Richard B. McHugh

The Wiskott-Aldrich syndrome in the United States and Canada (1892-1979).

Information was collected on 301 cases of the Wiskott-Aldrich syndrome in the United States and Canada Examination of available medical records, death certificates and published case reports on these patients showed that they came from a wide geographic area and many diverse ethnic and racial groups. No significant difference was found in the incidence of cases born between 1947 and 1976; the overall rate was 4.0 per million live male births in the United States. Median survival has increased with time from eight months for patients born before 1935 to 6.5 years for those born after 1964. Seventy-six of the 301 patients (25%) were still alive at last follow-up and ranged in age from 1 to 36 years with a median of 10 years. Causes of death were primarily limited to infections or bleeding, but malignancy represented a significant problem. Twelve percent of the group (36 of 301) developed malignancy, the predominant types being lymphorecticular tumors (23 of 36) and leukemia (7 of 36). The overall relative risk for malignancy was found to be greater than 100 times that of the general population and was found to increase with increasing age.

The earlier detection of colorectal cancers. A preliminary report of the results of the occult blood study

A long‐term clinical study is underway to evaluate the merit of occult stool blood testing in the earlier detection of colorectal cancers; 48,000 participants have been enrolled. Thus far, 873 patients with occult stool blood have been examined, and 77 gastrointestinal cancers have been found in 74 patients. Although data from the control group are not yet available for comparison, most of the cancers found appear to be relatively early in their development. Conventional barium‐enema examinations were noted to have “missed” one third of the colon cancers and two‐thirds of the colon polyps which were found on colonoscopy. Preliminary results of the study appear encouraging. Definitive analysis will await the availability of additional pertinent data.

Osmolality Changes during Hemodialysis: Natural History, Clinical Correlations, and Influence of Dialysate Glucose and Intravenous Mannitol

We studied the influence of both a high-glucose-concentration dialysate (717 mg/dl) and intravenous mannitol (1g/kg) on the serum osmolality changes in stable patients on chronic dialysis. During regular dialysis, serum osmolality fell 10 mosmol/kg H2O. This fall was reduced to 5.2 mosmol/kg H2O when the high-glucose-concentration dialysate was used, and to 4.3 mosmol/kg H2O when intravenous mannitol was used. When the two methods were combined, the serum osmolality fall was reduced to 1.7 mosmol/kg H2O. The clinical signs of disequilibrium declined (from 67% to 10%) in parallel with the decline in serum osmolality changes. This fall was independent of the ultrafiltration rate. A high-glucose-concentration dialysate and intravenous mannitol can each reduce the osmolality changes that occur during hemodialysis, but when used alone, intravenous mannitol is more effective of the two. The reduction of osmolality changes also leads to reduction of the mild clinical signs usually associated with disequilibrium.

Second neoplasms following megavoltage radiation in a pediatric population

Previous reports of radiation‐related neoplasia have relied primarily upon patients treated by orthovoltage to low doses for benign disease. This survey is believed to be the first to assess the incidence of second neoplasms following megavoltage therapy. The source was the records of all long‐term pediatric survivors (88 patients) who were treated with megavoltage radiation (cobalt 60) at the University of Minnesota. There was an average follow‐up period of 14 years during which 7 second neoplasms were discovered (8%). Five were not associated with prior radiation. Both radiation‐related neoplasms were associated with low doses and one was without significant morbidity. Two of the seven neoplasms were malignant; one was not associated with radiation while the other was associated with prolonged chemotherapy and low dose radiation (1%). The only fatal second neoplasm was not associated with radiation but developed 5 years after prolonged chlorambucil treatment. This review reveals the tendency of childhood cancer victims to develop other neoplasms regardless of radiation. The finding of neoplasia induction only at low radiation doses supports the Gray hypothesis of decreased tumor induction at high doses through increased cell killing.

The design of a study to assess occult-blood screening for colon cancer.

Abstract It is our experience to date that large numbers of high risk individuals can be induced to use the self-administered Hemoccult test on a periodic basis. The study will determine not only whether a significant reduction in mortality can be effected by such periodic screening for colorectal cancer, but will also attempt to arrive at such parameters as the optimal period for rescreening by estimating mean lead time gained at different rescreening intervals using the methodology of Zelen and Feinleib [10] and Prorok [11, 12]. In addition, screening at two different intervals (Groups I and II) will yield empirical data about the effect of screening frequency on mortality and survivorship. Combining these methodologies may yield new information on optimal screening frequency. Such information could then be used to set up screening programs which would significantly reduce mortality from colorectal cancer on a nation-wide basis.

Radiotherapy in the postoperative treatment of operable cancer of the breast. Part II. A re-examination of Stjernswärd's application of the Mantel-Haenszel statistical method. Evaluation of the effect of the radiation on immune response and suggestions for postoperative radiotherapy.

A re‐examination of the statistical methods used to develop the claim that radiation postoperatively decreases survival was carried out. This study demonstrates that a) when correct figures are used, statistical significance is not demonstrated, i.e. there is not statistically significant evidence that irradiation of the peripheral lymphatics and/or chest wall following mastectomy has a deleterious effect on survival, b) the use of the Mantel‐Haenszel procedure was inappropriate for the purpose for which it was used. A survey of the available evidence fails to substatiate the claim that the immunological system effects of local irradiation relate in any way to decreased survival. Recommendations for the use of irradiation postoperatively in the treatment of breast cancer are made.

Post-Stratification in the Randomized Clinical Trial

A topic of current biometric discussion is whether stratification should be used in randomized clinical trials and, if so, which kind. An approach based upon randomization theory is used to evaluate pre- versus post-stratification. The results obtained relate specifically to the effect of the size of the clinical trial on the bias and precision of estimated treatment contrasts.

Clinical staging system for cancer of the salivary gland: a retrospective study.

A comprehensive retrospective study of 861 patients with cancer of the salivary glands from 12 U. S. and Canadian participating institutions was carried out, and a TNM classification system is proposed for the staging of salivary gland cancer. This involves use of five clinical variables: size and local extension of the primary tumor, palpability and suspicion of the regional lymph nodes, and the presence or absence of distant metastases. We recommend its use for the staging of this cancer.

Radiotherapy in the postoperative treatment of operable cancer of the breast. Part I. Critique of the clinical and biometric aspects of the trials

A statistical assessment of several “randomized” clinical trials was carried out and the following conclusions were noted. 1. There is no statistically significant evidence that radiation to the peripheral lymphatics and/or chest wall following radical mastectomy affects survival. 2. There is significant evidence that postoperative irradiation to the peripheral lymphatics and/or chest wall does decrease local recurrence rate. 3. There is reliable evidence that the treatment of local recurrence, once it develops, is successful in only 50% of the cases. 4. There is evidence that radiation plus simple mastectomy is as effective in the treatment of breast cancer as radical mastectomy alone. It is our considered opinion that radiation remains a useful adjuvant and complementary agent in the treatment of breast cancer, is not harmful vis a vis survival and should be used when and where indicated.

Analysis of accrual randomized clinical trials with balanced groups in strata

Abstract A frequent objective of treatment allocation in an accrual clinical trial is periodic balancing by means of group randomization (‘permuted blocks’) of the number of patients receiving each treatment within a stratum. For this design, data analysis based upon finite model randomization theory is formulated. A normal theory approximation of the exact randomization distribution is also proposed. Finally, the validity of this analysis is contrasted with that of a data analysis, apparently in common use, which ignores the periodic balance in the design.