot study is to confirm the safety and efficacy of neoadjuvant therapy and also treatment duration efficacy using modified FOLFIRINOX for patients with borderline resectable pancreatic cancer (BRPC).Methods: The study is a prospective multicenter pilot trial conducted on patients with BRPC. Intervention for clinical trials: Modified FOLFIRINOX (without bolus 5-FU and LV, also decreased the dose of irinotecan; FIRINOX) was given to the first five patients in the 4-cycle group of the regimen and next five patients in the 8-cycle group. The primary end point was the toxicity of the therapy and one of the secondary end points were the optimal duration.Results: The overall rate of grade 3 and 4 events was 80 %: 3 patients (60 %) in the four-cycle group and five patients (100 %) in the eight-cycle group had grade 3 or 4 adverse events. There was no incidence of serious adverse effect such as febrile neutropenia, sepsis, liver abscess or uncontrollable diarrhea. There was no clinically relevant morbidity presented in patients who underwent surgery. R0 rates by intention to treat were 60.0 % in the four-cycle group and 40 % in the eight-cycle group (P = 0.999). The histopathologic treatment effect based on the Evans grade revealed grade I (n = 1), IIa (n = 3) in the four-cycle group and grade I (n = 2), IIa (n = 1) in the eight-cycle group.Conclusions: FIRINOX therapy was feasible and safe for strictly selected patients with BRPC. Four cycles of FIRINOX would be sufficient for patients with BRPC as neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Purpose: Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) copy number (mtDNAcn) and relative telomere length (RTL) may be implicated in the tumorigenesis of several malignancies. Alterations of both RTL and mtDNAcn are generally accepted as independent biomarkers for predicting risk and prognosis in various cancers. The aim of this study was to evaluate the prognostic value of combining leukocyte RTL with mtDNAcn (RTL-mtDNAcn) in hepatocellular carcinoma (HCC).Methods: RTL and mtDNAcn in peripheral blood leukocytes (PBLs) were measured using a real-time PCR-based method in a total of 250 HCC patients treated with transcatheter arterial chemoembolization (TACE). We evaluated the associations between RTL and/or mtDNAcn and HCC overall survival using Kaplan-Meier curve analysis and Cox proportional hazards regression model.Results: We found that patients with longer leukocyte RTL or lower mtDNAcn had shorter overall survival time. The univariate analysis (HR 1.63, 95 % CI 1.23-2.17, P = 7.7 × 10(-4)) and multivariate analysis (HR 1.78, 95 % CI 1.31-2.42, P = 2.4 × 10(-4)) indicated that longer leukocyte RTL was significantly associated with poorer OS in HCC patients. Kaplan-Meier curve analysis showed that patients with longer RTL had shorter overall survival time than those with shorter RTL (log-rank P = 0.001). Patients with lower mtDNA copy number was significantly associated with poorer OS by Cox proportional hazards model using both univariate (HR 1.60, 95 % CI 1.21-2.13, P = 0.001) and multivariate analyses (HR 1.77, 95 % CI 1.30-2.41, P = 2.8 × 10(-4)). Kaplan-Meier curve analysis showed that patients with lower mtDNA content had significantly shorter overall survival time than those with higher mtDNA content (log-rank P = 0.001). Furthermore, combination of leukocyte RTL and mtDNAcn significantly improved the efficacy of predicting HCC prognosis. Patients with longer RTL and lower mtDNAcn exhibited a significantly poorer overall survival in both the univariate analysis (HR 2.21, 95 % CI 1.52-3.22, P = 3.5 × 10(-5)) and multivariate analysis (HR 2.60, 95 % CI 1.73-3.90, P = 4.3 × 10(-6)). The effect on patient prognosis was more evident in patients with longer RTL and lower mtDNAcn than in those with shorter RTL and lower mtDNA (HR 2.11, 95 % CI 1.34-3.32, P = 0.001) or in those with longer RTL and higher mtDNA (HR 2.10, 95 % CI 1.34-3.27, P = 0.001).Conclusions: Our data suggest that combination of leukocyte RTL-mtDNAcn may be a potential efficient prognostic marker for HCC patients receiving the TACE treatment. