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1.  Breakthrough cancer medicine and its impact on novel drug development in China: report of the US Chinese Anti-Cancer Association (USCACA) and Chinese Society of Clinical Oncology (CSCO) Joint Session at the 17th CSCO Annual Meeting 
Chinese Journal of Cancer  2014;33(12):620-624.
The US Chinese Anti-Cancer Association (USCACA) teamed up with Chinese Society of Clinical Oncology (CSCO) to host a joint session at the17th CSCO Annual Meeting on September 20th, 2014 in Xiamen, China. With a focus on breakthrough cancer medicines, the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China. The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China. A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.
doi:10.5732/cjc.014.10246
PMCID: PMC4308658  PMID: 25418191
Breakthrough; clinical trial; cancer medicine
2.  Selectively targeting the toll-like receptor 9 (TLR9) – IRF 7 signaling pathway by polymer blend particles 
Biomaterials  2013;34(27):6464-6472.
Signaling through toll-like receptor 9 (TLR9) has been exploited for cancer therapy. The stimulation of TLR9 leads to two bifurcating signaling pathways – NF-κB-dependent pro-inflammatory cytokines pathway and IRF-7-dependent type I interferons (IFNs) pathway. In this study, we employ polymer blend particles to present the synthetic ligand, CpG oligonucleotides (CpG ODNs) to TLR9. The polymer blend particles are made from the blend of pH-insensitive and pH-sensitive copolymer. By tailoring the composition of the pH-sensitive polymer, CpG ODNs are presented to TLR9 in a way that only activates the IRF-7 signaling pathway. CpG ODNs have been used for cancer therapy in both preclinical and clinical studies. The selective activation of IRF-7 could potentially enhance the apoptosis of tumor cells and immunological control of tumor progression without inadvertently activating NF-κB-dependent oncogenesis.
doi:10.1016/j.biomaterials.2013.05.016
PMCID: PMC3696521  PMID: 23755833
pH-sensitive polymer; carcinogenesis; inflammation; apoptosis; immunotherapy
3.  Immune checkpoint inhibitors in clinical trials 
Chinese Journal of Cancer  2014;33(9):434-444.
Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called “immune checkpoints.” These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody-based therapies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.
doi:10.5732/cjc.014.10122
PMCID: PMC4190433  PMID: 25189716
Immune checkpoints; PD-1; PD-L1; CTLA4; immunotherapy; immune modulators
4.  Cancer immunotherapy 
Chinese Journal of Cancer  2014;33(9):413-415.
doi:10.5732/cjc.014.10153
PMCID: PMC4190430  PMID: 25478631
5.  Overcoming Platinum Drug Resistance with Copper-lowering Agents 
Anticancer research  2013;33(10):4157-4161.
Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, up-regulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Cu-lowering agents through enhanced hCtr1 expression by up-regulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy.
PMCID: PMC4001922  PMID: 24122978
Cisplatin; high-affinity human copper transporter 1 (hCtr1); copper chelator; review
6.  Are We Ready for the 10% Solution? 
The Oncologist  2014;19(5):439-440.
The limitations of the Response Evaluation Criteria in Solid Tumors (RECIST) for the assessment of molecularly targeted agents have been increasingly recognized with the advance of new therapies. The current study and others focusing on vascular endothelial growth factor-pathway inhibitors in advanced renal cell carcinoma highlight that tumor shrinkage below the RECIST threshold can be associated with significant clinical benefit, and flexibility in size change categorization should be considered in future modification of the criteria.
doi:10.1634/theoncologist.2014-0126
PMCID: PMC4012974  PMID: 24755462
7.  Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial 
The lancet oncology  2013;14(4):371-382.
Summary
Background
Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
Methods
We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
Findings
Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
Interpretation
The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
Funding
National Cancer Institute and Cycle for Survival Fund, Memorial Sloan-Kettering Cancer Center.
doi:10.1016/S1470-2045(13)70049-4
PMCID: PMC3766955  PMID: 23477833
8.  Incidence of Mucositis in Patients Treated With Temsirolimus-Based Regimens and Correlation to Treatment Response 
The Oncologist  2014;19(4):426-428.
Mucositis may limit the therapeutic window for mammalian target of rapamycin inhibitor-based combination therapy, necessitating treatment interruptions and/or dose reductions. Optimizing treatment or prophylactic interventions for mucositis will enable patients to continue effective treatment while maintaining good quality of life.
doi:10.1634/theoncologist.2013-0231
PMCID: PMC3983812  PMID: 24668327
9.  Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors 
SUMMARY
Purpose
Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).
