N-cadherin directs the collective Schwann cell migration required for nerve regeneration through Slit2/3-mediated contact inhibition of locomotion.

Collective cell migration is fundamental for the development of organisms and in the adult for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective SC migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased SC collective migration and increased clustering of SCs within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.

Synergistic lignin degradation between Phanerochaete chrysosporium and Fenton chemistry is mediated through iron cycling and ligninolytic enzyme induction.

Removal of recalcitrant lignin from wastewater remains a critical bottleneck in multiple aspects relating to microbial carbon cycling ranging from incomplete treatment of biosolids during wastewater treatment to limited conversion of biomass feedstock to biofuels. Based on previous studies showing that the white rot fungus Phanerochaete chrysosporium and Fenton chemistry synergistically degrade lignin, we sought to determine optimum levels of Fenton addition and the mechanisms underlying this synergy. We tested the extent of degradation of lignin under different ratios of Fenton reagents and found that relatively low levels of H2O2 and Fe(II) enhanced fungal lignin degradation, achieving 80.4 ± 1.61 % lignin degradation at 1.5 mM H2O2 and 0.3 mM Fe(II). Using a combination of whole-transcriptome sequencing and iron speciation assays, we determined that at these concentrations, Fenton chemistry induced the upregulation of 80 differentially expressed genes in P. ch including several oxidative enzymes. This study underlines the importance of non-canonical, auxiliary lignin-degrading pathways in the synergy between white rot fungi and Fenton chemistry in lignin degradation. We also found that, relative to the abiotic control, P. ch. increases the availability of Fe(II) for the production of hydroxyl radicals in the Fenton reaction by recycling Fe(III) (p < 0.001), decreasing the Fe(II) inputs necessary for lignin degradation via the Fenton reaction.

Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves.

The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a 'bridge' of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as "tracks" to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

(18)F-fluorodeoxyglucose positron-emission tomography-computed tomography to diagnose recurrent cancer.

BACKGROUND: Sometimes the diagnosis of recurrent cancer in patients with a previous malignancy can be challenging. This prospective cohort study assessed the clinical utility of (18)F-fluorodeoxyglucose positron-emission tomography-computed tomography ((18)F-FDG PET-CT) in the diagnosis of clinically suspected recurrence of cancer. METHODS: Patients were eligible if cancer recurrence (non-small-cell lung (NSCL), breast, head and neck, ovarian, oesophageal, Hodgkin's or non-Hodgkin's lymphoma) was suspected clinically, and if conventional imaging was non-diagnostic. Clinicians were asked to indicate their management plan before and after (18)F-FDG PET-CT scanning. The primary outcome was change in planned management after (18)F-FDG PET-CT. RESULTS: Between April 2009 and June 2011, 101 patients (age, median 65 years; 55% female) were enroled from four cancer centres in Ontario, Canada. Distribution by primary tumour type was: NSCL (55%), breast (19%), ovarian (10%), oesophageal (6%), lymphoma (6%), and head and neck (4%). Of the 99 subjects who underwent (18)F-FDG PET-CT, planned management changed after (18)F-FDG PET-CT in 52 subjects (53%, 95% confidence interval (CI), 42-63%); a major change in plan from no treatment to treatment was observed in 38 subjects (38%, 95% CI, 29-49%), and was typically associated with (18)F-FDG PET-CT findings that were positive for recurrent cancer (37 subjects). After 3 months, the stated post-(18)F-FDG PET-CT management plan was actually completed in 88 subjects (89%, 95% CI, 81-94%). CONCLUSION: In patients with suspected cancer recurrence and conventional imaging that is non-diagnostic, (18)F-FDG PET-CT often provides new information that leads to important changes in patient management.

[Juvenile nasopharyngeal angiofibroma with orbital extension]. / Angiofibroma nasofaríngeo juvenil con extensión orbitaria.

CLINICAL CASE: The case is presented of a 21 year-old male with a history of left proptosis and diplopia of two weeks of onset. The MRI showed an ethmoid-orbital vascular lesion with anterior skull base invasion and orbital extension. Biopsy of the ethmoid confirmed fibrovascular tissue, which supported the diagnosis of angiofibroma. DISCUSSION: It is a benign neoplasm with local characteristics of malignancy due to its ability to invade adjacent areas. In this case, the debut presented with manifestations of orbital extension. A broad and multidisciplinary approach is needed in order to improve prognosis.

