Multiplex PCR system for the rapid diagnosis of respiratory virus infection: systematic review and meta-analysis.

OBJECTIVES: To provide a summary of evidence for the diagnostic accuracies of three multiplex PCR systems (mPCRs)-BioFire FilmArray RP (FilmArray), Nanosphere Verigene RV+ test (Verigene RV+) and Hologic Gen-Probe Prodesse assays-on the detection of viral respiratory infections. METHODS: A comprehensive search up to 1 July 2017 was conducted on Medline and Embase for studies that utilized FilmArray, Verigene RV+ and Prodesse for diagnosis of viral respiratory infections. A summary of diagnostic accuracies for the following five viruses were calculated: influenza A virus (FluA), influenza B virus, respiratory syncytial virus, human metapneumovirus and adenovirus. Hierarchical summary receiver operating curves were used for estimating the viral detection performance per assay. RESULTS: Twenty studies of 5510 patient samples were eligible for analysis. Multiplex PCRs demonstrated high diagnostic accuracy, with area under the receiver operating characteristic curve (AUROC) equal to or more than 0.98 for all the above viruses except for adenovirus (AUROC 0.89). FilmArray, Verigene RV+ and ProFlu+ (the only Prodesse assay with enough data) demonstrated a summary sensitivity for FluA of 0.911 (95% confidence interval, 0.848-0.949), 0.949 (95% confidence interval, 0.882-0.979) and 0.954 (95% confidence interval, 0.871-0.985), respectively. The three mPCRs were comparable in terms of detection of FluA. CONCLUSIONS: Point estimates calculated from eligible studies showed that the three mPCRs (FilmArray, Verigene RV+ and ProFlu+) are highly accurate and may provide important diagnostic information for early identification of respiratory virus infections. In patients with low pretest probability for FluA, these three mPCRs can predict a low possibility of infection and may justify withholding empirical antiviral treatments.

Mutagen sensitivity as measured by induced chromatid breakage as a marker of cancer risk.

Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in the chromosomes of peripheral blood lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related maladies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by clastogenic agents, such as the γ-radiation mimetic DNA cross-linking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-nitroquinoline and the tobacco smoke constituent benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.

Profiles of circulating endothelial cells and serum cytokines during adjuvant chemoradiation in rectal cancer patients.

INTRODUCTION: This research aimed to demonstrate the correlation of circulating endothelial cells (CECs) count and serum cytokine levels with side effects and prognosis in rectal cancer patients receiving adjuvant chemoradiation. METHODS: Eleven patients received proctectomy, chemoradiotherapy and follow-up for 4 years. Fifty-five blood samples were taken before radiation and during the course. The quantities of CECs were estimated by flow cytometry, and serological factors were measured by ELISA. RESULTS: The CEC level in patients without tumor recurrence was significantly lower than in patients with tumor recurrence (p < 0.01). The IL-6 and TGF-ß1 levels exhibited a similar profile (p < 0.01). For morbidity, the mean CEC level in patients with grade 3 diarrhea was significantly greater than patients with grades 1 (p < 0.001) and 2 diarrhea (p < 0.005). CONCLUSIONS: Levels of CECs, serum IL-6, TGF-ß1 and TNF-α during post-operative chemoradiation in rectal cancer patients might be candidate biomarkers for prognosis and morbidity (NCT00325871).

The association of psychosocial factors and smoking with periodontal health in a community population.

