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c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers. [ABSTRACT FROM AUTHOR]

The role of thromboxane A2 (TxA2) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA2 synthase (TxAS) expression and thromboxane B2 (TxB2) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA2 synthesis and activates its receptor in lung cancer cells. The increased TxA2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells. [ABSTRACT FROM AUTHOR]

Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. Eligibility criteria included hormone refractory prostate cancer with a rising PSA at least 6 weeks after peripheral anti-androgen withdrawal, ECOG performance status (PS) 0–1, and no prior chemotherapy. Fenretinide was administered orally at 900 mg m−2 twice daily for 7 of every 21 days. PSA was measured before each cycle. The primary endpoint was a ≥50% reduction in PSA maintained for at least 3 weeks; secondary endpoints included duration of PSA response, time to treatment failure (TTF: treatment stopped for progression or toxicity) and adverse events (AE). Twenty seven pts were recruited from 7 centres over 27 months. Median age was 74 (range 49–86), median baseline PSA was 129 (range 19–1,000), and 70% had a PS of 0. The median number of cycles received was 2 (range 0–11) and 20 pts completed at least 1 cycle. One pt (4%) achieved a 50% reduction in PSA lasting 39 days and 15 pts (56%) had not progressed within 6 weeks of starting fenretinide. The median TTF was 54 days (IQR 19–73): 22 (81%) failed with tumour progression, 3 (11%) failed with toxicity and 2 (7%) never commenced the drug. Grade 3 rash occurred in 1 patient, all other AE were grade 1 or 2. The most common AE were nausea (40%), hot flushes (36%), constipation (32%) and nyctalopia (32%). High-dose fenretinide had limited anti-tumour activity in patients with advanced hormone refractory prostate cancer: further evaluation in this setting is not warranted. [ABSTRACT FROM AUTHOR]

