A novel candidate gene in autosomal dominant facial pruritus.

In the clinical investigation of a family with debilitating centrofacial pruritus by exome sequencing, we have observed a clear segregation of the TRPM3 variant outlined, which is highly suggestive of a causal relationship.

Patient characteristics in tardive COVID-19 pseudoperniosis: a case series of 16 patients.

BACKGROUND: Acute pseudoperniosis (PP) has a recognized association with COVID-19 and tends to occur without cold precipitation in young, healthy patients, often without a clear history of COVID-19. These lesions usually resolve within 2 weeks and without long-term sequelae. In the early months of 2021, patients with delayed and protracted PP began to emerge. We have called this presentation 'tardive COVID-19 PP (TCPP)'. AIM: To consolidate and expand knowledge on TCPP, we describe the clinical characteristics, treatments and outcomes of 16 patients with TCPP who were reviewed by our outpatient dermatology service. RESULTS: The initial clinical manifestations were erythema, swelling and PP of the fingers in 56.2%, and of the toes in 31.2%, desquamation in 56.2% and acrocyanosis in 12.5%. Ten patients had eventual involvement of all acral sites. The median duration of symptoms was 191 days. Six patients reported close contact with a confirmed or suspected case of COVID-19, but only two had positive COVID-19 tests. Four patients experienced complete or almost complete resolution of symptoms, while the rest remain under active treatment. CONCLUSION: Unlike acute PP, TCPP has a protracted and delayed presentation that is typically associated with profound acrocyanosis. Patients with TCPP represent a new phenomenon that is part of the post-COVID-19 syndrome, with risk factors and pathophysiology that are not yet fully understood. Our data indicate that likely predisposing factors for developing TCPP include young age, a preceding history of cold intolerance and an arachnodactyloid phenotype. Anorexia, connective tissue disorders or sickle cell trait may also predispose to TCPP. In addition, low titre antinuclear antibody positivity, the presence of cryoglobulins, or low complement levels may represent further risk factors. Finally, prolonged low temperatures are also likely to be contributing to the symptoms.

Occupational exposure and risk of central nervous system demyelination.

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.

Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially.

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18-59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'.

The influence of weather on community gastroenteritis in Australia.

Infectious gastroenteritis is a common illness in Australia as elsewhere. Data from a year-long national gastroenteritis survey in 2001-2002 showed that gastroenteritis was more common in the northern and hotter part of Australia. These data were used to quantify associations between local weather variables and gastroenteritis in people aged >5 years while controlling for socioeconomic status. A distributed lag model was used to examine the influence of weather over a period of days prior to an event and the maximal effect was found at a lag of 2-5 days. The total effect over the preceding week indicated a relative increase from baseline in the probability of gastroenteritis of 2·48% (95% CI 1·01-3·97) for each degree rise (°C) over that period. Given the very high burden of gastroenteritis, this represents a substantial effect at the population level and has relevance for health predictions due to climate change.

Potential methanol toxicity and the importance of using a standardised alcohol-based hand rub formulation in the era of COVID-19.

OBJECTIVES: Hand sanitisers are urgently needed in the time of COVID-19, and as a result of shortages, some people have resorted to making their own formulations, including the repurposing of distilleries. We wish to highlight the importance of those producing hand sanitisers to avoid methylated spirits containing methanol and to follow WHO recommended formulations. METHODS: We explore and discuss reports of methanol toxicity through ingestion and transdermal absorption. We discuss the WHO formulations and explain the rationale behind the chosen ingredients. SHORT CONCLUSION: We advise those producing hand sanitisers to follow WHO recommended formulations, and advise those producing hand sanitisers using methylated spirits, to avoid formulations which contain methanol.

Childhood infections, vaccinations, and tonsillectomy and risk of first clinical diagnosis of CNS demyelination in the Ausimmune Study.