Competing events in patients with malignant disease who are at risk for recurrent venous thromboembolism.

Patients with malignant disease enrolled in trials of thrombotic disorders may experience competing events such as death. The occurrence of a competing event may prevent the thrombotic event from being observed. Standard survival analysis techniques ignore competing risks, resulting in possible bias and distorted inferences. To assess the impact of competing events on the results of a previously reported trial comparing low molecular weight heparin (LMWH) with oral anticoagulant (OAC) therapy for the prevention of recurrent venous thromboembolism (VTE) in patients with advanced cancer, we compare the results from standard survival analysis with those from competing risk techniques which are based on the cumulative incidence function (CIF) and Gray's test. The Kaplan-Meier method overestimates the risk of recurrent VTE (17.2% in the OAC group and 8.7% in the LMWH group). Risk of recurrence using the CIF is 12.0% and 6.0% in the OAC and LMWH groups, respectively. Both the log-rank test (p=0.002) and Gray's test (p=0.006) suggest evidence in favor of LMWH. The overestimation of risk is 30% in each treatment group, resulting in a similar relative treatment effect; using the Cox model the hazard ratio (HR) is 0.48 (95% confidence interval [CI], 0.30 to 0.78) and HR=0.47 (95% CI, 0.29 to 0.74) using the CIF model. Failing to account for competing risks may lead to incorrect interpretations of the probability of recurrent VTE. However, when the distribution of competing risks is similar within each treatment group, standard and competing risk methods yield comparable relative treatment effects.

[Spinal pleomorphic xantoastrocytoma. Case report]. / Xantoastrocitoma pleomórfico espinal. Caso clínico.

INTRODUCTION: we report the clinical, radiological and pathological features of a spinal pleomorphic xanthoastrocytoma, an unusual neoplastic entity in a really rare location, establish an appropriated management of these lesions and review the short available english literature. CASE REPORT: a 60 years old woman consulted with doctor because she felt progressive clumsiness accompanied by occasional paresthesias on her left hand. Neurological examination showed up weakness and slight propioceptive disturbances. The differential imagine diagnosis was established between intramedullary astrocytoma and ependimoma. Patient underwent surgical gross total remove. Histopathological examination confirmed the diagnosis of pleomorfic xanthoastrocytoma. We performed MRI controls at 6, 12, 24 and 36 months that did not reveal recurrence. Nowadays, the patient has regained her previous quality of life. DISCUSSION AND CONCLUSION: comparing to published cases about intracranial pleomorphic xanthoastrocytomas, spinal pleomorphic xanthoastrocytomas (SPXA) present different epidemiological characteristics. The known SPXAs affected to cervical and/or high thoracic levels. The hypothesis about a more aggressive behaviour of PXA in spinal cord may be corroborated after literature review. Extension examination is mandatory since dissemination along the neuroaxis has been described. Removal extension is crucial in the prevention of tumour recurrence. Adyuvant radiotherapy should only be considered when there is postoperative residual tumour and/or anaplastic features. Randomized clinical trials or databases are necessary to know all the aspects of this pathological entity.

PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma.

BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) occurs in 20-30% of patients with malignant glioma per year of survival. We tested the efficacy of long-term dalteparin low-molecular-weight heparin (LMWH) for prevention of VTE in these patients. PATIENTS/METHODS: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti-Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. RESULTS: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety-nine patients were randomized to LMWH and 87 to placebo. Twenty-two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19-1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48-36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12-month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73-2.0, P = 0.48). CONCLUSIONS: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long-term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.

Lymphedema in women with breast cancer: characteristics of patients screened for a randomized trial.

