Quality control in radiotherapy: the reduction of field placement errors.

A 'blind' study using treatment verification films has been performed on two series of patients to assess the accuracy of placement of complex infradiaphragmatic fields planned to include para-aortic nodes. Sequential verification films (VF) for each field on all patients studied were compared to determine variations in field position relative to the anatomy, especially lymph nodes, and the simulator plan. Nodes included in the plan but partially or completely missed by one or more treatments were identified, as were the error types involved. In series I, 21% of 157 VF showed a nodal miss, and after changes in practice designed to minimize the error types responsible for those, the figure was reduced in series II to 5.5% of 194 VF. In series II a 50% reduction in magnitude of the average systematic lateral shift and rotation of posterior fields is attributed mainly to the discontinuation of the practice of treating posterior fields through the couch. Apart from a prescribed width of less than 9 cm, three quantitative key factors were derived: greater than 6 mm lateral shift, greater than 7 mm field narrowing, 2 degree or more rotation of fields. The correction of these errors if identified on verification films, should eliminate the subsequent occurrence of node misses. The value of routine clinical treatment verification films at the start of treatment to identify and correct systematic errors is emphasized, as is the importance of precise and standardized technical practice.

Time trend in annual kidney graft survival.

First cadaver, unrelated kidney graft survival at one year from 50 Eurotransplant centers was analyzed and found to show marked changes in survival rates over the 20-year period from 1967 to 1986 inclusive. Full information on HLA-A, -B, and -DR matching and use of cyclosporine therapy was only available for the period 1981 to 1986. When these factors were allowed for, the number (and type) of HLA mismatches was shown to have a significant and independent effect on differences in survival rates whereas the effect of cyclosporine differed over the different years.

The impact of center variation on the HLA-DR matching effect in kidney graft survival.

Data from 7436 cases of first-cadaver transplants between 1981 and 1986 from 50 transplant follow-up centers within Eurotransplant, were analyzed with respect to the effect of HLA-DR matching on graft prognosis within the first year posttransplant. The use of cyclosporine was allowed for as well as the variation in graft survival rate between transplant follow-up centers. After adjustment for these variables, HLA-DR matching was still very significant. The effect of CsA on graft survival varied between centers--i.e., interaction was observed--but the effect of HLA-DR mismatching did not vary significantly between centers. Over all the centers there was a 1.4-fold increase in relative risk for each increase in HLA-DR mismatch, corresponding to predicted one-year graft survivals of 86.5%, 81.9%, and 75.4% for 0, 1, and 2 HLA-DR mismatches respectively, in patients receiving CsA, and 72.5%, 64.2%, and 53.6% in patients not receiving CsA.

Prognostic indices to predict survival of first and second renal allografts.

In order to predict kidney graft survival, the influence of independent prognostic factors can be examined multivariately and the factors combined into a prognostic index. Data on 7121 patients receiving an unrelated first and 1033 patients receiving an unrelated second transplant from nonliving donors, between 1 January 1984 and 31 December 1987, were analyzed to ascertain the most important prognostic variables up to 4.5 years posttransplantation. Factors found to be significant for graft survival were donor and recipient age and sex, recipient blood group, whether the recipient was diabetic, cold ischemic period, number of HLA-B and - DR mismatches, highest percent panel-reactive antibody, transplant center, and--for second transplants--duration of first graft. A risk score for graft failure, based on the prognostic factors, was developed using these factors and five risk groups (from excellent to very poor prognosis) were identified. This index was tested on an independent data set and showed a good fit when compared with the observed Kaplan-Meier graft survival: patients allocated by the risk score into the "excellent prognosis" group had an observed one-year graft survival of 90.4%, compared with a predicted value of 90.3% for first transplants. Corresponding results for second transplants were 86.2% (observed) and 86.0% (predicted). For the "very poor" prognosis group, the results were 73.4% (observed) and 74.4% (predicted), for first transplants, and 60.9% (observed) and 60.1% (predicted), for second transplants. A prognostic index can therefore identify patients likely to have a high or low graft survival, leading to improved decision-making and aiding the choice of patient management once a recipient has been transplanted.