BACKGROUND AND OBJECTIVE: The association between psychosocial factors and periodontal disease has been widely reported and might be modified by smoking status. This study investigated the association of periodontal status with psychosocial factors and smoking in a community population. MATERIAL AND METHODS: A structured questionnaire was administered to a total of 1,764 civilian noninstitutional (general population excluding from nursing homes, sanitariums and hospitals) Taiwanese individuals to assess the presence and severity of psychosocial factors [using the 12-item Chinese health questionnaire (CHQ-12)], smoking habits and other related factors. Periodontal status was established using the community periodontal index and by measuring clinical loss of attachment. RESULTS: Psychological factors and smoking were significantly associated with loss of attachment (odds ratio = 1.69, 95% confidence interval = 1.01-2.77, comparing the CHQ-12 score of >or= 6 with the CHQ-12 score of 0-2 and p = 0.032 for linear trend; odds ratio = 2.21, 95% confidence interval = 1.45-3.37, comparing smokers with nonsmokers) but not with community periodontal index. The association was found to be stronger among smokers than among nonsmokers. Smokers with a CHQ-12 score of >or= 6 had a higher odds ratio of loss of attachment (odds ratio = 2.49, 95% confidence interval = 0.91-6.49) than nonsmokers (odds ratio = 1.43, 95% confidence interval = 0.76-2.58). For periodontal health measured using the community periodontal index, married and divorced/widowed subjects tended to have poorer periodontal health (odds ratio = 3.38, 95% confidence interval = 1.26-10.81 and odds ratio = 3.83, 95% confidence interval = 1.21-13.83, respectively) than single subjects among nonsmokers but not among smokers. CONCLUSION: Poor mental health had a stronger association with periodontal disease among smokers than among nonsmokers, especially in accumulative attachment loss. Our findings suggest that mental health and smoking might have a synergistic effect on the risk of developing periodontal disease.

4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of nonmelanoma skin cancer: a case-control analysis.

The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P<0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.

Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells.

Human parvovirus B19 (B19) has been associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We have demonstrated previously that B19 non-structural protein (NS1) induced apoptosis through the mitochondria cell death pathway in COS-7 epithelial cells and that B19 NS1 may play a role in the pathogenesis of autoimmune diseases. In order to examine the expression profiles of cytokines and chemokines in B19 NS1 transfected COS-7 cells, we constructed the NS1 gene in the pEGFP-C1 vector named enhanced green fluorescence protein gene (EGFP)-NS1. COS-7 cells were transfected with EGFP or EGFP-NS1 plasmid. The expression profiles of cytokines and chemokines, including interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene alpha (GROalpha), interferon gamma-inducible protein (IP)-10, stromal cell derived factor (SDF)-1, macrophage inflammatory protein (MIP)-1beta, monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), Fractalkine, CX3CR1, CCR2, CCR5 and CCR11 were examined in COS-7 cells, EGFP and EGFP-NS1 transfected cells using enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). Increased expression and levels of IL-6 were found in EGFP-NS1 transfected cells using RT-PCR and ELISA. There were no significant increases in the expression of IL-1beta, IL-8, IP-10, SDF-1, RANTES, Fractalkine, CX3CR-1, CCR2, CCR5, CCR11, TNF-alpha, GM-CSF and TGF-beta using RT-PCR. There were no significantly increased levels of IL-5, IL-10, TNF-alpha, TGF-beta, GROalpha, MIP-1beta and MCP-1 found by ELISA in this study. Our results show that increased expression and secretion of IL-6 in B19 NS1 transfected epithelial cells may play a role in the pathogenesis of autoimmune diseases.

Mutagen-induced chromatid breakage as a marker of cancer risk.

Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in peripheral lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related malignancies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by chromosome breaking agents, such as the gamma-radiation radiomimetic DNA crosslinking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-NQO and the tobacco smoke constituent, benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.

Germline Telomere Length Dynamics and Mutagen Sensitivity Studies in a Family with Acute Reactions to Sun Exposure: Involvement of Three Generations.

Most cancers are the result of an interaction between germline genetic susceptibility and exposure to environmental carcinogens. We studied chromosomal aberrations, telomeric associations, telomere signal intensity by fluorescence in situ hybridization, p53 germline mutation, bleomycin (Bleo) and 4-nitroquinoline-1-oxide (4NQO) sensitivity, and chromosome-specific telomere signals in T and B lymphocytes in a Caucasian family involving three generations and 13 family members. This family was chosen because eight of its members are extremely sensitive to sunlight and burn easily even upon short exposure. The family members have shown: (a) hypersensitivity either to Bleo or 4NQO mutagens, with values much higher than 1.00 breaks/cell (b/c) for Bleo and 0.40 b/c for 4NQO; (b) an increased rate of telomeric associations; (c) variable amounts of telomeric DNA not common for the person's age; (d) the presence of intron 7 polymorphism in the proband and no significant effect on N-methyl-N'-nitosoguanidine (MNNG)-induced p53 expression in two key family members; and (e) an incidence of epithelial malignancies in two family members. Seven additional members showed polymorphism of telomeric signals in the short arm of two homologous chromosome 17s, where the p53 gene is localized. A 78-year-old grandmother, who had developed colon cancer, was predicted to have metastatic cancer based on the telomeric DNA amount in her lymphocytes (2.90%); she subsequently developed metastatic lesions within a year and died. Based on these observations, we conclude that telomere erosion is the initial cause of genomic instability/susceptibility which, in turn, may be causal for the reproductive complications, premature aging phenotypes and, in some cases, predisposition to cancer development.

