Topoisomerase IIIß Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice.

Topoisomerase IIIß (Top3ß), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3ß with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3ß on neuro-behavior using newly generated Top3ß deficient (Top3ß-/-) mice. We found that Top3ß-/- mice showed decreased anxiety and depression-like behaviors. The lack of Top3ß was also associated with changes in circadian rhythm. In addition, a clear expression of Top3ß was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3ß-/- mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3ß is essential for normal brain function and behavior in mice and that Top3ß could be an interesting target to study neuropsychiatric disorders in humans.

Importin-11 is Essential for Normal Embryonic Development in Mice.

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in Ipo11 gene utilized by gene trapping. The Ipo11-/- embryos showed an embryonic lethal phenotype. The Ipo11-/- embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with Ipo11+/+ or Ipo11+/- embryos and died by E11.5. Whereas Ipo11+/- mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the Ipo11-/- or Ipo11+/- embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.

A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

Anhedonia in depressed patients on treatment with selective serotonin reuptake inhibitor anti-depressant--A two-centered study in Malaysia.

OBJECTIVE: Anhedonia is the reduced ability to experience pleasure. It is a core symptom of depression and is particularly difficult to treat. This study aims to compare the level of anhedonia between depressed patients on anti-depressants and healthy subjects. METHOD: A total of 111 depressed patients on selective serotonin reuptake inhibitor (SSRI) and 82 healthy subjects were recruited from the outpatient psychiatric services at two major general hospitals in a cross-sectional study. Subjects were assessed using the Mini International Neuropsychiatric Interview 5.0.0 or MINI, Beck's Depression Index (BDI), and Snaith-Hamilton Pleasure Scale (SHAPS). Relevant personal and sociodemographic information were also collected. RESULTS: There was a significant association between educational level and SHAPS-M scores (P < 0.01) among the participants. Most items in the SHAPS scores were significantly different (P < 0.01) in the depressed subjects treated with anti-depressant compared with the healthy subjects, after adjusting the confounding factors, BDI score, and educational level. CONCLUSION: Anhedonia often persists in depressed patients despite on SSRI anti-depressant treatment.

Stability of mandibular setback surgery with and without presurgical orthodontics.

PURPOSE: The purpose of this study was to compare stability after mandibular setback surgery in patients with skeletal Class III malocclusion with and without presurgical orthodontics. MATERIALS AND METHODS: This retrospective cohort study included consecutive patients with skeletal Class III malocclusion who underwent only mandibular surgery. Patients treated with the surgery-first approach without presurgical orthodontics (SF group) were compared with a control group (conventional surgery with presurgical orthodontics; CS group) using lateral cephalograms taken preoperatively, immediately postoperatively, and at the time of debonding. Predictor variables (group and timing), outcome variables (cephalometric measurements over time), and other variables, such as baseline characteristics, were evaluated to determine the difference in stability of mandibular positions such as the B point. RESULTS: Sixty-one patients were enrolled in this study (CS group, n = 38; SF group, n = 23). Baseline demographic variables were similar in the 2 groups except for orthodontic treatment period. The mean setback of the mandible at the B point was similar (CS group, 8.7 mm; SF group, 9.1 mm; difference, P > .05), but the horizontal relapse in the SF group (2.4 mm) was significantly greater than in the CS group (1.6 mm; P < .05). Patients with a horizontal relapse greater than 3 mm comprised 39.1% of the SF group compared with 15.8% of the CS group (P < .05). CONCLUSION: Mandibular sagittal split ramus osteotomy without presurgical orthodontic treatment was less stable than conventional orthognathic surgery for mandibular prognathism. Before performing a surgery-first approach, skeletal stability needs to be considered.

Validation of Malay Version of Snaith-Hamilton Pleasure Scale: Comparison between Depressed Patients and Healthy Subjects at an Out-Patient Clinic in Malaysia.