BACKGROUND: The association between childhood vaccinations and infections and risk of multiple sclerosis is unclear; few studies have considered age at vaccination/infection. OBJECTIVE: To explore age-related associations between childhood vaccinations, infection and tonsillectomy and risk of a first clinical diagnosis of CNS demyelination. METHODS: Data on case (n = 275, 76.6% female; mean age 38.6 years) and age- and sex-matched control (n = 529) participants in an incident population-based case-control study included self-reported age at time of childhood vaccinations, infections, and tonsillectomy. Conditional logistic regression models were used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: Poliomyelitis vaccination prior to school-age was associated with increased risk of a first clinical diagnosis of CNS demyelination (AOR = 2.60, 95%CI 1.02-6.68), based on a very small unvaccinated reference group. Late (11-15 years) rubella vaccination (compared to none) was associated with lower odds of being a case (AOR = 0.47, 95%CI 0.27-0.83). Past infectious mononucleosis at 11-15 years (AOR = 2.84, 95%CI 1.0-7.57) and 16-20 years (AOR = 1.92, 95%CI 1.12-3.27) or tonsillectomy in adolescence (11-15 years: AOR = 2.45, 95%CI 1.12-5.35), including after adjustment for IM, were associated with increased risk of a first clinical diagnosis of CNS demyelination. CONCLUSIONS: Age at vaccination, infection or tonsillectomy may alter the risk of subsequent CNS demyelination. Failing to account for age effects may explain inconsistencies in past findings.

Atrial fibrillation and anticoagulation in a stroke unit population.

BACKGROUND: Atrial fibrillation (AF) is an important predisposing factor for ischaemic stroke. There is evidence to suggest that even in appropriate candidates warfarin therapy is underutilized. We assessed the prevalence of AF in an Australian stroke unit to determine the degree of undertreatment at presentation. METHODS: A retrospective analysis of all patients admitted to our Stroke Unit between October 2004 and September 2006 was carried out. All patients with a diagnosis of AF, either new or old, were then selected from this group to determine the overall prevalence and anticoagulation status. Data regarding prior stroke, stroke severity and discharge anticoagulation status were also determined. RESULTS: Data from a total of 500 patients were analysed. Our results showed that AF-related strokes accounted for a large proportion (28%) of all admissions and were associated with a larger neurological deficit. Most patients (68%) with a prior diagnosis of AF without having obvious contraindications were either not anticoagulated or under-anticoagulated when presenting with an ischaemic stroke or transient ischaemic attack. CONCLUSION: Our results stress the importance of initiating and maintaining anticoagulation in patients with AF and without obvious contraindications to minimize the risk of subsequent stroke.

Higher maternal dietary protein intake in late pregnancy is associated with a lower infant ponderal index at birth.

AIM: A high ponderal index at birth has been associated with later obesity and it has been suggested that intervention to prevent obesity and its sequela should consider the antenatal period. In this context, we investigated the association between maternal nutrition and birth anthropometry. DESIGN: We analyzed data on 1040 mother-infant pairs collected during the Tasmanian Infant Health Survey (TIHS), Tasmania, 1988-1989. Maternal dietary intake during pregnancy was measured by food frequency questionnaire (FFQ) applied soon after birth. Outcomes of interest were birth weight, birth length, head circumference, ponderal index, head circumference -to-ponderal index ratio, placenta-to-birth weight ratio and head circumference-to-birth length index. RESULTS: In multiple regression model, an increase of 10 g of absolute protein intake/day was associated with a reduction in birth weight of 17.8 g (95% CI: -32.7, -3.0; P=0.02). Protein intake was also associated negatively with ponderal index (beta=-0.01; 95% CI: -0.02, -0.00; P=0.01). A 1 % increase in carbohydrate intake resulted in a 1% decline in placental weight relative to birth weight. Higher protein intake in the third trimester was associated with a reduced ponderal index among large birth weight infants but not low birth weight infants. CONCLUSIONS: This raises the possibility that any effect of high protein in altering infant anthropometry at birth may involve changes in body composition and future work to examine how a high-protein diet influences body composition at birth is warranted.

Adverse effects of a multicentre system for ethics approval on the progress of a prospective multicentre trial of cancer treatment: how many patients die waiting?