Objectives This is a single center, randomized, double-blind placebo-controlled study to evaluate the NK(1)-receptor antagonist, aprepitant, in Chinese breast cancer patients. The primary objective was to compare the efficacy of aprepitant-based antiemetic regimen and standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who received moderately emetogenic chemotherapy. The secondary objective was to compare the patient-reported quality of life in these two groups of patients. Patients and Methods Eligible breast cancer patients were chemotherapy-naive and treated with adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2). Patients were randomly assigned to either an aprepitant-based regimen (day 1, aprepitant 125 mg, ondansetron 8 mg, and dexamethasone 12 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, aprepitant 80 qd) or a control arm which consisted of standard regimen (day 1, ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, ondansetron 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary, patients quality of life were assessed by self-administered Functional Living Index-Emesis (FLIE). Results Of 127 patients randomized, 124 were assessable. For CINV in Cycle 1 AC, there was no significant difference in the proportion of patients with reported complete response, complete protection, total control, ‘no vomiting’, ‘no significant nausea’ and ‘no nausea’. The requirement of rescue medication appears to be lesser in patients treated with the aprepitant-based regimen compared to those with the standard regimen (11% vs. 20%; P = 0.06). Assessment of FLIE revealed that while there was no difference in the nausea domain and the total score between the two groups; however, patients receiving standard antiemetic regimen had significantly worse quality of life in the vomiting domain (mean score [SD] = 23.99 [30.79]) when compared with those who received the aprepitant-based regimen (mean score [SD] = 3.40 [13.18]) ( P = 0.0002). Both treatments were generally well tolerated. Patients treated with the aprepitant-based regimen had a significantly lower incidence of neutropenia (53.2% vs. 35.5%, P = 0.0468), grade ≥ 3 neutropenia (21.0% vs. 45.2, P = 0.0042) and delay in subsequent cycle of chemotherapy (8.1% vs. 27.4%, P = 0.0048). Conclusion The aprepitant regimen appears to reduce the requirement of rescue medication when compared with the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide, and is associated with a better quality of life during adjuvant AC chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR) is commonly overexpressed in nasopharyngeal carcinoma (NPC) and gefitinib inhibits NPC growth in vitro. Method: Patients who progressed after prior platinum-based chemotherapy for recurrent NPC were given gefitinib orally at 500 mg/day at a 28-day cycle. Plasma Epstein-Barr virus (pEBV) DNA levels were obtained at specific intervals. Results: Sixteen patients enrolled and 15 were evaluable for response. The median age was 49 years (range 34-64 years), and most patients were males with metastatic NPC. No objective response was seen and three patients had stable disease (SD) for 2.8 to 8.5 months. Radiological progression of disease coincided with rising levels of pEBV DNA in most patients, while the level of a patient with the longest duration of SD fell to an undetectable level at study completion. The mean time to progression and overall survival was 2.7 (standard error, SE +/- 0.5 months) and 12 months (SE +/- 1.7 months), respectively. No unexpected drug-related toxicities were seen. The study was prematurely terminated because there was insufficient activity to warrant progression to the second stage of accrual. Conclusion: This study found limited activity of gefitinib in recurrent NPC. Further evaluation of pEBV DNA as a biomarker of response in clinical trials of target-based agents is warranted. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is endemic in parts of Asia and Africa and most patients are not suitable for treatment with a curative approach. Little is known about the cost of palliative care for HCC.Objective: To determine: (i) patient-specific costs of palliative care of HCC; and (ii) individual factors that drive patient-specific costs and to develop a model of cost per case under alternative circumstances.Methods: 204 patients with inoperable HCC were prospectively tracked from first hospitalisation until death for health service utilisation. A societal perspective of cost was taken, including costs of formal and informal services incurred by payers, caregivers and patients. Observational data from a large Hong Kong cancer care programme were used. A regression analysis was performed using formal costs only, with the cost per observed day as the dependent variable.Results: The median survival was 95 days and the mean observation period was 153 days. The mean value per person for formal healthcare cost was 30 983 Hong Kong dollars [$HK] ($US3872, 1998 values). The distribution of cost values were positively skewed. The regression analysis showed that age, days of observation and survival were negatively related to cost per observed day, and the Child-Pugh grading of severity of liver cirrhosis was positively related to cost per observed day. A sensitivity analysis based on the regression equation indicated that nonsurvivorship doubles the cost per case, increased severity as measured by the Child-Pugh Index adds about 50% to the cost, and chemotherapy increases cost 2-fold.Conclusions: The relatively modest average cost per patient with HCC in Hong Kong reflects the short median survival and subsequently the limited use of inpatient care and chemotherapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which describes the case of a 59-year-old male patient who presented to the neurology services with progressive bilateral proximal upper limb weakness and bilateral shoulder pain.

Purpose: A single-institution phase II trial of Temodal (temozolomide, SCH52365) in Chinese patients with advance nasopharyngeal carcinoma was undertaken to determine the efficacy and safety of the drug in this population.Methods: A total of 14 patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma were entered into the study. One patient was unevaluable. Temodal was given at doses of 150 or 200 mg/m2 daily on days 1-5 every 28 days.Results: In all, 30 cycles of Temodal were given with no significant toxicity. All 13 (100%) evaluable patients had progressive disease after 2 (84.6%) or 4 (15.4%) courses.Conclusion: Temodal given on this schedule has no activity in advanced nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Robust topological edge modes may evolve into complex-frequency modes when a physical system becomes non-Hermitian. We show that, while having negligible forward optical extinction cross section, a conjugate pair of such complex topological edge modes in a non-Hermitian -symmetric system can give rise to an anomalous sideway scattering when they are simultaneously excited by a plane wave. We propose a realization of such scattering state in a linear array of subwavelength resonators coated with gain media. The prediction is based on an analytical two-band model and verified by rigorous numerical simulation using multiple-multipole scattering theory. The result suggests an extreme situation where leakage of classical information is unnoticeable to the transmitter and the receiver when such a -symmetric unit is inserted into the communication channel. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the occurrence of lymphoma followed by t-myeloproliferative disease.