Stromal features are predictive of disease mortality in oral cancer patients.

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvß6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvß6-dependent TGF-ß1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage.

Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis.

PURPOSE: To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS: TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION: This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

First-trimester or second-trimester screening, or both, for Down's syndrome.

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates.

Combining nuchal translucency and serum markers in prenatal screening for Down syndrome in twin pregnancies.

A method is described to combine the ultrasound marker nuchal translucency (NT) with serum markers so that they can be used together in prenatal screening for Down syndrome in twin pregnancies. For monochorionic twin pregnancies (taken as monozygous), the two fetus-specific NT measurements are averaged before risk is calculated and before the contribution of the serum markers is incorporated. For dichorionic twin pregnancies (taken as dizygous), the risk for each fetus based on the individual NT measurements is calculated, the two fetus-specific risks are added together, and then the contribution of the serum markers is incorporated. In this way, all the screening markers can be used in combination to produce a pregnancy-specific "pseudo-risk", rather than a fetus-specific pseudo-risk. We refer to pseudo-risk because in the absence of sufficient data on the screening markers in affected twin pregnancies, a true risk estimate cannot be calculated. Tentative estimates are given of screening performance in twins using NT, the combined test (NT with first-trimester serum markers), and the integrated test (NT with first- and second-trimester serum markers), all interpreted with maternal age.

Antenatal screening for Down's syndrome with the quadruple test.

Second trimester screening for Down's syndrome is widely practised throughout the world. We assessed the performance of antenatal serum screening for Down's syndrome with the quadruple test in 46193 pregnancies from 14 hospitals over 5 years. Women who screened positive (risk > or =1 in 300) were offered diagnostic amniocentesis or chorionic villus sampling. Of 88 observed Down's syndrome pregnancies, 71 (81%) had a positive screening result (81% detection rate, 95% CI 72-89), and of 46105 unaffected pregnancies, 3200 tested positive (7% false-positive rate). These results show that the quadruple test is a better method of screening for Down's syndrome than use of maternal age alone (51% detection rate, 14% false-positive rate) and is more effective than other second trimester screening tests. Therefore, we conclude that the quadruple test should be the test of choice in second trimester screening for Down's syndrome.

Influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance.

OBJECTIVES: To determine the influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance. METHODS: First, a meta-analysis of cohort and case-control studies was performed to estimate the effect of maternal smoking on the live birth prevalence of Down syndrome. Then, data from 8779 women screened using the quadruple test (alphafetoprotein (AFP), unconjugated estriol (uE(3)), human chorionic gonadotrophin (free beta-hCG), and inhibin-A levels with maternal age) were used to determine the effect of smoking on the serum markers. A Monte Carlo simulation was used to assess the impact of adjusting for smoking status on screening performance. RESULTS: The relative risk of Down syndrome in smokers (versus non-smokers) was 0.95 (95% confidence interval (CI) 0.87 to 1.03). Serum marker levels were determined as multiples of the median for non-smokers of the same gestational age and adjusted for maternal weight (MoM). The MoM values for AFP were 5% higher (95% CI 2-7%), uE(3) 4% lower (95% CI 2-5%), free beta-hCG 20% lower (95% CI 17-23%) and inhibin-A 62% higher (95% CI 57-67%) in smokers compared with non-smokers. Adjusting marker levels for smoking resulted in less than a 1 percentage point increase in the detection rate for a 5% false positive rate with the double, triple or quadruple tests. CONCLUSIONS: There is no evidence of an association between the birth prevalence of Down syndrome and maternal smoking. The case for adjusting screening marker levels for smoking is not compelling. But if smoking data are collected routinely adjustment could be made and this would yield similar detection and false positive rates in smokers and non-smokers.