Genetic instability of specific chromosomes associated with a family history of cancer.

This study evaluated the association between family history of cancer and bleomycin-induced mutagen breaks at specific chromosomes. The authors' hypothesis was that individuals exhibiting mutagen-induced specific chromatid breaks might have genetic instability and thus be more likely to report a family history of cancer. The study included 78 healthy individuals. All subjects completed a personal interview to collect epidemiologic information, including a detailed family history of cancer, and donated a 10-mL blood sample. Bleomycin-induced mutagen sensitivity on specific chromosomes was quantified by counting the bleomycin-induced specific chromosomal breaks with Q-banding techniques. We found that chromosome 4 breaks were significantly associated with a positive family history of cancer in first-degree relatives with an odds ratio of 3.18 and 95% confidence interval of 1.05-9.61. However, none of the other chromosomes showed significantly increased risk with family cancer history. In addition, the mutagen-induced chromosome 4 breaks were not associated with age, sex, ethnicity, or smoking status. These findings suggested that chromosome 4 mutagen sensitivity might be a predictor of familial susceptibility to cancer.

Transformation nonresponsive cells owe their resistance to lack of p65/nuclear factor-kappaB activation.

Clonal variants of mouse epidermal JB6 cells that are genetically susceptible (P+) or resistant (P-) to tumor promoter-induced neoplastic transformation exhibit differential activator protein-1 (AP-1) response. Transactivation of AP-1 appears to be necessary but not sufficient to promote transformation in JB6 cells. Inhibition of AP-1 is invariably accompanied by inhibition of nuclear factor-kappaB (NF-kappaB) when transformation is suppressed, suggesting that NF-kappaB may also play a role in neoplastic transformation. We report here that transactivation of NF-kappaB is inducible by tumor promoters in P+ but not in P- JB6 cells. Inhibition of NF-kappaB using a nondegradable mutant of IkappaBalpha suppressed inducible anchorage-independent transformation of P+ JB6 cells, suggesting that NF-kappaB activation is required for tumor promotion. Induced degradation of IkappaBalpha occurred in both P+ and P- JB6 cells, indicating that failure to activate NF-kappaB in P- JB6 cells cannot be attributed to failure to degrade IkappaBalpha. Slightly higher levels of nuclear p65 were seen in P+ than in P- JB6 cells. The p65-specific DNA binding activity was also higher in P+ cells upon induction by tumor necrosis factor-alpha, suggesting that differential NF-kappaB activation may be attributable to changes in p65 activity. Transactivation of p65 protein was substantially higher in P+ than in P- JB6 cells, as determined by assay of Gal4-p65 fusion constructs. Thus activated, p65 may be a limiting factor for NF-kappaB activation and transformation responses. Stable expression of p65 in P- JB6 cells conferred not only inducible NF-kappaB and AP-1 activation but also transformation response to tumor promoters. Therefore, p65/NF-kappaB appears to be not only necessary for but also sufficient to confer tumor promotion response. Although stable expression of p65 in P- cells produced p65 increases in whole cell extracts, only the transfectants exhibiting increased nuclear p65 showed transformation response. Thus, elevation of nuclear p65 appears to be a necessary step for a transformation response. The P-/p65 transfectants showing acquired transformation response also showed elevated p65-specific transactivation response, thus recapitulating the NF-kappaB phenotypes seen in P+ cells. Expression of a transactivation-deficient mutant of Jun or dominant-negative extracellular signal-regulated kinase suppressed both AP-1 activation and p65-specific transactivation in JB6 cells, suggesting that AP-1 activity is needed for p65 transactivation and consequently for NF-kappaB activation. Thus, the transformation nonresponsive P- JB6 cells owe their resistance to lack of NF-kappaB activation and p65 transactivation that appears in turn to be attributable to insufficient AP-1 activation.