Factors contributing to long-term kidney graft survival in Eurotransplant.

We examined the graft survival of 12,883 first unrelated kidney grafts from nonliving donors, transplanted between 1 January 1971 and 31 December 1987 within 52 renal transplantation centers participating in the Eurotransplant organization. The 5-year graft survival increased from 38.8% for the period 1971-1975 to 66.0% for the period 1981-1987 for patients treated with cyclosporine, whereas the half-life increased by only 2 years, from 9.7 years to 11.6 years over the same period, based on grafts functioning at 1 year posttransplantation. Results per HLA locus showed considerable improvements within mismatch groups over the entire period. Large differences between mismatch groups for the early years were observed, but within the cyclosporine era only HLA-B showed a statistically significant difference in half-lives (13.2 versus 9.0 years, for 0 and 2 mismatches respectively, P = 0.013). When other prognostic factors were taken into account, it was revealed by means of an exponential model that number of HLA-B mismatches, donor and recipient age and sex, and recipient diagnosis of diabetes had significant effects on the long-term outcome of the grafts. Depending on the combination of these parameters, estimates of half-life varied from 4.9 to 14.5 years. These results show that matching for HLA-B is still of benefit in the longer term and that other prognostic factors play an important role in predicting the late outcome of renal allografts.

The impact of HLA-A matching on long-term survival of renal allografts.

An important contribution of HLA-A antigen matching in renal transplantation was reported initially, hut later publications showed a minor or absent role. We analyzed the contribution of HLA-A locus matching to graft survival in 17,672 first renal transplants from unrelated, nonliving donors. We show that an independent HLA-A matching effect still exists. Due to its relative weakness and late appearance, large numbers and longer follow-up periods are required. The HLA-A matching effect is a significant factor in first renal allograft survival up to 6 years after transplantation, with an increasing effect over time. This is in contrast to the strong, short-lived, effects of HLA-DR and -B matching, which can only be detected up to 6 months and 2 years after transplantation, respectively. A clear additive beneficial effect of HLA-A matching is shown in the group without B and DR mismatches. Therefore, prospective matching for the HLA-A antigens remains important for renal allograft survival.

The effect of HLA matching on kidney graft survival in separate posttransplantation intervals.

The effect of matching for the HLA antigens has been well established as important in the prognosis of kidney grafts. By analyzing the effect of matching on first transplants from unrelated donors in specific intervals up to 3 years posttransplantation, we show that the effect of HLA-DR matching is strongest in the first 5 months following transplantation (relative risks of graft failure 1.31 and 1.77 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches). For patients whose grafts remained functioning after 5 months, there was no significant further improvement in graft survival to 3 years (relative risks 1.16 and 0.98 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches)--i.e., the gain in graft survival by matching for HLA-DR appears to be due to its influence in the first 5 months following transplantation. For HLA-B, the matching effect was evident both before and after 5 months (relative risks 1.11 and 1.27 for 1 and 2 HLA-B mismatches, respectively, compared with no mismatches and modelled as constant over the 3-year period), whereas no effect of HLA-A matching was evident in the period up to 3 years.

An unexpected effect of matching for HLA-A9 in renal transplantation.

The observation of elevated levels of HLA class I molecules in sera of HLA-A9-positive individuals, and their potential role in the regulation of the immune response, motivated us to study the effect of the presence of HLA-A9 in either kidney donor or recipient on graft survival. Analysis of data from unrelated first transplants performed within the Eurotransplant area revealed that in the group of patients who were not treated with cyclosporine (n = 2051), transplants with no HLA-DR mismatches in which donors (D) and recipients (R) shared the HLA-A9 antigen (D+R+), had significantly poorer graft survival (P = 0.0001) than all other combinations, reaching a 20% difference at 5 years posttransplantation. This effect, which was not found in the CsA-treated patient group (n = 7297), was specific for HLA-A9. The implications of this findings are discussed in relation to the mechanisms of the alloimmune response.

The clinical significance of allospecific antibodies against endothelial cells detected with an antibody-dependent cellular cytotoxicity assay for vascular rejection and graft loss after renal transplantation.

