Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Transverse technique: complementary approach to measurement of first-trimester uterine artery Doppler.

OBJECTIVES: To define a protocol for the first-trimester assessment of uterine artery pulsatility index (UtA-PI) using the new transverse technique, to evaluate UtA-PI measured using the transverse approach vs that obtained using the conventional sagittal approach and to determine if accelerated onsite training (in both methods) of inexperienced sonographers can achieve reproducible UtA-PI measurements comparable with those obtained by an experienced sonographer. METHODS: This was a prospective observational study of women with a singleton pregnancy attending for routine combined first-trimester screening at 11 to 13 + 6 weeks' gestation. The study consisted of two parts, each conducted at a different center (Part 1 in Calgary, Canada and Part 2 in Hong Kong). In Part 1, UtA-PI measurements were performed using the transverse and sagittal techniques by four sonographers trained in both methods, in 10 cases each, and measurement indices (PI), time required and subjective difficulty in obtaining satisfactory measurements were compared. The one sample t-test and Wilcoxon signed rank test were used when appropriate. Bland-Altman plots were used to assess measurement agreement, and intraclass correlation coefficient (ICC) was used to evaluate measurement reliability. A target plot was used to assess measures of central tendency and dispersion. In Part 2, one experienced and three inexperienced sonographers prospectively measured UtA-PI using both approaches in 42 and 35 women, respectively. Inexperienced sonographers underwent accelerated onsite training by the experienced sonographer. Measurement approach and sonographer order were on a random basis. ICC, Bland-Altman and Passing-Bablok analyses were performed to assess measurement agreement and reliability and effect of accelerated training. RESULTS: In Part 1, no difference was observed between the two techniques in mean time to acquire the measurements (118 s for sagittal vs 106 s for transverse; P = 0.38). The four sonographers reported that the transverse technique was subjectively easier to perform (P = 0.04). Bias and ICC for mean UtA-PI between sagittal and transverse measurements were -0.05 (95% limits of agreement, -0.48 to 0.37) and 0.94, respectively. Measurements obtained using the transverse technique after correcting for gestational age were significantly closer to the expected distribution than those obtained using the sagittal technique. In Part 2, there were no significant differences in median UtA-PI measured using the different approaches for both experienced and inexperienced sonographers (P > 0.05 for all sonographers). Mean UtA-PI measurement reliability between approaches was high for the experienced (ICC = 0.92) and inexperienced (ICC > 0.80) sonographers. UtA-PI measurement approaches did not deviate from linearity, while bias ranged from -0.10 to 0.07. The median time required was similar between the techniques (56.1 s for sagittal vs 49.3 s for transverse; P = 0.054). CONCLUSIONS: This novel transverse approach for the measurement of UtA-PI in the first trimester appears to be comparable with the sagittal approach in terms of reliability, reproducibility and time required, and may be easier to perform. Providing accelerated onsite training can be helpful for improving the reliability of UtA-PI measurements and could potentially facilitate the broad implementation of first-trimester pre-eclampsia screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer).

BACKGROUND: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. RESULTS: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. CONCLUSION: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. CLINICAL TRIAL NUMBER: Japan Pharmaceutical Information Center, JapicCTI-101155.

Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079).

BACKGROUND: This study investigated the activity of MK-2206, an AKT inhibitor, in metastatic or recurrent nasopharyngeal carcinoma (NPC). METHOD: Oral MK-2206 at a dose of 200 mg was administered on days 1, 8, 15 and 22 of a 28-day cycle until progression. Plasma EBV DNA clearance during the first month of treatment was measured, and archived tumors were analyzed for the expression of AKT and PIK3CA mutation and PIK3CA amplification. The dual primary endpoint was objective response rate and 6-month progression-free survival (PFS) rate. RESULTS: 21 patients were enrolled and one patient achieved a partial response (5 %) and 11 had stable disease (52 %), with a median PFS of 3.5 months (95 % confidence interval, CI: 0.9-7.3). The 6-month PFS rate was 43 % (95 % CI: 22-66 %) and the median OS was 10 months (95 % CI: 5.9 months-not reached). Seven patients (33 %) experienced grade 3 toxicities which could be related to MK-2206. Macular-papular rash was the most common (n = 6), followed by hyperglycemia (n = 2) and fatigue (n = 1). In the 12 tumor samples analyzed, PIK3CA amplification was detected in one patient's primary NPC, who had SD lasting over 12 months. Patients with decreasing EBV DNA values over time were more likely to be alive and progression-free for at least 6 months than those without a decrease (p = 0.001). CONCLUSION: The study was terminated due to the limited activity observed in this heavily pre-treated group of patients. Further studies are needed to elucidate the optimal way of selecting patients for AKT inhibitors.

Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer.

BACKGROUND: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. PATIENTS AND METHODS: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). RESULTS: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. CONCLUSION: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis.

BACKGROUND: This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%). CONCLUSION: In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER: NCT00460317.

A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma.