BACKGROUND: As cancer survival is improving approximately by 1-2% per year, delays in the clinical trials that lead to that improvement could cost lives. AIMS: To review the process of ethics committee approval for a multicentre clinical trial of cancer treatment and to estimate the delay it will cause in obtaining the results and the effects of such delays on survival for all cancers in Australia. METHODS: A survey was sent to each of the 15 centres participating in the study to obtain details about submissions they had made to their ethics committees and the replies received from them. RESULTS: The survey response rate was 100%. The average time required to complete an ethics submission was 12 h, and the average length of time for a final reply was 70 days. Wide variation was noted in the replies, 40% were considered constructive. Most centres said the effort in ethics submissions is sufficient to limit participation in other clinical trials that are available. CONCLUSION: The multicentre system of ethics approval has significantly delayed this multicentre trial and may delay advances in cancer care. Extrapolating this delay to determine an influence on improvements in cancer survival suggests that it may be responsible for 60 cancer deaths per year. A method for measuring the effect on the shape of the accrual curve is defined, and the term DIABOLECAL (Delays in Accrual Brought On Largely by Ethics Committee Activity Lag-time) is proposed to describe it. Attempts to overcome this problem have been introduced overseas.

Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis.

BACKGROUND: Acute bronchitis leading to ongoing exacerbations is a serious condition predisposed to by viruses, bacteria or environmental factors. It can be fatal. Antibiotic therapy is not particularly useful. An oral Haemophilus influenzae vaccine has been developed. OBJECTIVES: To assess the effects of an oral, monobacterial whole-cell, killed, nontypeable H. influenzae vaccine in protecting against recurrent acute episodes in chronic bronchitis. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to January Week 4 2006), EMBASE (1990 to September 2005) and ISI Current Contents (2004 to May 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of the H. influenzae vaccine on patients with recurrent acute exacerbations of chronic bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Three authors extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable H. influenzae measured in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. The vaccine reduced the incidence of bronchitic episodes at three months after vaccination (rate ratio is 0.69; 95% CI 0.41 to 1.14) and at six months after vaccination (rate ratio 0.82; 95% CI 0.62 to 1.09). If these results been statistically significant, they would have represented a reduction in acute bronchitic attacks for vaccinated individuals of 31% at three months, and 18% at six. The effect had disappeared by nine months. The severity of exacerbations in the treatment group, as measured by requirement to prescribe antibiotics, was likewise reduced by 58% at three months (Peto odds ratio = 0.42; 95% CI 0.16 to 1.13), and by 65% at six months (Peto odds ratio = 0.35; 95% CI 0.16 to 0.75). AUTHORS' CONCLUSIONS: Vaccinating patients with recurrent acute exacerbations of chronic bronchitis in the autumn may reduce the number and severity of exacerbations over the following winter. A large clinical trial is needed.

Changing trends in the UK management of upper GI bleeding: is there evidence of reduced UK training experience?

OBJECTIVE: The aim of this study was to evaluate UK trainee experience in endoscopy for acute upper gastrointestinal bleeding (AUGIB). METHODS: Data was prospectively collected from all patients presenting to South Yorkshire Hospitals with AUGIB from September 2011 to December 2011 and compared with data from 1996. Concurrently, all gastroenterology trainees registered with the British Society of Gastroenterology were invited to respond to a web-based questionnaire regarding their experience in AUGIB management. RESULTS: 77% (589/766) of the patient cohort underwent endoscopy for AUGIB; 15% (90/589) were performed by trainees. 7.2% (9/125) of the out of hours endoscopy case load was performed by trainees; all were low-risk or medium-risk cases (pre-endoscopy Rockall score ≤4). During the study period, dual therapy was delivered by a trainee on only four occasions. Comparison with the 1996 cohort demonstrated a marked reduction in the number of trainee performed endoscopies (76% vs 15%; p<0.001). Questionnaires were returned by 51% (245/478) of British Society of Gastroenterology trainees. 81% (198/245) thought that <10% of the gastroscopies they had performed involved therapeutic intervention. 23% (57/245) felt they would not be competent in AUGIB endoscopy by completion of specialty training. CONCLUSIONS: This study demonstrates the decline over time in trainee experience in AUGIB endoscopy. It also highlights a lack of trainee exposure to more challenging cases, out of hours endoscopy and therapeutic procedures. Furthermore, trainees are concerned that a level of competency may not be attained during specialty training. We advocate reviewing UK endoscopic training provision for AUGIB to ensure that experienced endoscopists are produced to meet future service needs.

A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study.