BACKGROUND: The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-assessment scale designed to evaluate anhedonia in various psychiatric disorders. In order to facilitate its use in Malaysian settings, our current study aimed to examine the validity of a Malay-translated version of the SHAPS (SHAPS-M). METHODS: In this cross-sectional study, a total of 44 depressed patients and 82 healthy subjects were recruited from a university out-patient clinic. All participants were given both the Malay and English versions of the SHAPS, Fawcett-Clark Pleasure Scale (FCPS), General Health Questionnaire 12 (GHQ-12), and the Beck Depression Inventory (BDI) to assess their hedonic state, general mental health condition and levels of depression. RESULTS: The results showed that the SHAPS-M has impressive internal consistency (α = 0.96), concurrent validity and good parallel-form reliability (intraclass coefficient, ICC = 0.65). CONCLUSION: In addition to demonstrating good psychometric properties, the SHAPS-M is easy to administer. Therefore, it is a valid, reliable, and suitable questionnaire for assessing anhedonia among depressed patients in Malaysia.

Genome sequence of the Brown Norway rat yields insights into mammalian evolution.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Oxidation of refractory sulfur compounds over Ti-containing mesoporous molecular sieves prepared by using a fluorosilicon compound.

Titanium containing mesoporous molecular sieve (Ti-MMS) catalysts were studied for the oxidative desulfurization of refractory sulfur compounds. Ti-MMS catalysts were synthesized from fluorosilicon compounds and Ti with the hydrolysis reaction of H2SiF6 in an ammonia-surfactant mixed solution. The solid products were characterized by XRD, XRF, nitrogen adsorption, and diffuse reflectance UV-vis spectroscopy. Effects of Ti loading and oxidant/sulfur mole ratio, and sulfur species on ODS activity were investigated.

Study of an experimental microthreaded scalloped implant design: proximal bone healing at different interimplant distances in a canine model.

PURPOSE: The aim of the present study was to evaluate the validity of a new experimental microthreaded scalloped (MTS) implant design in comparison to a conventional flat-top (FT) implant by measuring the proximal bone loss at different interimplant distances in a canine model. MATERIALS AND METHODS: MTS implants were placed in one side of the posterior mandible and conventional flat-top (FT) implants were placed in the other side of the mandible in 10 beagle dogs. In five dogs, four each of the MTS and FT implants were placed with an interimplant distance of 2 mm. In another five dogs, three each of the MTS and FT implants were placed at an interimplant distance of 5 mm. All 70 implants (35 MTS and 35 FT implants) were placed in a nonsubmerged (one-stage) manner. The animals were sacrificed 4 months after implant placement, and the crestal bone levels around the MTS and FT implants were measured and compared on radiographs and histologic sections. RESULTS: The experimental MTS implants showed significantly less crestal bone loss (0.81 ± 0.34 mm) than the FT implants (1.60 ± 0.42 mm) on radiographs (P < .001). Histologic measurement also demonstrated that there was significantly less (P < .001) marginal bone loss around the MTS implants (0.74 ± 0.41 mm) than around the FT implants (1.53 ± 0.52 mm). There was no statistically significant difference in bone loss between the 2-mm and 5-mm interimplant distances for either MTS or FT implants (P > .05). CONCLUSION: The experimental MTS implant was more effective in preserving the proximal bone than the conventional FT external-hex implant with the same surface. In this canine model, placement of the implants at either a 2-mm and or a 5-mm interimplant distance did not result in significant differences in marginal bone loss for both MTS and FT implants. This experiment demonstrated a potential benefit of the microthread design on a scalloped implant.

FTIR studies of CO adsorption on Al2O3- and SiO2-supported Ru catalysts.