Experimental Design
Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months.
Results
Twenty patients (17 with Ewing’s sarcoma [EWS], 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled). Twelve patients (60%) were men; median age, 24 years; median number of prior systemic therapies in metastatic setting, 6. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1–2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses. Tumor regression of over 20% (23%, 23%, 27%, 100%, 100%) occurred in 5/17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six EWS patients who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose.
Conclusion
Cixutumumab combined with temsirolimus was well tolerated and showed preliminary evidence of durable antitumor activity in heavily-pretreated EWS family tumors.
doi:10.1158/1078-0432.CCR-12-0061
PMCID: PMC3875297  PMID: 22465830
Phase I clinical trials; IGF-1R pathway; mTOR pathway; Ewing’s sarcoma; Desmoplastic small-round-cell tumor
10.  Estimating the lifelong health impact and financial burdens of different types of lung cancer 
BMC Cancer  2013;13:579.
Background
Owing to the high mortality and rapidly growing costs related to lung cancer, it is worth examining the health benefits of prevention for major types of lung cancer. This study attempts to quantify the quality-adjusted life expectancy (QALE), loss-of-QALE, and lifetime healthcare expenditures of patients with different pathological types of lung cancer.
Methods
A national cohort consisting of 66,535 patients with pathologically verified lung cancer was followed for 13 years (1998–2010) to obtain the survival function, which was further extrapolated to lifetime. Between 2011 and 2012, EuroQol 5-dimension questionnaires were used to measure the quality of life (QoL) for 1,314 consecutive, cross-sectional samples. After multiplying the lifetime survival function by the utility values of QoL, we estimated the QALE and loss-of-QALE. We also collected the monthly healthcare expenditures, which included National Health Insurance-reimbursed and out-of-pocket direct medical costs, for 2,456 patients from 2005 to 2012. These values were multiplied by the corresponding survival probabilities to calculate lifetime healthcare expenditures after adjustments with medical care inflation rates and annual discount rates.
Results
The QALE for patients with small cell lung cancer, squamous cell carcinoma, and adenocarcinoma were 1.21, 2.37, and 3.03 quality-adjusted life year (QALY), with the corresponding loss-of-QALE of 13.69, 12.22, and 15.03 QALY, respectively. The lifetime healthcare expenditures were US$ 18,455 ± 1,137, 20,599 ± 1,787, and 36,771 ± 1,998, respectively.
Conclusions
The lifelong health impact and financial burdens in Taiwan are heavier for adenocarcinoma than for squamous cell carcinoma. The cost-effectiveness of prevention programs could be directly compared with that of treatment strategies to improve patient value. And the methodology could be applied to other chronic diseases for resources planning of healthcare services.
doi:10.1186/1471-2407-13-579
PMCID: PMC4234193  PMID: 24308346
Lung cancer prevention; Life expectancy; Quality-adjusted life expectancy; Costs; Out-of-pocket money
11.  Mechanistic Basis for Overcoming Platinum Resistance Using Copper Chelating Agents 
Molecular cancer therapeutics  2012;11(11):2483-2494.
Platinum (Pt)-based antitumor agents are widely used in cancer chemotherapy. Drug resistance is a major obstacle to the successful use of these agents because once drug resistance develops, other effective treatment options are limited. Recently, we have conducted a clinical trial using a copper (Cu)-lowering agent to overcome Pt drug resistance in ovarian cancer patients and the preliminary results are encouraging. In supporting this clinical study, using three pairs of cisplatin (cDDP)-resistant cell lines and two ovarian cancer cell lines derived from patients who had failed in Pt-based chemotherapy, we demonstrated that cDDP resistance associated with reduced expression of the high affinity copper transporter (hCtr1) which is also a cDDP transporter, can be preferentially re-sensitized by copper-lowering agents due to enhanced hCtr1 expression, as compared with their drug-sensitive counterparts. Such a preferential induction of hCtr1 expression in cDDP-resistant variants by Cu chelation can be explained by the mammalian Cu homeostasis regulatory mechanism. Enhanced cell-killing efficacy by a Cu-lowering agent was also observed in animal xenografts bearing cDDP-resistant cells. Finally, by analyzing a public gene expression dataset, we found that ovarian cancer patients with elevated levels of hCtr1 in their tumors, but not ATP7A and ATP7B, had more favorable outcomes after Pt-drug treatment than those expressing low hCtr1 levels. This study reveals the mechanistic basis for using Cu chelation to overcome cDDP resistance in clinical investigations.