Serum samples of 64 consecutive patients who underwent renal transplantation in our institution were examined for the presence of antibody-dependent cellular cytotoxicity (ADCC) activity against endothelial cells (EC). From each patient serum samples were obtained immediately before transplantation and 1 week, 1 month and 1 year thereafter. The results were evaluated in the context of tests to measure donor-specific humoral immunity against lymphocytes and monocytes, and related to parameters of presensitization, graft survival, and histology. Sera from 10 patients were positive for ADCC on a panel of HLA-typed endothelial cells. In 8 patients sera were already positive before transplantation and remained positive thereafter. In 4 patients a positive crossmatch with donor T and B cells and monocytes could be observed after transplantation. In only one patient were these crossmatches positive before transplantation. A significant correlation was found between ADCC positivity and vascular rejection (P = 0.015); in addition graft survival was significantly better in the ADCC negative group vs. the positive group (P = 0.0004). These data demonstrate the significance of allospecific anti EC antibodies for the occurrence of vascular rejection and graft loss after renal transplantation.

The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection.

Chronic rejection of renal allografts is a major cause of late graft loss. However, time of onset, relation with acute early rejection episodes, and risk factors are largely unknown. We undertook a cohort study of 482 consecutive patients from a single center who received a cadaveric renal allograft between January 1983 and April 1991. During the first 3 months after transplantation, 76 (15.8%) patients developed vascular rejection and 115 (23.9%) developed interstitial rejection. One-year graft survival of patients without rejection, with interstitial rejection, and with vascular rejection was 87.8%, 87%, and 48.7%, respectively. Five-year graft survival was 73.5% for the group without rejection, 71.4% for patients with interstitial rejection, and 34.3% for patients with vascular rejection. The adjusted relative risk of graft loss was 4.92 (95% CI 3.25-7.43) for patients with vascular rejection and 1.27 (95% CI 0.80-2.02) for patients with interstitial rejection compared with patients without early rejection, taking the time dependency of the rejection events and prognostic factors into account. The incidence of vascular rejection was increased in patients with primary nonfunction (RR 1.69, 95% CI 1.01-2.84), with 1 HLA-DR mismatch (RR 2.38, 95% CI 1.44-3.93), with 2 HLA-DR mismatches (RR 3.24, 95% CI 1.25-8.42), with a prolonged cold ischemia time (RR 1.03, 95% CI 1.00-1.06 per hr), and with 1 or more previous transplantations (RR 1.76, 95% CI 1.01-3.07). Risk of developing vascular rejection was decreased in patients using CsA as compared with azathioprine (RR 0.41, 95% CI 0.24-0.67). Early vascular rejection, occurring within 3 months after transplantation, is the most important predicting variable of both early and late graft loss. Use of CsA, less HLA-DR mismatching, and a cold ischemia time of short duration possibly prevent the development of vascular rejection.

Quality assessment in cervical cytology: a pilot study.

A pilot study of an external quality assessment scheme was run between February 1985 and September 1986 to (i) assess the feasibility of running one from a district general hospital; (ii) to estimate the time required to organise and run it with a computer; (iii) to provide sound statistical results with which future schemes could be compared. Seven laboratories participated, and the 20 smears selected from each laboratory were circulated in three rounds in batches of seven, seven, and six according to a prearranged order. Results analysed using the kappa statistic showed moderate levels of interlaboratory agreement, with complete agreement emerging only on a small proportion of cases.

A pilot study of cyclical chemotherapy with high-dose methotrexate and CHOP (MTX-CHOP) in poor-prognosis non-Hodgkin's lymphoma (NHL).