The adsorption of CO on Al2O3- and SiO2-supported Ru catalysts has been investigated through FTIR spectroscopy. Deconvolution of the spectra obtained reveals the presence of 11 distinct bands in the case of Ru/Al2O3 and 10 bands in the case of Ru/SiO2, which were assigned to different carbonyl species adsorbed on reduced as well as partially oxidized Ru sites. Although most of these bands on both supports are similar, they exhibit substantial differences in terms of stability. In general, the analogous CO species on Ru/Al2O3 are adsorbed stronger than those on Ru/SiO2, with the most stable species observed being a dicarbonyl adsorbed on metallic Ru (i.e., Ru0(CO)2). Following sintering of the Ru, the ratio of multicarbonyl to monocarbonyl adsorption is reduced substantially because of the lack of isolated sites or small Ru clusters that enable the formation of multicarbonyl species via oxidative disruption. Finally, in the presence of O2, the main features observed correspond to monocarbonyl, dicarbonyl, and tricarbonyl species adsorbed on partially oxidized Run+. The intensities of all bands decrease drastically at temperatures above 210 degrees C because of the onset of CO oxidation, which results in substantially reduced surface coverage.

A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix.

Squamous cell carcinomas of the head and neck (HNSCC) and of the cervix (CC) are particularly sensitive to the apoptotic effects of lovastatin in vitro. In this Phase I study, the safety and maximum related dose (MTD) of lovastatin was evaluated in these specific clinical settings. This was a Phase I open-label study to determine the recommended Phase II dose (RPTD) of lovastatin in advanced HNSCC or CC. This study involved a dose and duration escalation of lovastatin starting at 5/mg/kg/day x 2 weeks, every 21 days, until the MTD was reached. Plasma samples were collected for pharmacokinetic analysis. All 26 patients enrolled were evaluable. Dose-limiting toxicity (DLT) consisting of reversible muscle toxicity was seen at 10 mg/kg/day x 14 days. Toxicity may be related to relative renal insufficiency. The MTD was determined to be 7.5 mg/kg/day x 21 days, every 28 days. The low lipid levels experienced on study did not translate into adverse events. Biologically relevant plasma lovastatin levels were obtained. No objective responses were seen but the median survival of patients on study was 7.5 months (mean 9.2 +/- 1.5 months). Stable disease (SD) for more than 3 months was seen in 23% of patients. One patient achieved SD and clinical benefit for 14 months on study and a further 23 months off treatment. The disease stabilisation rate of 23% seen in these end-stage patients is encouraging. We conclude that the administration of lovastatin at 7.5 mg/kg/day for 21 consecutive days on a 28-day schedule is well tolerated in patients with good renal function and warrants further clinical evaluation.

Effects of reduction temperature and metal-support interactions on the catalytic activity of Pt/gamma-Al2O3 and Pt/TiO2 for the oxidation of CO in the presence and absence of H2.

TiO2- and gamma-Al2O3-supported Pt catalysts were characterized by HRTEM, XPS, EXAFS, and in situ FTIR spectroscopy after activation at various conditions, and their catalytic properties were examined for the oxidation of CO in the absence and presence of H2 (PROX). When gamma-Al2O3 was used as the support, the catalytic, electronic, and structural properties of the Pt particles formed were not affected substantially by the pretreatment conditions. In contrast, the surface properties and catalytic activity of Pt/TiO2 were strongly influenced by the pretreatment conditions. In this case, an increase in the reduction temperature led to higher electron density on Pt, altering its chemisorptive properties, weakening the Pt-CO bonds, and increasing its activity for the oxidation of CO. The in situ FTIR data suggest that both the terminal and bridging CO species adsorbed on fully reduced Pt are active for this reaction. The high activity of Pt/TiO2 for the oxidation of CO can also be attributed to the ability of TiO2 to provide or stabilize highly reactive oxygen species at the metal-support interface. However, such species appear to be more reactive toward H2 than CO. Consequently, Pt/TiO2 shows substantially lower selectivities toward CO oxidation under PROX conditions than Pt/gamma-Al2O3.

The evaluation of a scoring system in airway management after oral cancer surgery.