doi:10.1158/1535-7163.MCT-12-0580
PMCID: PMC3496003  PMID: 22914438
Cisplatin; high-affinity copper transporter; Cu-lowering agents; drug-resistance
12.  Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals 
Platinum-based antitumor agents have been the mainstay in cancer chemotherapy for many human malignancies. Drug resistance is an important obstacle to achieving the maximal therapeutic efficacy of these drugs. Understanding how platinum drugs enter cells is of great importance in improving therapeutic efficacy. It has been demonstrated that human high-affinity copper transporter 1 (hCtr1) is involved in transporting cisplatin into cells to elicit cytotoxic effects, although other mechanisms may exist. In this communication, we demonstrate that cisplatin transcriptionally induces the expression of hCtr1 in time- and concentration-dependent manners. Cisplatin functions as a competitor for hCtr1-mediated copper transport, resulting in reduced cellular copper levels and leading to upregulated expression of Sp1, which is a positive regulator for hCtr1 expression. Thus, regulation of hCtr1 expression by cisplatin is an integral part of the copper homeostasis regulation system. We also demonstrate that Ag(I) and Zn(II), which are known to suppress hCtr1-mediated copper transport, can also induce hCtr1/Sp1 expression. In contrast, Cd(II), another inhibitor of copper transport, downregulates hCtr1 expression by suppressing Sp1 expression. Collectively, our results demonstrate diverse mechanisms of regulating copper metabolism by these heavy metals.
doi:10.1007/s00775-013-1051-z
PMCID: PMC3889686  PMID: 24132751
Cisplatin; High-affinity copper transporter; Sp1; Copper homeostasis; Platinum drug resistance
13.  Role of the Human High-Affinity Copper Transporter (hCtr1) in Copper Homeostasis Regulation and Cisplatin Sensitivity in Cancer Chemotherapy 
Cancer research  2012;72(18):4616-4621.
The high-affinity copper transporter (Ctr1) (SCLC31A1) plays an important role in regulating Cu homeostasis because copper (Cu) is an essential micronutrient and Cu deficiency is detrimental to many important cellular functions but excess Cu is toxic. Recent research has revealed that human Cu homeostasis is tightly controlled by interregulatory circuitry involving Cu, Sp1 and hCtr1. This circuitry uses Sp1 transcription factor as a Cu sensor in modulating hCtr1 expression which in turn controls cellular Cu and Sp1 levels in a three-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by Cu stresses has also been described in the literature. Because hCtr1 can also transport platinum (Pt) drugs, this finding underscores the important role of hCtr1 in Pt drug sensitivity in cancer chemotherapy. Consistent with this notion is the findings that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies demonstrated that elevated hCtr1 expression can be induced by depleting cellular Cu levels, resulting in enhanced cisplatin uptake and its cell killing activity. A phase 1 clinical trial using a combination of trientine (a Cu chelator) and carboplatin has been performed with encouraging results. This review discusses new insights into the role of hCtr1 in regulating Cu homeostasis and explains how modulating cellular Cu availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation.
doi:10.1158/0008-5472.CAN-12-0888
PMCID: PMC3445735  PMID: 22962276
Cisplatin; High-affinity copper transporter; Cu-lowering agents; Drug-resistance; Drug transport
14.  Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma 
Journal of Clinical Oncology  2012;30(20):2509-2515.
Purpose
Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.
Patients and Methods
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.
Results
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.
Conclusion
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
doi:10.1200/JCO.2011.41.5869
PMCID: PMC3397785  PMID: 22665541
15.  IGF-1R as an anti-cancer target—trials and tribulations 
Chinese Journal of Cancer  2013;32(5):242-252.
Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R–targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non–small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.
doi:10.5732/cjc.012.10263
PMCID: PMC3845553  PMID: 23601239
IGF-1R; insulin receptor
16.  Phase II Trial Evaluating the Clinical and Biologic Effects of Bevacizumab in Unresectable Hepatocellular Carcinoma 
Purpose
To determine the clinical and biologic effects of bevacizumab, an anti–vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC).
Patients and Methods
Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients’ plasma to support angiogenesis via an in vitro assay.
Results
The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma.
Conclusion
We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.
doi:10.1200/JCO.2007.15.9947
PMCID: PMC3635806  PMID: 18565886
17.  Cetuximab is Associated With Excessive Toxicity When Combined With Bevacizumab Plus mFOLFOX6 in Metastatic Colorectal Carcinoma 
Clinical colorectal cancer  2010;9(5):290-296.