INTRODUCTION: Accrual rates for a randomized trial of decongestive therapy in breast cancer patients with lymphedema were lower than anticipated. In two centres, patients presenting to lymphedema clinic were screened for eligibility to understand the accrual process and help define the patient population. MATERIALS AND METHODS: All breast cancer patients presenting to two lymphedema clinics in regional cancer centres were screened for study entry. Circumferential arm measurements were taken and volumes calculated. Patients were then screened for trial eligibility. All report forms were sent to the trial coordinating centre. RESULTS: A total of 408 patients were screened. Median arm volume excess was 239 ml (9.5%). One third of patients had little or no excess volume. Only 28.3% of patients had sufficient excess volume for trial eligibility. Of these, a significant number of patients were excluded because of active malignancy or previous decongestive therapy. CONCLUSIONS: The finding of moderate to severe lymphedema observed in clinics screening for trial eligibility was less than expected. The natural history of lymphedema in breast cancer patients is potentially changing. Some patients may be presenting with sensory changes suggestive of lymphedema but due to other causes, such as nerve disruption following axillary dissection.

Colposcopists' agreement on cervical biopsy site.

OBJECTIVE: To determine the inter-observer agreement among colposcopists on the most abnormal area of the cervix from which a biopsy would be obtained and whether any attributes predict agreement. MATERIAL AND METHODS: Fifty cervigrams were reviewed and 72 colposcopists from five countries indicated the site to biopsy and whether an ECC should be obtained. Prior to the study, six Canadian colposcopists met to achieve consensus on the most diseased area for biopsy. Consensus was also reached on whether an ECC was indicated. For each cervigram, percent agreement was determined between each study colposcopist and the consensus. Data were analyzed to determine the attributes associated with the consensus response. RESULTS: The percent overall agreement of the colposcopists with the consensus diagnoses had a mean of 0.70 (95% CI, 0.65-0.75). The use of ECC was most common in Canada (15% of cases). The following factors were assessed by multivariate analysis to determine their influence on individual agreement with the consensus recommendation for the site to biopsy: country, duration of practice (less than or greater than 1 year), professional group (nurse, family doctor, pathologist, gynecologist, gynecologic oncologist), expert status (recognized national/international expert vs colposcopist), and gender. No factor was significantly associated. CONCLUSION: This international study was feasible and the level of inter-observer agreement among colposcopists on the location of the most severe lesions in cervical images is good.

Cross-border referral for early breast cancer: an analysis of radiation fractionation patterns.

Because of increasing waiting times for adjuvant radiation in the province of Ontario, patients from one Canadian centre were referred to two centres in the United States. This situation provided an opportunity to compare radiation practices.We performed a retrospective review of radiation prescribed to patients following breast-conserving surgery for invasive breast cancer. Patients with positive margins, 4 or more positive lymph nodes, recurrent disease, or large tumours (>5 cm) were excluded. For comparison, we reviewed a random sample of similar patients treated at the Canadian centre during the same period. A total of 120 referred and 217 non-referred patients were eligible for comparison. The analysis included 98 pairs of patients (N = 196), fully matched on age, nodal status, T stage, grade, and estrogen receptor (er) status.Mean patient age was 60.7 years. The median total dose and number of fractions differed between centres [6040 cGy in 32 fractions (United States) vs. 4250 cGy in 16 fractions (Canadian), both p < 0.001). Boost was used more often in the United States (97% vs. 9%, p < 0.001). Variation in prescribing patterns was seen. In the United States, seven different schedules for whole-breast irradiation were used; at the Canadian centre, two schedules were prescribed. Predicted radiobiologic effects of these schedules were calculated to be similar.Differences in fractionation patterns were observed between and within U.S. and Canadian centres. Such variability is likely to affect patient convenience and resource utilization. Although patient selection, referring surgeon, and change in policies may account for some of the observed differences, further research is necessary to better understand the causes.

Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.

BACKGROUND: Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. METHODS: We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. RESULTS: One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). CONCLUSION: The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

Bilateral vs. ipsilateral venography as the primary efficacy outcome measure in thromboprophylaxis clinical trials: a systematic review.