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the clinical activity and toxicity of (131)I-rituximab as consolidation therapy for patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone).Methods: Patients who had been diagnosed with advanced stage (Ann Arbor III or IV) or bulky stage II DLBCL and achieved complete or partial response after six to eight cycles of R-CHOP were enrolled.Results: A total of 16 patients were enrolled and treated with a single dose of (131)I-rituximab as consolidation therapy after the completion of six or eight cycles of R-CHOP between December 2005 and June 2011. This trial was terminated before the scheduled enrollment owing to low recruitment. Among the 16 patients who were treated with consolidative (131)I-rituximab, 6 achieved complete response (CR) after three cycles of R-CHOP, and another 9 patients further achieved CR after the completion of six or eight cycles of R-CHOP. During the median follow-up period of 73 months, only four patients (25 %) experienced relapse. Two-year relapse-free survival was 88 %, and 5-year relapse-free survival was 81 %. Grade 3 or 4 treatment-related toxicity occurred in four patients and included neutropenia and thrombocytopenia.Conclusions: (131)I-rituximab showed promising efficacy as consolidation treatment for patients with DLBCL. A future randomized phase III study to confirm our results is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Xenograft studies are commonly used to assess the efficacy of new compounds and characterise their dose-response relationship. Analysis often involves comparing the final tumour sizes across dose groups. This can cause bias, as often in xenograft studies a tumour burden limit (TBL) is imposed for ethical reasons, leading to the animals with the largest tumours being excluded from the final analysis. This means the average tumour size, particularly in the control group, is underestimated, leading to an underestimate of the treatment effect.Methods: Four methods to account for dropout due to the TBL are proposed, which use all the available data instead of only final observations: modelling, pattern mixture models, treating dropouts as censored using the M3 method and joint modelling of tumour growth and dropout. The methods were applied to both a simulated data set and a real example.Results: All four proposed methods led to an improvement in the estimate of treatment effect in the simulated data. The joint modelling method performed most strongly, with the censoring method also providing a good estimate of the treatment effect, but with higher uncertainty. In the real data example, the dose-response estimated using the censoring and joint modelling methods was higher than the very flat curve estimated from average final measurements.Conclusions: Accounting for dropout using the proposed censoring or joint modelling methods allows the treatment effect to be recovered in studies where it may have been obscured due to dropout caused by the TBL. [ABSTRACT FROM AUTHOR]

Purpose: Standard care for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is concurrent chemoradiotherapy, but survival remains limited. Neoadjuvant chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) has demonstrated promising activity, with a pathological complete response (CR) of 17 % for resectable stage II/III ESCC. Here, we conducted a multicenter study to assess the efficacy and safety of induction chemotherapy with DCF followed by CRT in patients with unresectable locally advanced ESCC.Methods: Eligibility criteria included clinical T4 and/or M1 lymph node ESCC, PS 0-1 and age 20-70 years. Treatment consisted of docetaxel 70 mg/m(2) and cisplatin 70 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1-5, repeated every 3 weeks for three cycles, followed by cisplatin 70 mg/m(2) on days 64 and 92, and fluorouracil 700 mg/m(2) on days 64-67 and 92-95, concurrently with radiotherapy (60 Gy in 30 fractions, 5 days/week). Primary endpoint of the phase II part was CR rate.Results: Thirty-three patients were enrolled. The completion rate of protocol treatment was 88 %. Thirteen patients (39.4 %) achieved a CR. With a median follow-up period of 41 months (range 24-49 months), median progression-free survival was 12.2 months, and median survival was 26.0 months, with a survival rate of 40.4 % at 3 years. The most common grade 3 or 4 toxicities were neutropenia, leukopenia, anorexia and dysphagia. No treatment-related death was observed.Conclusion: Induction chemotherapy with DCF followed by CRT is tolerable and shows promising efficacy for unresectable locally advanced ESCC. [ABSTRACT FROM AUTHOR]