Background
The bevacizumab-cetuximab combination has shown promising activity in chemotherapy-refractory metastatic colorectal cancer (mCRC). We sought to determine the safety and efficacy of cetuximab added to bevaci-zumab plus standard mFOLFOX6 (modified 5-fluorouracil [5-FU]/leucovorin/oxaliplatin) as first-line therapy for mCRC.
Patients and Methods
Sixty-six patients received cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly intravenously [I.V.]) plus bevacizumab 5 mg/kg and mFOLFOX6 chemotherapy every 2 weeks. The primary endpoint was toxicity.
Results
The most common grade 3–4 events included diarrhea (14%), fatigue (14%), neuropathy (12%), venous thrombosis (9%), acneiform rash (8%), and desquamation (8%). A protocol-defined prohibitive adverse event occurred in 4 patients (6%), including 2 treatment-associated deaths. Thirty-seven patients (56%) discontinued therapy before disease progression because of either toxicity (n = 19; 29%) or patient withdrawal (n = 18; 27%). Twenty-eight of 37 patients (76%) who discontinued therapy before disease progression did so because of cetuximab-associated toxicity.
Conclusion
Although the addition of cetuximab to bevacizumab plus mFOLFOX6 was not associated with excessive life-threatening toxicity, many patients discontinued therapy because of cetuximab-associated toxicity. Taken together with the results of recently reported phase III trials, cetuximab should not be used concurrently with bevacizumab and infusional 5-FU, leucovorin, and oxaliplatin chemotherapy for the treatment of mCRC.
doi:10.3816/CCC.2010.n.042
PMCID: PMC3623373  PMID: 21208843
KRAS mutation; Oxaliplatin; Vascular endothelial growth factor
18.  Routine defunctioning stoma after chemoradiation and total mesorectal excision: A single-surgeon experience 
AIM: To investigate the 10-year results of treating low rectal cancer by a single surgeon in one institution.
METHODS: From Oct 1998 to Feb 2009, we prospectively followed a total of 62 patients with cT2-4 low rectal cancer with lower tumor margins measuring at 3 to 6 cm above the anal verge. All patients received neoadjuvant chemoradiation (CRT) for 6 wk. Among them, 85% of the patients received 225 mg/m2/d 5-fluorouracil using a portable infusion pump. The whole pelvis received a total dose of 45 Gy of irradiation in 25 fractions over 5 wk. The interval from CRT completion to surgical intervention was planned to be approximately 6-8 wk. Total mesorectal excision (TME) and routine defunctioning stoma construction were performed by one surgeon. The distal resection margin, circumferential resection margin, tumor regression grade (TRG) and other parameters were recorded. We used TRG to evaluate the tumor response after neoadjuvant CRT. We evaluated anal function outcomes using the Memorial Sloan-Kettering Cancer Center anal function scores after closure of the defunctioning stoma.
RESULTS: The median distance from the lower margin of rectal cancer to the anal verge was 5 cm: 6 cm in 9 patients, 5 cm in 32 patients, 4 cm in 10 patients, and 3 cm in 11 patients. Before receiving neoadjuvant CRT, 45 patients (72.6%) had a cT3-4 tumor, and 21 (33.9%) patients had a cN1-2 lymph node status. After CRT, 30 patients (48.4%) had a greater than 50% clinical reduction in tumor size. The final pathology reports revealed that 33 patients (53.2%) had a ypT3-4 tumor and 12 (19.4%) patients had ypN1-2 lymph node involvement. All patients completed the entire course of neoadjuvant CRT. Most patients developed only Grade 1-2 toxicities during CRT. Thirteen patients (21%) achieved a pathologic complete response. Few post-operative complications occurred. Nearly 90% of the defunctioning stomas were closed within 6 mo. The local recurrence rate was 3.2%. Pathologic lymph node involvement was the only prognostic factor predicting disease recurrence (36.5% vs 76.5%, P = 0.006). Nearly 90% of patients recovered sphincter function within 2 year after closure of the defunctioning stoma.
CONCLUSION: Neoadjuvant CRT followed by TME, combined with routine defunctioning stoma construction and high-volume surgeon experience, can provide excellent surgical quality and good local disease control.
doi:10.3748/wjg.v19.i11.1797
PMCID: PMC3607756  PMID: 23555168
Rectal cancer; Neoadjuvant chemoradiation; Total mesorectal excision; Pathologic complete response; Defunctioning stoma
19.  Antenatal Mental Health and Retinal Vascular Caliber in Pregnant Women 
Purpose
Depression, anxiety, and poor sleep are associated with increased risks of cardiovascular diseases. Previous studies have demonstrated the relationship between negative emotion and retinal microvascular changes among adults, yet no study has been done in pregnant women so far. This study aims to examine the association of antenatal mental health and retinal vascular caliber among Asian pregnant women.