PURPOSE: This clinical trial was designed to compare the effectiveness of the standard melphalan and prednisone regimen to that of melphalan, prednisone, and interferon in patients with untreated multiple myeloma. PATIENTS AND METHODS: Between October 1985 and March 1988, 278 patients were accrued to a multi-institutional, randomized clinical trial. Responding patients were treated for 2 years before termination of therapy. RESULTS: After a median follow-up of 23 months, the overall remission rate for the melphalan/prednisone treatment group was 44% compared with 33% for the group receiving melphalan/prednisone/interferon alfa-2b. The durations of response and survival were identical for the two treatment groups. Median survival was 3.17 years on melphalan/prednisone treatment and 3.0 years on melphalan/prednisone/interferon alfa-2b treatment. Both hematologic and nonhematologic toxicities were greater in the melphalan/prednisone/interferon alfa-2b treatment group, but were usually of a mild or moderate degree and did not interfere with the completion of therapy. The frequency of deaths in the two treatment groups attributable to the treatment itself was similar. CONCLUSION: This study shows no advantage to the concomitant delivery of interferon alfa-2b with standard melphalan and prednisone as initial treatment for patients with multiple myeloma.

Upward bias in estimates of pacemaker reliability: effect of unreported patient mortality.

OBJECTIVES: This study attempted to determine the effect of unreported patient deaths on estimates of pacemaker reliability. BACKGROUND: The reliability of pacemakers is usually reported with reference to implant registration data and returned product analysis without censoring when follow-up data are missing. METHODS: We studied 73 patients (mean [+/- SD] age 77 +/- 8 years) undergoing implantation of a ventricular-inhibited (VVI) pacemaker who were subsequently found to be at increased risk of experiencing premature pacemaker failure. Survival curves for patients and pacemakers were constructed by the Kaplan-Meier method with appropriate censoring at the time of unrelated death or elective explantation of a normal device. To examine the effect of unreported loss of follow-up data, patient mortality was then ignored, and follow-up for pacemakers without known failure was assumed to continue to the date of analysis. RESULTS: There were 13 device failures, with a median pacemaker survival time of 37 months. Twenty-three patients died, all of causes unrelated to the pacemaker system; median patient survival time was only 44 months. Ignoring this attrition inflated follow-up time from 122 to 188 patient-years and reduced the apparent pacemaker failures at 30 months by almost half, from 37% to only 20%. Modeling the process shows that when the patient mortality rate is more than half the pacemaker failure rate, ignoring censoring inflates the device survival estimate by > or = 10% from the median survival onward. CONCLUSIONS: When medical device survival curves are generated by implant registration data and returned product analysis, they should be adjusted for unreported loss of follow-up.

Randomized trial of a hospital-based exercise training program after acute myocardial infarction: cardiac autonomic effects.

OBJECTIVES: This study sought to determine whether a moderate intensity supervised exercise training program, performed immediately after an uncomplicated acute myocardial infarction, improves recovery in cardiac autonomic function compared with standard advice about activity at home. BACKGROUND: Exercise training has beneficial effects on cardiac autonomic function and may improve prognosis after acute myocardial infarction. METHODS: Thirty-nine male and 10 female patients, mean (+/-SE) age 57 +/- 1 years, with an uncomplicated acute myocardial infarction were randomized to either a 6-week moderate intensity supervised hospital-based exercise training program (exercise group) or to an unsupervised low intensity home walking program (control group). Outcome measures included changes in baroreflex sensitivity (phenylephrine bolus method) and heart rate variability (24-h Holter monitoring) and the endurance time at 85% of peak oxygen consumption. RESULTS: At baseline, there were no significant differences in left ventricular ejection fraction (57 +/- 2% vs. 53 +/- 2%), frequency of anterior infarction (27% vs. 18%) and peak creatine kinase (1,256 +/- 170 vs. 2,599 +/- 295 IU) between the exercise and control groups. Baroreflex sensitivity (10.5 +/- 1.0 vs. 8.4 +/- 1.2 ms/mm Hg) and time domain measures of heart rate variability were also similar. After completion of the program, the exercise group exercised for a median of 15 min (interquartile range 12 to 25) at a workload of 104 +/- 7 W compared with 7 min (interquartile range 3.5 to 12) at a workload of 89 +/- 8 W in the control group (p < 0.01). There were significant (p < 0.001) improvements in baroreflex sensitivity and heart rate variability for the 49 patients combined but no differences between the exercise and control groups. Baroreflex sensitivity improved by 3.4 +/- 1.0 and 1.7 +/- 1.0 ms/mm Hg and the standard deviation of 24-h RR intervals by 36 +/- 6 and 40 +/- 10 ms, respectively (p > 0.1). CONCLUSIONS: A hospital-based exercise training program increased endurance capacity but did not improve recovery of cardiovascular antonomic function after uncomplicated acute myocardial infarction.