BACKGROUND: The purpose of this retrospective study was to investigate the usefulness of tracheostomy scoring system in the decision of postoperative airway management in oral cancer patients. MATERIALS AND METHODS: A total of 104 patients were reviewed in this retrospective study, who underwent radical resection with or without neck dissection and free flap reconstruction due to oral cancer. The patients were classified into three groups according to the timing of the extubation; extubated groups (n = 51), overnight intubation group (n = 45), and tracheostomy group (n = 8). Cameron's score was used to evaluate the relation between the state of the patient's airway and the type of the operation. RESULTS: Tracheostomy was performed in eight patients (8/104, 7.7 %). A total of 22 patients (21.2 %) had more than 5 points of which 17 patients (77.3 %) did not have a tracheostomy and any postoperative emergency airway problems. The tracheostomy scores were significantly different among the three groups. Hospital stay showed a significant correlation with the tracheostomy score. CONCLUSIONS: The scoring system did not quite agree with the airway management of the authors' clinic; however, it can be one of the clinical factors predicting the degree of the postoperative airway obstruction and surgical aggressiveness for recovery. The further studies are needed for clinically more reliable scoring systems.

Expression of transient receptor potential ankyrin 1 in human dental pulp.

INTRODUCTION: Transient receptor potential ankyrin 1 (TRPA1) is activated by noxious cold (<17°C) and contributes to cold and mechanical hypersensitivity after inflammation and nerve injury. METHODS: To investigate whether TRPA1 is involved in the mediation of nociception, including noxious cold and cold hypersensitivity in teeth, we examined the expression of TRPA1 and sodium channel Nav1.8 in human dental pulp using fluorescent and electron microscopic immunocytochemistry. RESULTS: TRPA1 was expressed in a large number of axons branching extensively in the peripheral pulp and in a few axons within the nerve bundles in the core of the coronal pulp and in the radicular pulp. Under electron microscopy, TRPA1 immunoreactivity was typically localized near the plasma membrane of unmyelinated axons in the peripheral pulp, suggesting that in these axons it may act as a functional receptor. The proportion of axons expressing TRPA1 in neurofilament 200-positive axons significantly increased in the painful pulp compared with the normal pulp. TRPA1 was also densely expressed in the processes and the cell body of odontoblasts. A large number of axons coexpressed TRPA1 and Nav1.8. CONCLUSIONS: These findings support the notion that TRPA1 is involved in the perception of noxious cold and cold hypersensitivity in human dental pulp and that TRPA1-mediated nociception is primarily mediated by axons and odontoblasts in the peripheral pulp.

Aspirin induces apoptosis in YD-8 human oral squamous carcinoma cells through activation of caspases, down-regulation of Mcl-1, and inactivation of ERK-1/2 and AKT.

NSAIDs and COX-2 inhibitors show anti-cancer activities in many cancer cells. In this study, we investigated the effects of NSAIDs (aspirin or indomethacin) and COX-2 inhibitor (NS-398) on growth of YD-8 human oral squamous carcinoma cells. Interestingly, among drugs tested, aspirin showed strongest inhibitory effects on viability and survival of YD-8 cells. Profoundly, aspirin treatment resulted in severe cell shrinkage and nuclear DNA fragmentation in YD-8 cells, suggesting the aspirin-induced apoptosis in YD-8 cells. Data of Western blot further demonstrated that aspirin treatment caused activation of caspases, down-regulation of Mcl-1 protein, dephosphorylation of ERK-1/2 and AKT, and also IkappaB-alpha proteolysis-dependent NF-kappaB activation in YD-8 cells. Aspirin, however, had no effect on expressions of Bcl-2, XIAP, and HIAP-1 in YD-8 cells. Importantly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor blocked the aspirin-induced apoptosis and Mcl-1 down-regulation in YD-8 cells. These findings collectively suggest that aspirin induces apoptosis in YD-8 cells and the induction may be correlated to activation of caspases, caspase-dependent Mcl-1 proteolysis, inactivation of ERK-1/2 and AKT, and activation of NF-kappaB. It is suggested that aspirin may be applied a potential anti-cancer drug against human oral squamous carcinoma.