Methods
Nine hundred and fifty two Asian pregnant women aged 18 to 46 years were included in this study, who were recruited from two Singapore cohort studies, the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study and the In Vitro Fertilization (IVF) study conducted from 2009 onwards. A total of 835 Asian pregnant women underwent retinal photography at 26 weeks follow up, of whom 800 had gradable photographs. Symptoms of depression, anxiety, and sleep quality were assessed with self-administered questionnaires.
Results
In multiple linear regression models adjusted for age, ethnicity, household income, pregnancy outcome history, means of conception, hypertension history, diabetes history, cigarette smoking history, mean arterial blood pressure, body mass index, and spherical equivalent, each standard deviation (SD) increase in the Edinburgh Postnatal Depression Scale (EPDS) (4.49 scores) and in the Pittsburgh Sleep Quality Index (PSQI) (2.90 scores) was associated with a 0.80 μm (P = 0.03) and a 1.22 μm (P = 0.01) widening in retinal arteriolar caliber, respectively.
Conclusions
Our study demonstrates relationships of antenatal depressive symptoms and poor sleep quality with retinal arteriolar widening in pregnant women.
Translational Relevance
We speculate that this might possibly indicate an effect of antenatal depression and poor sleep on the microcirculation during pregnancy.
doi:10.1167/tvst.2.2.2
PMCID: PMC3763888  PMID: 24049713
antenatal mental health; retinal vascular caliber; pregnancy; antenatal depression; poor sleep quality
20.  Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2011;30(3):256-262.
Purpose
A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES).
Patients and Methods
Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels—6 and 9 mg/kg—were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level.
Results
Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES.
Conclusion
Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.
doi:10.1200/JCO.2011.37.4355
PMCID: PMC3269952  PMID: 22184397
21.  Metabolic Side-Effects of the Novel Second-Generation Antipsychotic Drugs Asenapine and Iloperidone: A Comparison with Olanzapine 
PLoS ONE  2013;8(1):e53459.
Background
The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.
Methods
Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).
Results
Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.
Conclusions
In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.
doi:10.1371/journal.pone.0053459
PMCID: PMC3541274  PMID: 23326434
22.  Prime-Boost Immunization of Rabbits with HIV-1 gp120 Elicits Potent Neutralization Activity against a Primary Viral Isolate 
PLoS ONE  2013;8(1):e52732.
Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates. Rabbits were immunized with the gp120 subunit of HIV-1 JR-CSF envelope (Env) using a DNA-prime protein-boost regimen. We analyzed five sera that showed potent autologous neutralizing activity (IC50s at ∼103 to 104 serum dilution) against pseudoviruses containing Env from the primary isolate JR-CSF but not from the related isolate JR-FL. Pseudoviruses were created by exchanging each variable and constant domain of JR-CSF gp120 with that of JR-FL or with mutations in putative N-glycosylation sites. The sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions located on the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs (targeting conserved sites on Env) or other type-specific responses (targeting V1, V2, or V3 variable regions). The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120. Our findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.
doi:10.1371/journal.pone.0052732
PMCID: PMC3541383  PMID: 23326351
23.  Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition 
Oncotarget  2013;4(1):80-93.
Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.
PMCID: PMC3702209  PMID: 23328114
MPNST; AURKA; RHAMM; TPX2; cancer stem cell
24.  Functional activation for imitation of seen and heard speech 
Journal of neurolinguistics  2011;24(6):611-618.
This study examined fMRI activation when perceivers either passively observed or observed and imitated matched or mismatched audiovisual (“McGurk”) speech stimuli. Greater activation was observed in the inferior frontal gyrus (IFG) overall for imitation than for perception of audiovisual speech and for imitation of the McGurk-type mismatched stimuli than matched audiovisual stimuli. This unique activation in the IFG during imitation of incongruent audiovisual speech may reflect activation associated with direct matching of incongruent auditory and visual stimuli or conflict between category responses. This study provides novel data about the underlying neurobiology of imitation and integration of AV speech.
doi:10.1016/j.jneuroling.2011.05.001
PMCID: PMC3182484  PMID: 21966094
fMRI; audiovisual; speech perception; speech production; imitation; McGurk effect
25.  Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats 
Background
The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents.
Methods
We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapine-induced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation.
Results
Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.
Limitations
We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments.
Conclusion
The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.
doi:10.1503/jpn.110140
PMCID: PMC3493097  PMID: 22640703

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