Contrast venography, in combination with symptomatic venous thromboembolism (VTE), is the standard efficacy outcome measure in clinical trials of thromboprophylaxis in major orthopedic surgery. It is uncertain whether performing bilateral venography offers any real advantage over venography of the operated leg alone. This study was undertaken to determine the risk of isolated contralateral deep vein thrombosis (DVT) following major orthopedic surgery and to evaluate whether bilateral venography, rather than venography on the operated leg alone, offers any gain in DVT detection and, thereby, improves efficiency in clinical study design. A systematic review of prospective studies that reported DVT incidence as the primary efficacy outcome based on mandatory bilateral venography in patients undergoing elective hip or knee arthroplasty or hip fracture repair was conducted. Based on the use of bilateral venography as a primary efficacy outcome measure, the incidence of any DVT is 16.7% following total hip replacement, 18.8% after hip fracture repair, and 33.8% after total knee replacement. While DVT risk in the operated leg varies depending on the type of surgery, the risk of isolated DVT in the non-operated leg is approximately 4% to 5% in all three procedures. By increasing the detection of any DVT, the use of bilateral venography reduces required sample size by 16% to 25% compared to ipsilateral venography. In clinical trials evaluating the efficacy of thromboprophylaxis in major orthopedic surgery, bilateral venography reduces the risk of undiagnosed DVT in the non-operated leg and improves the efficiency of study design by substantially reducing the sample size requirement.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Clinical utility of a rapid whole-blood D-dimer assay in patients with cancer who present with suspected acute deep venous thrombosis.

BACKGROUND: Although D-dimer assays have high negative predictive values for the diagnosis of deep venous thrombosis, their accuracy in patients with cancer is uncertain. OBJECTIVE: To compare the clinical utility of a whole-blood D-dimer assay for the diagnosis of deep venous thrombosis in patients with and those without cancer. DESIGN: Retrospective analysis of three prospective studies. SETTING: Two tertiary care hospitals. PATIENTS: 1068 consecutive outpatients with suspected deep venous thrombosis. MEASUREMENTS: All patients underwent D-dimer testing and assessment with a priori diagnostic strategies that incorporated impedance plethysmography, compression ultrasonography, or contrast venography. Patients in whom deep venous thrombosis was not diagnosed initially were followed for 3 months for the development of thrombosis. Results of D-dimer testing were assessed according to the final diagnosis based on objective testing and clinical follow-up. Cancer status was identified at presentation. RESULTS: The prevalence of deep venous thrombosis was 48.8% in 121 patients with cancer and 14.6% in 947 patients without cancer. Although the sensitivity of the D-dimer assay was similar in patients with and those without cancer (86.4% [95% CI, 75.0% to 94.0%] and 82.6% [CI, 75.2% to 88.5%], respectively), the specificity was significantly lower in patients with cancer (48.4% [CI, 35.5% to 61.4%] and 82.2% [CI, 79.4% to 84.8%]), as was the negative predictive value (78.9% [CI, 62.7% to 90.4%] and 96.5% [CI, 94.9% to 97.8%]). In contrast, the likelihood ratios of a negative test result (0.28 [CI, 0.14 to 0.56] and 0.21 [CI, 0.15 to 0.31]) did not differ significantly. CONCLUSIONS: A negative D-dimer test result in patients with cancer does not reliably exclude deep venous thrombosis because the negative predictive value of the test is significantly lower in these patients than in patients without cancer.

Mortality from cancer and other causes of death among synthetic rubber workers.

OBJECTIVES: This study evaluated the mortality experience of workers from the styrene-butadiene rubber industry. Concerns about a possible association of 1,3-butadiene and styrene with lymphohaematopoietic, gastrointestinal, and lung cancers prompted the investigation. METHODS: A retrospective follow up study was conducted of 15,649 men employed for at least one year at any of eight North American styrene-butadiene rubber plants. Analyses used standardised mortality ratios (SMRs) to compare styrene-butadiene rubber workers' cause specific mortalities (1943-91) with those of the United States and Ontario general populations. RESULTS: On average, there were 25 years of follow up per subject. The standardised mortality ratio (SMR) was 87 (95% confidence interval (95% CI) 85 to 90) for all causes of death combined and was 93 (95% CI 87 to 99) for all cancers. There was an excess of leukaemia (SMR 131, 95% CI 97 to 174), restricted to hourly workers (SMR 143, 95% CI 104 to 191). For causes of death other than leukaemia, SMRs were close to or below the null value of 100. Results by work area (process group) were unremarkable for non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer. Maintenance workers had a slight increase in deaths from lung cancer, and certain subgroups of workers had more than expected deaths from cancer of the large intestine and the larynx. CONCLUSION: This study found an excess of leukaemia that is likely to be due to exposure to butadiene or to butadiene plus other chemicals. Deaths from non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer did not seem to be related to occupational exposure. The excess deaths from lung cancer among maintenance workers may be due in part to confounding by smoking, which was not controlled for, and in part to an unidentified occupational exposure other than butadiene or styrene. Increases in cancer of the large intestine and larynx were based on small numbers, did not seem to be due to exposure to butadiene or styrene, and may be chance observations.