Traits that influence longevity in mice: a second look.

Analysis of genetic interactions in the F2 of an intercross of (C57BL/6 x DBA/2) F1J revealed influences of genetic factors on life span. Females lived longer than males. Dilute brown females died sooner than females of other colors. H-2b/H-2b males died sooner than H-2b/H-2d or H-2d/H-2d males, except that among dilute brown males those of typeH-2b/H-2d died sooner. Cluster analysis suggested that male and female genotypes each fall into two groups, with female dilute brown mice having shorter lives than other females, and male H-2b/H-2b mice except dilute brown and dilute brown H-2b/H-2d mice having shorter lives than other males. The association of heterozygosity with life span was clearer in females than in males, yet the longest-lived female genotype was homozygous H-2d/H-2d, of dominant Black phenotype at the Brown locus of chromosome 4, and homozygous dd at the Dilute locus of chromosome 9. The shortest-lived females were dilute brown H-2b/H-2b. The longest-lived and shortest-lived male genotypes were dilute brown H-2d/H-2d and dilute brown H-2b/H-2d, respectively. Although histological findings at postmortem differed between the sexes, there was no association of particular disorders with other genetic markers. The importance of H-2 in males was confirmed, but the allelic effects were perturbed, possibly by the absence of Sendai infection in this experiment. Overall our studies suggest that genetic influences on life span involve interactions between loci, and allelic interactions may change with viral infections or other environmental factors.

Reporting of age data in clinical trials of arthritis. Deficiencies and solutions.

OBJECTIVE: We studied recent nonsteroidal anti-inflammatory drug (NSAID) randomized control trials of arthritis to identify the age and number of older people (> or = 65 years) and to document the way information on age was presented. We hypothesized that older people, who are most likely to take NSAIDs are underrepresented and underreported. STUDY SELECTION AND DATA EXTRACTION: All NSAID articles (n = 1008) in MEDLINE between September 1987 and May 1990 were identified. Eighty-three trials employing NSAIDs in a randomized control trial of arthritis reported in 73 articles were identified and studied in detail for age-related information. RESULTS: A total of 9664 subjects with a female-to-male ratio of 2.3:1 were enrolled. Forty-four trials studied osteoarthritis (53.0%), 37 studied rheumatoid arthritis (44.6%), and two studied both conditions (2.4%). More than half of the studies reviewed included people 65 years of age or older, only 207 people in this older age group could be identified (2.1%). While there was inclusion of the 'young-old' (65 to 74 years of age), only 14 of the 9664 people studied were between 75 and 84 years of age, and no one 85 years or older could be identified. The inclusion of the young-old is documented by the weighted mean age that ranged from 59.6 to 64.9 years for patients with osteoarthritis (mean, 62.9; SD, 1.67) and from 47.4 to 53.0 years (mean, 49.9; SD, 2.16) for those with rheumatoid arthritis. CONCLUSION: We demonstrate that older people, who represent a high proportion of the population treated with NSAIDs in practice, are generally omitted from drug trials. Recommendations designed to improve the reporting of age information to make clinical trials more informative and applicable to older people are presented.

Non-centralised service for palliative stenting of malignant gastric outlet obstruction.

INTRODUCTION: Malignant gastric outlet obstruction (GOO) is a common, debilitating and frequently pre-terminal symptom of intra-abdominal malignancies. Traditional 'gold standard' treatment has been palliative surgical gastro-enterostomy. Over the past two decades, use of self-expanding metallic stents (SEMSs) to relieve malignant GOO has become first-line treatment. We present the results from a single district general hospital in the UK in which malignant GOO was treated with SEMSs over a six-year period. METHODS: All patients who underwent palliative stenting for malignant gastro-duodenal tumours in our centre for six years up to January 2013 were assessed retrospectively. Outcomes were assessed with regard to: technical and clinical success; return to oral nutrition; prevalence of complications and re-intervention; and overall survival. RESULTS: Thirty-two stents were implanted in 29 patients. Technical success was 100%. Clinical success and return to oral nutrition were both 91%. The prevalence of complications was 16%. The prevalence of re-intervention was 13%. Mean survival was 91 (range, 5-392) days. Median wait from decision to implant a stent to stent implantation was 1 (range, 0-14) day. Overall, 25 covered and nine uncovered stents were implanted. CONCLUSION: Stent implantation for GOO in this patient group is an established and preferable alternative to surgical intervention. Much of the treatment for malignancies of the upper gastrointestinal tract has now been centralised. Our data showed comparable results with published data for these procedures, with a high prevalence of success and low prevalence of major complications. It is of considerable benefit to these patients not to have to travel to a regional centre for stent implantation.