Comparative efficacy as antioxidants between ascorbic acid and epigallocatechin gallate on cells of two human lymphoblastoid lines.

Both ascorbic acid and epigallocatechin gallate, which is one of the key polyphenols contained in green tea leaves, have been considered excellent antioxidants. The present study compared the efficacy as antioxidants between the two agents on an equimolar basis. Cells of two lymphoid lines were used as test material to determine the reduction of chromosome damage induced by the radiomimetic antibiotic bleomycin. Without bleomycin, both agents, at concentrations of 10(-7), 10(-6), 10(-5), and 10(-4) M, showed chromosome damage similar to the untreated controls. With bleomycin, the weakest concentration of both showed no protective effect. At concentrations of 10(-6) and 10(-5) M, especially the latter, a significant reduction in frequencies of chromatid breaks was recorded. However, at the highest concentration, 10(-4) M, the chromatid break frequencies rose to the same level as that of cells treated with bleomycin alone, suggesting that both behaved like pro-oxidants.

Environmental tobacco smoking, mutagen sensitivity, and head and neck squamous cell carcinoma.

Although active tobacco smoking has been considered a major risk factor for head and neck cancer, few studies have evaluated environmental tobacco smoke (ETS) and its interaction with mutagen sensitivity on the risk of head and neck cancer. We investigated the relationship between ETS and head and neck cancer in a case-control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. A structured questionnaire was used to collect ETS exposure and other covariates including a history of active tobacco smoking and alcohol use. ETS measures include a history of ETS exposure at home and at workplace. The associations between passive smoking and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Additive and multiplicative models were used to evaluate effect modifications between ETS and mutagen sensitivity. The crude odds ratio (OR) for ETS exposure was 2.8 [95% confidence intervals (CI), 1.3-6.0]. Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and marijuana use, the risk of squamous cell carcinoma of the head and neck was increased with ETS (adjusted OR, 2.4; 95% CI, 0.9-6.8). Dose-response relationships were observed for the degree of ETS exposure; the adjusted ORs were 2.1 (95% CI, 0.7-6.1) for those with moderate exposure and 3.6 (95% CI, 1.1-11.5) for individuals with heavy exposure (P for trend = 0.025), in comparison with those who never had ETS exposures. These associations and the dose-response relationships were still present when the analysis was restricted to nonactive smoking cases and controls (crude OR, 2.2; 95% CI, 0.6-8.4). Crude odds ratios were 1.8 for those with moderate ETS exposure and 4.3 for individuals with heavy ETS exposure among nonsmoking cases and controls (P for trend = 0.008). More than multiplicative interaction was suggested between passive smoking and mutagen sensitivity. This study suggests that ETS exposure may increase the risk of head and neck cancer with a dose-response pattern. Our analysis indicated that passive smoking may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. Our results need to be interpreted with caution because of potential residual confounding effects of active tobacco smoking and other methodological limitations. Future large-scale studies are warranted to confirm our findings.

Assessment of intragastric pH value changes after early nasogastric feeding.

Studies have suggested that early feeding after injury decreases morbidity and mortality. Few reports, however, have focused on the change in pH inside the stomach after early tube feeding. The aim of the present study was the assessment of 1) the change in intragastric pH after surgery, and 2) the effect of early nasogastric tube feeding on intragastric pH value. From April 1997 to February 1998, 80 patients who underwent colon resection for colorectal cancer by a single surgeon entered the study and were randomized into four groups. Twenty patients (group I) were kept on NPO for 1 wk, and 20 patients per group (groups II, III, and IV) were fed through a nasogastric tube from the second to the seventh postoperative day with low-residual (Osmolite HN), high-fat (Pulmocare), and glutamine-containing (AlitraQ) enteral formulas. Feeding started at 500 kcal/500 cc/d. If the patient tolerated the formula well, feeding increased to 1500 kcal/1500 cc(-1)/d(-1) the following day. Intragastric pH was measured preoperatively and then twice daily until the sixth postoperative day. The pH value of intragastric juice increased significantly once feeding started (3. 67 +/- 1.33 on the third postoperative day; 4.28 +/- 1.26 on the six postoperative day). The pH value seemed only mildly affected by the patient's tolerance for tube feeding (poorly tolerated group, pH 3. 52 +/- 1.75 versus 3.75 +/- 1.21 in the well-tolerated group on the third postoperative day; poorly tolerated group, pH 3.67 +/- 1.02 versus 4.45 +/- 1.27 in the well-tolerated group on the sixth postoperative day). The pH value of intragastric juice was higher in group II than in groups III and IV (4.51 +/- 1.57, 3.90 +/- 1.20, 4. 42 +/- 0.89 respectively, on the sixth postoperative day). This series suggests that early nasogastric feeding can significantly elevate the intragastric pH value in patients after resection of colorectal cancer. Nasogastric feeding may decrease the incidence of stress ulceration by elevating the pH value of intragastric juice.