The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial.

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

Causes of death in Canadians with haemophilia 1980-1995. Association of Hemophilia Clinic Directors of Canada.

The life expectancy of individuals with haemophilia was close to that of the general population in the early 1980s. Since then, life expectancy has decreased, due to transfusion-transmitted virus infections. Deaths in individuals with haemophilia were investigated by analysing 2450 records from the Canadian Hemophilia Registry, for the years 1980-1995. Deaths were tabulated by age, year and cause, and compared with that of the Canadian male population by calculating standardized mortality ratios (SMRs). The median life expectancy at 1 year of age was calculated for various subpopulations and the impact of various population characteristics was assessed by survival regression modelling. There were 359 deaths and the annual number of deaths increased significantly after 1986. Risk factors were seropositivity to human immunodeficiency virus (relative risk 16.7, 95% CI 11.1-25.1), severe haemophilia (1.9, 1.3-2.7) and moderate haemophilia (1.8, 1.2-2.6). In HIV antibody negative individuals, the overall death rate was not increased (SMR 0.9, 95% CI 0.7-1.1) and only haemorrhage was significantly increased. In HIV antibody positive individuals, causes of death which were significantly increased were acquired immunodeficiency syndrome, liver failure, haemorrhage, lymphoma, liver cancer, nonspecific infections, and trauma or violence. Deaths due to the acquired immunodeficiency syndrome accounted for only 66% of the excess deaths in individuals who were HIV antibody positive. Life expectancy has markedly decreased since the onset of the HIV epidemic. The impact of HIV is underestimated by considering only deaths due to the acquired immunodeficiency syndrome; other HIV-linked causes need also to be considered.

Cancer of the respiratory tract in nickel sinter plant workers: effect of removal from sinter plant exposure.

The risk of death due to cancer of the nose or lung was studied in nickel sinter plant workers during the period after they left the sintering operations. It was found that the excess risk of death from both diseases continued for many years after leaving the sinter plant. No effect of age at first exposure could be found. Possible explanations for the continued risk include an irreversible cellular change or the persistence of carcinogenic nickel compounds in the mucosa.

Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough?

PURPOSE: To estimate the impact of chemotherapy on survival of patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Randomized controlled trials (RCTs) published in the English-language medical literature between 1970 and 1991 were identified through MEDLINE and the reference lists of relevant articles. Six RCTs that accounted for 635 patients and compared first-line chemotherapy with supportive care in advanced NSCLC and reported survival up to at least 1 year were identified. Cumulative proportions of survival at 3, 6, 9, and 12 months for chemotherapy and control groups were derived from survival curves. RESULTS: Within each study, the effect of chemotherapy was estimated with a pooled relative risk (RR) across the four 3-month periods. An overall estimate of the RR of death at 1 year (RRM-H) was then calculated and a survival curve for chemotherapy-treated patients was constructed applying the pooled estimate of the RR (RRW) for each 3-month period. Overall, chemotherapy was associated with a 24% (95% confidence interval [CI], 13% to 34%) reduction in the probability of death when compared with supportive care. However, the effect of treatment appeared to decrease significantly after the first 6 months from therapy inception and the mean potential gain in survival, as compared with supportive care, was approximately 6 weeks (95% CI, 1 to 10). CONCLUSION: Chemotherapy is effective in the treatment of advanced NSCLC, but its impact on the length of survival is limited. Future RCTs should still include an untreated control group and should measure quality of life in addition to survival.