The follicular non-Hodgkin's lymphomas--I. The possibility of cure.

The follicular lymphomas pursue an indolent course in many patients. Long-term follow-up in large series is therefore necessary to establish whether cure is taking place, and if so, at what stage in the dissemination of the disease process it becomes unlikely. The time to, and site of relapse, together with its impact on survival has been studied in 398 patients entered into the British National Lymphoma Investigation limited and disseminated disease trials between 1974 and 1980. Relapse data were compared with various models to obtain maximum likelihood estimates of the proportions permanently remaining relapse-free following treatment. Long-term relapse-free survival was observed in 54.8 +/- 14.9% (95% CI) of patients at 15 years with Ann Arbor stage I disease, 29.2 +/- 13.6% in patients with stage II disease, 18.1 +/- 6.6% with stage III and 13.0 +/- 5.9% with IV disease. Relapse time-course data for all trial arms conform closely to lognormal distributions allowing maximum likelihood estimates of proportions remaining permanently relapse-free to be derived. Using this methodology, over a quarter of patients treated with involved radiotherapy alone or radiotherapy plus 6 months of chlorambucil in the limited disease (Ann Arbor stage I and II) trial are unlikely to relapse at any time in the future. Over 10% of patients treated in the disseminated disease trials with disease classified as Ann Arbor stage III are also statistically unlikely to relapse. The finding that a proportion of patients is statistically unlikely to experience a clinically obvious relapse is consistent with clinical cure. It is especially interesting that a small proportion of patients with disseminated disease and treated by chemotherapy have fallen into this category, but additional data are required to know at what point statistical cure becomes unlikely. Whether "clinical cure" is the same as "pathological cure" in this disease remains uncertain.

The follicular non-Hodgkin's lymphomas--II. Prognostic factors: what do they mean?

The Ann Arbor staging classification has long been recognised to have shortcomings when used to stage the follicular lymphomas. To date, the identification of important prognostic variables has not succeeded in producing a superior staging classification that reflects the stages of dissemination of these processes in a way that can be used in the testing of new therapeutic strategies. A fresh look is taken at these factors. Data from 398 patients entered into the British National Lymphoma Investigation trials between 1974 and 1980, were analysed to evaluate the performance of the Ann Arbor staging classification. Multiple regression and proportional hazards techniques were used to determine what factors independently influence response to initial treatment, the durability of that response and ultimate survival, and to isolate factors that relate to disease progression from those that have other mechanisms of action. The Ann Arbor staging classification fared poorly, minimally separating relapse-free and cause-specific survival probabilities in patients with the largest staging groupings, III and IV. Significant prognostic heterogeneity was seen in both of these stage groupings, with 22% of patients with stage IV disease on the basis of marrow involvement having slightly better outcomes than patients with stage III disease. Significant differences in outcome were also observed between patients of different age and sex in each Ann Arbor stage grouping. Increasing number of lymph node regions involved, constitutional symptoms, the presence of splenomegaly and increasing age were observed to have powerfully independent adverse influence on probability of complete response to treatment and cause-specific survival. The evolution of the follicular lymphomas is reflected at the clinical level by an increase in the number of lymph node regions involved and splenomegaly. Simple classifications based on simple counts of lymph node regions involved and splenomegaly are more successful than the Ann Arbor staging classification in subdividing the series into patient subgroups that, regardless of gender or age, experience significantly different probabilities of responding completely to therapy and, as a consequence, relapse-free and cause-specific survival expectations. The definition of poor prognosis in subgroups may be of value in selecting patients for newer and more intensive therapeutic approaches.