Interaction between tobacco and alcohol consumption and the risk of cancers of the upper aero-digestive tract in Brazil

The authors investigated the joint effects of tobacco and alcohol consumption on the risk of squamous cell carcinomas of the upper aero-digestive tract (UADT) using data from a hospital-based case-control study conducted in southern Brazil, 1986-1989. A total of 784 cases of cancers of the mouth, pharynx, and larynx and 1,578 non-cancer controls matched on age, sex, hospital catchment area, and period of admission were interviewed about their smoking and drinking habits and other characteristics. Using logistic regression, evidence was found for interaction between the cumulative exposures for smoking and alcohol on UADT cancer risk. The joint effects for pharyngeal cancers exceeded the levels expected under a multiplicative model for moderate smokers (p = 0.007). There was little statistical evidence, however, for interaction on cancers of the mouth (p = 0.28) or larynx (p = 0.95). Among never smokers, heavy drinkers had 9.2 times (95% confidence interval 1.7, 48.5) greater risk of cancers of mouth, pharynx, and supraglottis than never drinkers, with a dose-response trend (p = 0.013) with cumulative consumption. The authors conclude that the interaction occurring in the pharynx between smoking and alcohol on UADT cancers is not uniform, with varying effects depending on the level of smoking exposure. Alcohol may act as both a promoter for tobacco and as an independent risk factor.     

Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension.

AIMS: To describe the long-term clinical efficacy of inhaled iloprost as first-line vasodilator mono-therapy in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS AND RESULTS: Seventy-six IPAH patients were prospectively identified and treated with inhaled iloprost. Clinical, haemodynamic, and exercise parameters were obtained at baseline, after 3 and 12 months of therapy and yearly thereafter. Four endpoints were prospectively defined as follows: (i) death, (ii) transplantation, (iii) switch to intravenous (i.v.) therapy, or (iv) addition of or switch to other active oral therapy. During follow-up (535+/-61 days), 11 patients died, six were transplanted, 25 were switched to i.v. prostanoids, 16 received additional or other oral therapy, and 12 patients discontinued iloprost inhalation for other reasons. Event-free survival at 3, 12, 24, 36, 48, and 60 months was 81, 53, 29, 20, 17 and 13%, respectively. Among haemodynamic and exercise parameters, mixed venous oxygen saturation (P<0.001), right atrial pressure (P<0.001), and peak oxygen uptake (P=0.002) were associated with event-free survival. CONCLUSION: In this study, only a minority of patients could be stabilized with inhaled iloprost mono-therapy during a follow-up period of up to 5 years. In the presence of multiple treatment options, chronic iloprost inhalation as mono-therapy appears to have a limited role.     

Investigation of the urge-to-cough sensation in healthy volunteers

Background and objective: Recently, there has been interest in the sensation of irritation that precedes the motor act of coughing, which has been termed the urge‐to‐cough (UTC). The aim of this study was to perform the largest evaluation to date of the UTC threshold (C_u) in a healthy population. The specific aims were to investigate the relationship between C_u and cough reflex sensitivity, to evaluate gender differences in the UTC and to assess the reproducibility of measurements of C_u. Methods: Standard capsaicin cough challenge methodology was employed to measure cough reflex sensitivity in 100 healthy adult non‐smokers (50 females) with the additional measurement of C_u. A subgroup of 40 subjects (20 males) underwent repeat cough challenges after 1 week to examine the reproducibility of the measurements. Results: All 100 subjects demonstrated motor cough in response to capsaicin. Twenty‐one subjects (10 females) did not show a discernible C_u, as the motor cough event preceded a UTC sensation unaccompanied by cough. Although cough reflex sensitivity, as measured by the concentration of capsaicin inducing five or more coughs (C₅), was enhanced in women, there was no gender difference in C_u. Similar to standard cough reflex sensitivity measurements, the measurement of C_u was highly reproducible. Conclusions: These results demonstrate that the UTC threshold can be effectively and reproducibly measured using a modification of standard cough challenge methodology. Given its clinical significance as a prevalent symptom, UTC, as measured by C_u, represents an additional relevant end point for studies investigating the effects of pharmacological and other interventions in cough and cough reflex sensitivity.     

Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer

This study was designed to determine the efficacy and toxicity of weekly docetaxel in metastatic breast cancer when given alone (for HER2/neu negative disease) or with trastuzumab (for HER2/neu overexpressing disease). Patients with metastatic breast carcinoma received docetaxel given on 2 different schedules (group 1A, 33 mg/m2 weekly [n = 21]; group 1B, 40 mg/m2 weekly for 3 weeks with 1 week off [n = 14]). Patients with HER2/neu overexpressing disease also received trastuzumab 4 mg/kg on day 1, then 2 mg/kg on days 8 and 15 of each 28-day cycle (group 2). Fifty-two patients were treated with docetaxel alone (group 1A/B, n = 35) or in combination with trastuzumab (group 2, n = 17). Prior taxane therapy given every 3 weeks had been used for metastatic disease in 19 of 35 patients (54%) in group 1A/B and in 2 of 17 patients (12%) in group 2. The mean delivered dose intensity of docetaxel was 29 mg/m2 per week. Partial response occurred in 7 of 35 patients (21%; 95% exact binomial confidence interval [CI], 9%-38%) treated with docetaxel alone, including 3 of 19 taxane-pretreated patients (16%) and 4 of 16 taxane-naive patients (25%). Partial response occurred in 10 of 17 patients (59%; 95% CI, 34%-82%) treated with docetaxel/trastuzumab. The most common grade 3/4 toxicities, occurring in more than or equal to 10% of patients, included neutropenia (21%), pulmonary toxicity (12%), and hyperglycemia (10%). The median times to disease progression were 4.5 months (95% CI, 2.5-6.5 months) in the docetaxel group and 8.5 months (95% CI, 4.5-12.5 months) in the docetaxel/trastuzumab group. Weekly docetaxel/trastuzumab is an effective regimen for patients with HER2/neu overexpressing metastatic breast cancer. Weekly docetaxel may be effective in as many as 20% of patients who had progressive disease after treatment with taxanes given every 3 weeks.     