BACKGROUND: Individuals with metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (ΔLMP1) and full-length LMP2 (Ad-ΔLMP1-LMP2). MATERIALS AND METHODS: Sixteen subjects with metastatic NPC received Ad-ΔLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined. RESULTS: Most patients had extensive disease, with a median of three visceral sites of involvement (range 1-7). No significant toxicity was observed. Ad-ΔLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 7½ months) and two with stable disease (for 6½ and 7½ months). CONCLUSIONS: Ad-ΔLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma.

BACKGROUND: To evaluate the efficacy and toxicity of single-agent docetaxel (Taxotere) as therapy in patients with disseminated nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with histologically confirmed metastatic or recurrent NPC who have failed at least one line of palliative chemotherapy regimen but no prior docetaxel were eligible. Patients received weekly docetaxel every 28 days (docetaxel 30 mg/m(2) on days 1, 8 and 15) and were evaluated every two cycles of treatment of response assessment. Quality-of-life (QoL) assessments during the treatment period were done using the European Organization for Research and Treatment of Cancer QoL questionnaire QLQ-C30; version 3.0. RESULTS: Thirty patients were assessable for toxicity and response. The median age of the patients was 47 years (range 25-68 years) and the majority of patients had good performance status (Eastern Cooperative Oncology Group 0-1). Grade 3 or 4 toxicity included fatigue (13%), anemia (10%) and diarrhea (3%) of patients. Eleven (37%) and four (13.3%) patients achieved partial response and stable disease, respectively. The median progression-free survival was 5.3 months and median overall survival of 12.8 months. The partial responders had a mean duration of response of 4.1 months. Docetaxel caused a significant decline in QoL scores during treatment of patients responding or progressing with the treatment. CONCLUSIONS: Our findings suggest that weekly docetaxel is well tolerated and is an active agent in patients with disseminated NPC who were previously exposed and largely refractory to platinum-based chemotherapy but can cause a significant decline in QoL during treatment.

Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol-PM) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients. MATERIALS AND METHODS: Patients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m(2) and the maximum administered dose was 200 mg/m(2). RESULTS: The majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m(2). The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m(2). Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (C(max)) and the area under the concentration-time curve from zero to infinity (AUC(0-infinity)) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m(2). The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. CONCLUSION: The weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.

PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the commonest cause of cancer mortality worldwide. Growth factor receptor signalling pathways constitute an important mediator for tumor growth and proliferation. PTEN and pAKT play important roles in regulating signal transduction along this pathway. Separate cohorts of stage I (n=25) and stage IV (n=34) NSCLC were examined by immunohistochemistry for PTEN and pAKT expression. There was no correlation between PTEN expression and pAKT expression and neither were associated with age, sex or smoking status. Patients with stage IV disease who overexpressed pAKT (at least 2+) or were PTEN-null had poorer overall survival and progression-free survival. This suggests that PTEN-null or pAKT-positive tumors constitute more aggressive tumors whose clinical course is not altered by therapy. There was no difference in the clinical outcome for stage I disease by PTEN or pAKT expression. A greater proportion of the stage IV patients had PTEN-null disease compared to the stage I cohort, suggesting that loss of PTEN is important in the tumor biology of advanced disease. Loss of PTEN or overexpression of pAKT predicts for an aggressive subset of lung tumors that have a poor prognosis. This will allow identification of a poor prognosis subset that can be targeted with novel treatments that either restore PTEN function or target activated AKT, mTOR and other downstream signal transduction molecules.

CPT-11 and cisplatin in the treatment of advanced gastric cancer in Asians.

There is no standard chemotherapy for advanced gastric cancer. A combination of CPT-11 and cisplatin was evaluated for response and toxicity in Asians. 38 patients with histologically proven stage IV gastric/gastroesophageal junction adenocarcinoma were treated with CPT-11 50 mg/m2 and cisplatin 30 mg/m2 weekly for 3 weeks. Each cycle was repeated every 28 days. The median number of cycles was 1.66 (range 0.33-4.33). Dose delay was needed in 11 (29%) patients and dose reductions in 19 (50%) patients. The overall response rate was 42%. There was no complete response. Grade 3 and 4 hematological toxicity was 26%. Grade 3 or 4 diarrhea was not common. Median time to progression for all patients was 15 weeks. Median duration of survival of all patients was 42 weeks. Patients with better performance status and no prior chemotherapy did better. CPT-11 and cisplatin is a useful regimen with significant but manageable toxicity that can be administered without a central venous catheter.

Continuous infusion 5-fluorouracil as salvage chemotherapy in patients with advanced colorectal cancer.

For almost 40 years, 5-fluorouracil (5-FU) has been the only useful drug with clinically meaningful activity in metastatic colorectal carcinoma. When the disease progresses or recurs despite bolus 5-FU treatment, the options are limited. Our study shows that 5-FU given by continuous infusion is a viable alternative. Fifty-three patients received continuous infusion 5-FU. The overall response was 9%. Median survival of the entire cohort was 5 months. Patients with partial response and stable disease had median survival duration of 8 and 9 months, respectively. A dose-response relationship was observed. The commonest toxicities were mucositis (34%) and palmar-plantar syndrome (24%). There was no central line-related complication. Continuous infusion 5-FU is an effective "second-line" treatment. Further work is needed to ascertain its role, in comparison with newer agents like irinotecan (CPT-11), and oxaliplatin.