In a pilot study of cyclical chemotherapy in patients with poor-prognosis non-Hodgkin's lymphoma (NHL), high-dose methotrexate (MTX) 1 g/m2 with folinic acid rescue was given as initial treatment and then between cycles of a single-arm CHOP combination administered every 4 weeks. Of 21 patients with previously untreated or minimally treated grade 2 (high-grade) histology stage II/III/IV NHL, 13 (62%) achieved complete remission (CR); the CR rate for stage III/IV patients was 56%. Of all 25 patients with grade 2 stage II/III/IV NHL, including previously treated patients, 16 (64%) achieved CR. The median follow-up of patients who completed treatment is currently 22 months and only 1 relapse has been recorded in the CR group. Only five of 24 grade 2 patients given the initial 'test' MTX failed to show any response, and eight patients achieved partial remission (PR) as a result of this single treatment. The response to MTX-CHOP in nine patients with grade 1 (low-grade) histology NHL was poor; only two achieved CR. These findings lend support to other data which indicate a useful role for MTX in the induction chemotherapy of advanced high-grade NHL, though the optimum dosage and drug sequence have yet to be determined.

The effect of surgical technique on local recurrence rates following mastectomy.

The effects of two different axillary techniques, i.e. sampling and dissection, in combination with mastectomy for operable carcinoma are compared. The dissection technique when combined with radiotherapy gives better local disease control than sampling. This also confirms the proposition that an axillary sampling technique is an inefficient method of staging breast cancer and its use will result in inferior local disease control.

Observer variation in histological grading of breast cancer.

A multicentre study was conducted to assess the degree of agreement between pathologists grading breast tumours using the WHO criteria. Satisfactory correlation of grades was found to occur with observer variation of 21.9% on 874 tumours.

Histological grading of breast cancer; significance of grade on recurrence and mortality.

The influence of histological grade on the recurrence and mortality of patients with breast cancer is reported for 829 patients. The effect of the histological grade is also compared with the effect of axillary node involvement and the implications for clinical studies of the management of breast cancer discussed. The prognosis for both recurrence and death becomes increasingly poor as the degree of differentiation decreases, as reflected by the grading allocated to the tumour. This effect is independent of the clinical stage of the cancer at the time of treatment.

An audit of film reject and repeat rates in a department of dental radiology.

A study of film reject and repeat rates was undertaken in the Department of Dental Radiology of King's College School of Medicine and Dentistry over a 6 month period. The aim of the study was to assess the effects of changes implemented after a previous audit, and to carry out a more detailed analysis of the factors influencing the reject and repeat rates using a larger volume of data. The information recorded included the equipment and projection used, and the age of the patient if under 16 years. The overall reject rate was 3.06%, 1.84% less than recorded in the earlier study, and the repeat rate was 0.93%. Positioning errors were the most frequent cause for rejection. Significant differences in reject rates were noted between different projections, and also between qualified staff and those in training. The rejection rate for patients under 16 years was not significantly higher than for patients over 16 years, the most frequent cause of rejection was still positioning faults, but patient movement accounted for a larger proportion of the rejects than was the case in adult patients. The results demonstrate the role of audit in isolating factors leading to additional exposures. The effectiveness of changes implemented following a reject film analysis is also shown.

The use of discriminant analysis to guide palliative treatment for lung cancer patients.

The aim of this study was to develop a prognostic index for patients with inoperable non-small cell lung cancer which could predict survival to 3 months. This would enable less radiation dose to be given to patients where prognosis is limited by occult metastases, giving rise to less treatment morbidity and raising the therapeutic ratio. Data on 18 known prognostic factors were collected on 96 patients. Performance status, lymphocyte count, weight loss and extent of disease were the most predictive factors and were combined into an index. Logistic discriminant analysis was employed to give a numerical score of likelihood of survival to 3 months, ranging from 0 (not likely) to 1 (certain). In this first set of 96 patients, 16 deaths were observed before 3 months, of which 6 were predicted. There was one false positive prediction. Overall accuracy of prediction was therefore 89% with 99% specificity. The same 4 prognostic factors were measured on a second set of 80 patients. Nineteen died before 3 months, of which 5 were predicted with 2 false positives, giving an overall accuracy of 80% and 97% specificity. A probability of survival of less than or equal to 0.2, although highly specific, was only applicable to 9% of patients and this was the limiting factor in the clinical usefulness of the test. A 16-branch tree diagram allows any patient to be assigned a risk factor based on the four predictive factors at the first clinic attendance. Use of the index could encourage more rational prescribing of radiation dose.