Activator protein 1 (AP-1)- and nuclear factor kappaB (NF-kappaB)-dependent transcriptional events in carcinogenesis.

Generation of reactive oxygen species (ROS) during metabolic conversion of molecular oxygen imposes a constant threat to aerobic organisms. Other than the cytotoxic effects, many ROS and oxidants are also potent tumor promoters linking oxidative stress to carcinogenesis. Clonal variants of mouse epidermal JB6 cells originally identified for their differential susceptibility to tumor promoters also show differential reduction-oxidation (redox) responses providing a unique model to study oxidative events in tumor promotion. AP-1 and NF-kappaB, inducible by tumor promoters or oxidative stimuli, show differential protein levels or activation in response to tumor promoters in JB6 cells. We further demonstrated that AP-1 and NF-kappaB are both required for maintaining the transformed phenotypes where inhibition of either activity suppresses transformation response in JB6 cells as well as human keratinocytes and transgenic mouse. NF-kappaB proteins or extracellular signal-regulated kinase (ERK) but not AP-1 proteins are shown to be sufficient for conversion from transformation-resistant to transformation-susceptible phenotype. Insofar as oxidative events regulate AP-1 and NF-kappaB transactivation, these oxidative events can be important molecular targets for cancer prevention.

Mutagen sensitivity and environmental exposures as contributing causes of chromosome 3p losses in head and neck cancers.

The interaction between environmental exposures and host susceptibility may lead to specific mutational events within head and neck squamous cell carcinoma (HNSCC). Furthermore, this interplay may determine not only the probability of cancer development but also the biologic characteristics of the tumor once it occurs. To better understand the relationship of mutagen sensitivity and tobacco and/or alcohol consumption on HNSCC carcinogenesis, we examined loss of heterozygosity on chromosome 3p in 58 HNSCCs using 10 microsatellite markers. Mutagen sensitivity was determined in vitro by quantitating bleomycin-induced chromatid breaks utilizing peripheral blood lympocytes from respective patients. Forty-six of the 58 invasive cancers showed allelic loss at one or more loci. Consistent with previous investigations, three discrete regions of deletions were identified: 3p13-14.2, 3p21.1-21. 2, and 3p25.1-26.1. The frequency and types of deletions were dependent upon tobacco and alcohol exposures. The distal region of 3p but not the remaining two regions was most frequently influenced by tobacco exposure. In contrast, heavy alcohol use when combined with tobacco use was associated with whole-arm loss of 3p rather than identifiable site-specific damage. Furthermore, this combined influence of alcohol and tobacco exposures on whole-arm loss was most apparent in those patients who expressed mutagen-sensitivity; the odds ratio of whole-arm loss increasing from 2.67 (95% CI 0. 21-33.49) in those individuals who were mutagen resistant to 13.5 (95% CI 1.3-136.0; P = 0.02 by Fisher's exact test) in those who were mutagen sensitive. An assessment of clinical parameters in this population demonstrated that patients with whole-arm loss were more likely to present with cervical lymph node metastases and advanced stage disease than patients with partial losses. Results indicate that various environmental exposures as well as the expression of mutagen sensitivity will influence the types of chromosome 3p allelic losses in head and neck cancers as well as the behavior of disease once it develops.

Phase II study of oral tegafur-uracil and folinic acid as first-line therapy for metastatic colorectal cancer: Taiwan experience.