Choice of clinical outcomes in randomized trials of heart failure therapies: Disease-specific or overall outcomes?

Background There are different views regarding the appropriateness of using cause-specific events or all events as the primary outcome of clinical trials. Methods This is a methodologic essay in which we discuss the pros and cons of the 2 approaches and provide illustrative examples. Results Our preference is the use of cause-specific outcomes (as long as they can be classified with reasonable reproducibility and without bias) because they are more likely to be sensitive to change, less likely to lead to spurious conclusions by random variations in categories of outcomes that are unlikely to be affected by treatment, and relatively free from confounding. Overall benefit-risk ratios can be derived by examining the impact of treatment on various categories of outcomes and then developing a general judgment. Such an approach will also allow judgments to be made regarding generalizability of results across various groups of patients who are at differing risks for an event. Conclusions In general, cause-specific outcomes sensitive to the effects of a treatment are to be preferred as the principal outcome in trials of heart failure, as long as they are biologically sensible and can be classified without bias. Other outcomes, not expected to be affected, should also be reported separately. (Am Heart J 2002;143:22-8.)     

Phase II trial of infusional cyclophosphamide,idarubicin, and etoposide in poor prognosis non-Hodgkin's lymphoma

The purpose of this study was to determine the complete response (CR) rate, failure-free survival (FFS), and overall survival (OS) of patients with poor-prognosis intermediate-grade non-Hodgkin's lymphoma (NHL) after treatment with cyclophosphamide, idarubicin, and etoposide given as a continuous intravenous infusion (CIVI) over 96 hours (infusional CIE), including patients with relapsed/refractory disease and patients with no prior therapy but at least two poor-risk features by the age-adjusted International Prognostic Index. Forty-two patients with previously untreated NHL (N = 24) or relapsed/refractory (N = 18) NHL received cyclophosphamide (200 mg/m2/d), idarubicin (2.5-3.0 mg/m2/d) and etoposide (60 mg/m2/d) given by a 96-hour CIVI every 3 weeks for a maximum of 8 cycles. All patients also received granulocyte-colony-stimulating factor. CR occurred in 10 of 24 patients (42%; 95% confidence intervals [CI] 22%, 62%) treated with CIE as first-line therapy, and in 3 of 18 patients (17%; 95% CI 20%, 32%) treated with CIE as second-line or greater therapy. One-year FFS and OS were 42% and 64%, respectively, in patients with no prior therapy, and 17% and 56% in patients with prior therapy. Severe (grade III) or life-threatening (grade IV) toxicity included leukopenia (59%), anemia (61%), thrombocytopenia (31%), and infection (10%). Two patients (4%) died due to treatment related infectious complications. It is unlikely that infusional CIE produces a CR rate more than about 60% in poor-risk patients with intermediate-grade NHL when used as first-line therapy, or more than about 30% in patients receiving the regimen as second-line therapy. Substitution of idarubicin for doxorubicin in this setting, therefore, is not associated with an improved response rate.     

Polymorphism of the insulin gene is associated with increased prostate cancer risk

High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age.     

Modeling the time dependence of the association between human papillomavirus infection and cervical cancer precursor lesions

The authors studied the time-dependent association between human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) among women enrolled in a cohort study in Brazil (1993-2002), using repeated Papanicolaou cytologic examination and HPV testing by polymerase chain reaction. Through simulation with conceivable alternative cohort designs, they investigated different regression modeling approaches using time-varying covariates, time-varying hazard ratio functions, and repeated events to assess the effect of delay in lesion detection. Associations between HPV and early SIL were of high magnitude. The age-adjusted hazard ratios for the association between HPV at enrollment and low-grade SIL decreased gradually with time until 72 months for both oncogenic types of HPV (hazard ratio = 3.96, 95% confidence interval (CI): 2.5, 6.4) and nononcogenic types (hazard ratio = 2.37, 95% CI: 1.3, 4.3). The hazard ratio for incident high-grade SIL remained constant, ranging from 7.15 (95% CI: 2.0, 25.1) at 12 months to 6.26 (95% CI: 2.7, 14.5) at 72 months for oncogenic types of HPV. With oncogenic HPV as the time-dependent predictor variable, the hazard ratios for incident SIL and high-grade SIL events were 14.2 (95% CI: 8.7, 23.1) and 32.7 (95% CI: 8.4, 127.3), respectively. Investigators may underestimate the prognostic value of HPV detection using designs that rely on HPV ascertainment at a single time point. The waning in hazard ratios should be considered in the implementation of HPV testing-based screening programs.