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation.

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4-1147) days, the median PFS was 100 days (95% confidence interval (CI), 66-128 days), and median OS was 209 days (95% CI, 128-236 days). Patients with chronic GVHD had better survival-median OS 426 days (95% CI, 194-NE days) vs 143 days (95% CI, 114-226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.

Gefitinib is more effective in never-smokers with non-small-cell lung cancer: experience among Asian patients.

We retrospectively analysed the results of patients with advanced non-small-cell lung cancer treated with gefitinib to derive clinical factors predictive of response and a favourable survival outcome. Patients were treated with gefitinib 250 mg per day and re-evaluated 4-8 weeks later with repeat CT scan and every 8 weeks thereafter to assess response and the duration of response. Pathology review by a histopathologist was conducted, in particular to confirm a recently published result of bronchioloalveolar carcinoma histology or its components as predictive of response to gefitinib. Logistic regression and Cox regression analytical methods were applied to determine factors that could predict for response and improved overall survival. A total of 110 patients were treated. The overall response rate was 32% partial responses (PRs). Only never-smoking status was predictive of response in the logistic regression analysis, adjusted OR=6.1, 95% CI=1.7, 21.5. The presence of a PR and good performance status were predictive of a favourable survival outcome from the Cox regression modelling. Responders had an adjusted HR of 3.0, 95% CI=1.5-5.8 compared to nonresponders, while patients with ECOG status 0-1 had an adjusted HR of 0.42, 95% CI=0.25-0.72, compared with patients with ECOG status 2-4. Bronchioloalveolar carcinoma or its components were distinctly absent on pathology review. In conclusions, Never-smoking status is an important clinical predictor of a favourable response to gefitinib.

Silicone lymphadenitis secondary to implant degeneration.

The principal objective(s) of this presentation is to report a case of lymphadenitis secondary to implant degeneration. A review of the literature on the history and development of the silicone implant and the durability of the silicone elastomer is presented. A case report with radiologic and histologic documentation is also presented. Silicone lymphadenitis is a rare occurrence and the authors believe they have reported the first case to occur in the lower extremity.

Down-regulation of CXCR-4 and CCR-5 expression by interferon-gamma is associated with inhibition of chemotaxis and human immunodeficiency virus (HIV) replication but not HIV entry into human monocytes.

Alterations in the expression of CXCR4 and CCR5, the co-receptors for HIV entry, may be associated with susceptibility of monocytic cells to HIV infection. Interferon (IFN)-gamma has been shown to inhibit HIV replication in monocytic cells, but the molecular mechanism involved is not well understood. To determine if IFN-gamma regulates HIV replication by altering CXCR-4/CCR-5 expression and hence virus entry into monocytic cells, we investigated the effects of IFN-gamma on CXCR-4 and CCR-5 expression and its biological implications with respect to HIV entry, replication and chemotaxis towards the CXCR-4 and CCR-5 ligands SDF-1 and MIP-1alpha, respectively. IFN-gamma decreased CXCR-4 and CCR-5 expression on monocytes derived from HIV-negative adults, HIV-positive adults and HIV-negative cord blood. This down-regulation of chemokine receptor expression did not result in a corresponding change in mRNA expression but was associated with elevated levels of the endogenously produced chemokines SDF-1 and RANTES. Furthermore, IFN-gamma inhibited chemotaxis in response to SDF-1 and MIP-1alpha, inhibited HIV replication, but failed to inhibit virus entry in monocytic cells. These results suggest that although IFN-gamma-induced down-regulation of CXCR-4 and CCR-5 expression is associated with an inhibition of SDF-1-/MIP-1alpha-mediated chemotaxis, IFN-gamma-induced inhibition of HIV replication may be mediated at levels subsequent to the virus entry.

Quick-FLIC: validation of a short questionnaire for assessing quality of life of cancer patients.

A practically useful measure of quality of life should be simple and quick to complete. A shortened Chinese version of the Functional Living Index - Cancer (FLIC) was recently proposed and was called Quick-FLIC. This study aims to assess the measurement properties of the Quick-FLIC. A total of 190 patients who received care from the National Cancer Centre of Singapore completed a questionnaire package at baseline. Patients filled in a retest questionnaire on average 2 weeks after baseline to assess test-retest reliability and responsiveness to change. The Quick-FLIC scores correlated well with the Functional Assessment of Chronic Therapy - General scores (r=0.78). Patients with different treatment status, performance status and self-rated health had significantly different Quick-FLIC scores in the expected directions (ANOVA; each P<0.001). Internal consistency (Cronbach's alpha=0.87) and 2-week test-retest reliability (intraclass correlation=0.81) were also satisfactory. The measure was responsive to changes in health status (P<0.001). The Quick-FLIC is a valid and reliable measure of health-related quality of life of cancer patients. The shortening of established health-related quality of life instruments should be considered in order to reduce the burden of having patients to answer lengthy questionnaires.