Impact of a print intervention to increase annual mammography screening among Korean American women enrolled in the National Breast and Cervical Cancer Early Detection Program.

BACKGROUND: Although Korean American women have one of the lowest rates of mammography screening, only few interventions have been developed for them. We developed a theory-based Korean-language print intervention to increase annual mammography screening with the goal to disseminate it through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: Korean American staff and patients at a community clinic advised on the content and layout of the brochure. We pilot tested the intervention from July to September 2005 at a community clinic in Koreatown, Los Angeles County that provides free mammograms through the NBCCEDP. The proportion of Korean American women who received a repeat mammogram during the intervention period was compared to the pre-intervention period using a NBCCEDP database. RESULTS: We found a non-significant 6 percentage point increase in repeat screening from 32% to 38%. A debriefing survey with a subsample of 59 women revealed that only 32% recalled receipt of the brochure and a subsequent investigation revealed that only about 60% had identical address information in the NBCCEDP records and in their charts. CONCLUSIONS: Although dissemination of print information through NBCCEDP is very feasible, the reach and effectiveness of the intervention was limited due to incorrect or outdated address information.

Sorafenib for metastatic renal cancer: the Princess Margaret experience.

OBJECTIVE: Sorafenib, an oral multikinase inhibitor, prolonged progression-free survival when compared with placebo, as second-line therapy for patients with metastatic renal carcinoma (MRC). Grade 3/4 adverse events were reported in 12% of patients. This study presents sorafenib's efficacy and safety in a less selected cohort of patients enrolled in an expanded access program. METHODS: Patients with MRC received sorafenib 400 mg twice daily until disease progression. Tumor response was evaluated by RECIST criteria. Adverse events were graded by NCI common toxicity criteria. RESULTS: From November 2005 to August 2006, 58 patients were enrolled. The median progression-free survival was 7.5 months (95% CI: 5.4-11.3), and the best responses among 54 patients were 11 (20%) confirmed partial responses, 15 (28%) stable diseases for > or =6 months; 10 patients (18%) had early progression at 8 weeks. Grade 3/4 adverse events occurred in 37 patients (64%; 95% CI: 50%-76%), the most frequent being skin rash in 17 patients (29%), and hand-foot syndrome in 9 patients (15%). Thirty-six (62%) patients required dose reductions and/or treatment interruptions. CONCLUSIONS: Sorafenib is effective in a less selected patient population with MRC but leads to more toxicity than described previously.

Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma.

PURPOSE: To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had

Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study.

PURPOSE: To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. RESULTS: A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034). CONCLUSION: This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.

Phase I trial of gemcitabine, doxorubicin and cisplatin (GAP) in patients with advanced solid tumors.

A phase I study was conducted to determine the recommended phase II dose, safety profile and anti-tumor activity of a combination regimen of gemcitabine, doxorubicin and cisplatin (GAP). Gemcitabine (G) and doxorubicin (A) were administered on days 1 and 8 at increasing doses (starting level 800 and 15 mg/m, respectively). Cisplatin (P) was given at a fixed dose of 50 mg/m2 (day 1). Treatment cycles were repeated every 3 weeks. Nineteen patients received 76 cycles of treatment. A and G were escalated up to 20 and 1000 mg/m2, and finally de-escalated to 15 and 800 mg/m2. The dose-limiting toxicity was neutropenic fever that was observed in 21% of the patients. Non-hematological toxicities included mild/moderate nausea, vomiting, diarrhea and fatigue, observed in 58, 37, 21 and 95% of the patients, respectively. Of 19 patients with evaluable disease, six patients had a partial response yielding an overall response rate of 31.6 % (95% confidence interval 12.6-56.6%) by intention-to-treat. We conclude that GAP is an active and tolerable treatment combination, with minimal visceral organ toxicities.