BACKGROUND: Tegafur-uracil has become an important regimen in the treatment of metastatic colorectal cancer. Tegafur is a prodrug that is converted to 5-fluorouracil (5-FU) and has been reported to be less toxic and to have a higher therapeutic index. The additional advantage of tegafur is oral administration, an important consideration to improve the quality of life in these patients. Tegafur in combination with uracil is thought to have greater anti-tumor activity due to the inhibitory effect of uracil on the degradation of 5-FU by hepatic dihydropyrimidine dehydrogenase. Tegafur with folinic acid has been reported with modest efficacy and acceptable toxicity. The purpose of this study was to evaluate the effectiveness and toxicity profile of oral tegafur-uracil plus folinic acid in Chinese patients with metastatic colorectal cancer. METHODS: Between May 1998 and August 1999, 40 patients with metastatic colorectal carcinoma were enrolled in this study. All the patients had to have measurable lesions. The initial dose of tegafur-uracil was 300 mg/m2/day for 28 days, followed by a 7-day rest period. Folinic acid was administered orally at a dose of 60 mg/day concurrently with tegafur-uracil. For patients with neutrophil count <1500/microl or a platelet count <100,000/microl after treatment, the treatment was postponed for a maximum of 2 weeks. After that time, if the neutrophil count was 1000-1500/microl and the platelet count was 70,000-100,000 microl, the dose of tegafur-uracil was reduced by 50%, and if lower values resulted, the treatment was discontinued. RESULTS: Forty patients received a total of 318 courses of treatment and a response rate of 32.5% (95% CI, 18-47%), including five complete remissions and eight partial remissions, was achieved. Toxicity was mild and generally tolerable. Gastrointestinal toxicities, including diarrhea, nausea and vomiting, were the major side effects. Seven incidences (17.5%) of grade 3-4 gastrointestinal toxicity were observed. Hematological toxicities were minimal with no evidence of severe (grade 3 or 4) leukopenia and thrombocytopenia. No episode of hepatic, renal, cardiac or neurological toxicity occurred. Two patients (5%) developed transient painful fissuring erythroderma over their palms and soles (the hand-foot syndrome). CONCLUSIONS: The data from our study indicate that oral tegafur-uracil plus folinic acid is an active and tolerable first-line treatment for Chinese patients with metastatic colorectal cancer, with the additional advantage of being easily administered at home.

Marijuana use and increased risk of squamous cell carcinoma of the head and neck.

Marijuana is the most commonly used illegal drug in the United States. In some subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana smoke are similar to those of tobacco, no epidemiological studies of the relationship between marijuana use and head and neck cancer have been published. The relationship between marijuana use and head and neck cancer was investigated by a case-control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. Epidemiological data were collected by using a structured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased with marijuana use [odds ratio (OR) comparing ever with never users, 2.6; 95% confidence interval (CI), 1.1-6.6]. Dose-response relationships were observed for frequency of marijuana use/day (P for trend <0.05) and years of marijuana use (P for trend <0.05). These associations were stronger for subjects who were 55 years of age and younger (OR, 3.1; 95% CI, 1.0-9.7). Possible interaction effects of marijuana use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use. Our results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. Our analysis indicated that marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. The results need to be interpreted with some caution in drawing causal inferences because of certain methodological limitations, especially with regard to interactions.

Mechanical properties of heel pads reconstructed with flaps.

We compared the mechanical properties of normal and reconstructed heel pads in seven patients. Four had latissimus dorsi flaps and one each an anterior thigh flap, a local dorsalis pedis flap and a sural arterial flap. The thickness of the heel pad was measured under serial incremental loads of 0.5 kg to a maximum of 3 kg and then relaxed sequentially. The load-displacement curve of the heel pad during a loading-unloading cycle was plotted and from this the unloaded heel-pad thickness (UHPT), compressibility index (CI), elastic modulus (Ep), and energy dissipation ratio (EDR) were calculated. The EDR was significantly increased in the reconstructed heels (53.7 +/- 18% v 23.4 +/- 6.5%, p = 0.003) indicating that in them more energy is dissipated as heat. Insufficient functional capacity in the reconstructed heel pad can lead to the development of shock-induced discomfort and ulceration.

High-resolution ultrasonography in detection and follow-up of a tumour of the forearm. Case report.

A 39-year-old man had a mass in his right flexor medial mid-forearm of unknown aetiology for two years. Preoperative high-resolution ultrasonography showed a well-defined solid mass with reduced echogenicity. The mass was excised and histopathological examination showed neurilemmoma. There had been no recurrence of the tumour six months after operation.