Analysis of lupin seed protein digestibility using gel electrophoresis and immunoblots.

Proteins from the seeds of 12 cultivars of three lupin species were analyzed by gel electrophoresis. Similarities between cultivars of the same species were noted. Antibodies raised against the three major globular proteins, conglutin alpha, beta, and gamma, of Lupinus albus cv. Ultra were used to probe immunoblots of crude extracts. The immunoblots revealed variations between cultivars not previously resolved and identified which protein-subunits were derived from which conglutin. In vitro digestibility studies were done on four of the lupin cultivars. During the digestion of these cultivars, the large protein units were shown to be degraded to smaller intermediates with specific molecular sizes. Some of the intermediate protein subunits were identified as being derived from conglutin beta. The digestibility of the four cultivars, based on the amount of identifiable protein in the ruminal fluid digest at 9 and 24 h, showed Ultra > Primorski > Juno > Danja. From this study a novel system of analyzing protein digestibility was devised.

Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.

Following mastectomy, patients aged 35 to 76 years with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy (NT), ovarian irradiation (R) 2000 rads in 5 days, or ovarian irradiation in the same dosage plus prednisone (R + P) 7.5 mg daily for up to five years. A total of 703 eligible patients received the randomly assigned treatment. The median follow up was 21 years with a range of 14 to 25 years. Overall, there was a delay in recurrence (p = 0.03) and survival was prolonged (p = 0.19) for patients who received R, but in neither case was the difference significant after adjusting for the multiplicity in our data. Overall, patients who received R + P experienced a significant delay in recurrence (p = 0.0003) and a significantly prolonged survival (p = 0.005), even after adjusting for multiple comparisons. In premenopausal patients who received R, the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more, R + P therapy significantly prolonged survival (p = 0.0004), while the delay in recurrence although significant (p = 0.02) was only marginally so after allowance for multiple comparisons. No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients. A new finding in this review was that contralateral breast cancer as the first failure was reduced by R + P compared to NT in the overall group.

Radiotherapy alone in breast cancer. Analysis of tumor and lymph node radiation doses and treatment-related complications. The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital.

This retrospective analysis was conducted on breast cancer patients treated by radiotherapy alone at The Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients had either operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Previous results showed that a radiation dose increase of 15 Gy can decrease the relative risk of tumor or lymph node recurrence twofold. In this third report, the same data were analyzed to determine the treatment-related complication rates and to correlate these to the radiation dose levels. Overall results were analyzed on 453 patients, but detailed analyses on complications were conducted on 372 patients not developing local recurrence in the first 6 months of follow-up. Each complication was graded on a 3-level previously defined scale. Most frequent complications were skin changes of different degrees, which were usually asymptomatic. More disabling complications were arm edema, impaired shoulder mobility, rib fractures and brachial plexopathy. The incidence of disabling complications was low. The only factor significantly increasing the risk of complications was the radiation dose level to the tumor and axilla. Technical factors such as overlapping fields should also be taken into account. As the more effective control of tumor and lymph nodes obtained in patients treated with higher radiation doses is counterbalanced by an increase in the complication rate, the dose to be delivered for each patient should be carefully chosen according to individual risk factors.

Testing the validity of a prognostic classification in patients with surgically optimal ovarian carcinoma: a 15-year review.

A retrospectively designed classification using stage, residuum and a variable which combines prognostic information from both grade and histology (histology-grade variable) has been used at our institution to predict prognosis, and choose therapy in patients with ovarian carcinoma, stages I-III having no or small residuum. In this study, multivariate analysis of prognostic factors were performed over two time periods: Group 1 (1971-1978), contains the patients from which the original classification was derived, and Group 2 (1979-1985), contains a different cohort of patients who are used to test the validity and reproducibility of the original classification. Multivariate analysis showed that the prognostic significance of two variables changed over the two study periods: tumor grade, and residuum. It was found that in the ideal combination of grade and histologic type, when used in conjunction with stage and residuum in a prognostic classification, was unique to each patient cohort. Because of these changes, new and more accurate prognostic classifications were derived for Group 2. However, when all classifications were examined, (including the original), the differences in their ability to stratify patients into risk categories was negligible, and there was no major advantage to using one classification over another for clinical applications. Thus, the retrospectively derived prognostic classification using grade, instead of a combined histology-grade variable, in conjunction with the other significant prognostic factors (stage and residuum), is preferred for prospective application, and for its simplicity.

Effects of raw pea flour on nutrient digestibility and immune responses in the preruminant calf.

Two milk substitute diets for which the protein was provided either exclusively by skim milk powder (control) or partially (34%) by dehulled raw pea flour were given for 2 and 4 wk, respectively, to five preruminant calves, each fitted with a reentrant ileocecal cannula. Ileal apparent digestibility was lower with the pea diet during wk 1 than with the control diet. Four of the cannulated calves exhibited significant intolerance to the pea diet, resulting in lower digestibility during wk 4. In contrast, fecal digestibility of the pea diet, measured in four additional calves without reentrant cannulas, did not significantly decrease between wk 1 and 4. The AA composition of ileal digesta from the first group of calves did not vary greatly, suggesting that the differences observed in their apparent digestibility of proteins were due mainly to changes in the loss of endogenous proteins. However, pea legumin survived digestion in the small intestine in amounts generally equivalent to 1 to 3% of intake. Most of that undigested fraction was smaller than the native legumin: 40 to 200 kDa instead of 360 kDa. Also, a 45-kDa fragment was detected in the urine. Increased intestinal permeability could have favored the development of the high systemic anti-pea antibody titers that were observed in all of the calves.

Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma.

Between 1971 and 1985, 598 patients with ovarian carcinoma were treated with abdomino-pelvic radiation therapy. Acute complications included nausea and vomiting in 364 patients (61%) which were severe in 36, and diarrhea in 407 patients (68%), severe in 35. Leukopenia (less than 2.0 x 10(9) cells/liter) and thrombocytopenia (less than 100 x 10(9) cells/liter) occurred in 64 patients (11%) each. Treatment interruptions occurred in 136 patients (23%), and 62 patients (10%) did not complete treatment. In both situations the most common cause was myelosuppression. Late complications included chronic diarrhea in 85 patients (14%), transient hepatic enzyme elevation in 224 (44%), and symptomatic basal pneumonitis in 23 (4%). Serious late bowel complications were infrequent: 25 patients (4.2%) developed bowel obstruction and 16 required operation. Multivariate analysis was unable to determine any significant prognostic factors for bowel obstruction; however, the moving-strip technique of radiation therapy was associated with a significantly greater risk of developing chronic diarrhea, pneumonitis, and hepatic enzyme elevation than was the open beam technique. We conclude that abdomino-pelvic radiation therapy as used in these patients is associated with modest acute complications and a low risk of serious late toxicity.

Complications of whole abdominal and pelvic radiotherapy following chemotherapy for advanced ovarian cancer.

We examined the records of 105 patients with advanced ovarian cancer who had been treated with cisplatin combination chemotherapy followed by abdominopelvic radiotherapy. The purpose was to define the morbidity of this approach, and identify those factors predictive of toxicity. Acute toxicity resulting in delay or failure to complete treatment was most commonly due to myelosuppression. Nine of 105 patients (8.6%) required surgery for bowel obstruction that was not due to recurrent disease, 3 had an episode of bowel obstruction that settled conservatively, and a further 5 underwent surgery for obstruction due to recurrent tumor. The presence of both a dose of abdominopelvic radiotherapy over 2250 cGy, as well as a second-look laparotomy prior to radiotherapy, was associated with an increased risk of serious bowel complications. The increased frequency of late bowel morbidity seen in the combined modality group is likely explained by the presence of these two factors, rather than the exposure to chemotherapeutic agents per se. These observations are supported by the published literature.

Outcome of patients with unfavorable optimally cytoreduced ovarian cancer treated with chemotherapy and whole abdominal radiation.

There is a subgroup of patients with Stage II or III ovarian cancer whose survival is poor despite optimal cytoreduction of tumor and abdominopelvic radiation. This study examined whether the survival of these patients, who have tumor with unfavorable histopathological characteristics and/or small residual disease, could be improved by giving chemotherapy before radiation. Forty-four out of fifty-one eligible patients, seen between 1981 and 1985, with Stage II or III disease were entered into the study. Following six courses of cisplatin-based chemotherapy, 33 (75%) received abdominopelvic radiotherapy. Survival was compared to that of 48 eligible matched control patients, treated with radiation between 1978 and 1981. The median follow-up is 6.6 years. The median survival was extended from 2.4 to 5.7 years (P = 0.13), and 42.6% of patients receiving combined therapy were free of relapse at 5 years, compared to 21.6% (P = 0.03) in the historical control group, treated with abdominopelvic irradiation alone. Only 2 of 44 patients in the combined group required surgery for bowel obstruction, as did 1 of 48 in the control group. Tolerance and toxicity of the combined approach were acceptable. Although we cannot be certain that the entire benefit we observed was not attributable to the chemotherapy alone, there is evidence that the radiotherapy may have been additive. Chemotherapy followed by abdominopelvic radiotherapy seems a reasonable management policy in these patients.

Outcome analysis of localized gastrointestinal lymphoma treated with surgery and postoperative irradiation.

One hundred thirteen patients with localized gastrointestinal lymphoma treated by surgery and postoperative irradiation between 1967 and 1985 were reviewed. At 15 years, actuarial survival of this group was 40.6%, with a cause-specific survival of 69.2% and a relapse-free rate of 64%. Two-thirds of relapses occurred at distant sites. In Stage IA and IIA patients with no residuum or with positive resection margins, (N = 90) only site of involvement and stage predicted for relapse. Age, histologic subtype group, and depth of bowel wall invasion did not affect relapse risk. In the very favorable group (Stage IA, IIA, no residuum or microscopic residuum), 8.4% of patients with stomach lymphoma relapsed compared to 25% of patients with small bowel lymphoma. The risk of early relapse was higher in those with Stage IIA small bowel lymphoma than those with Stage IA small bowel lymphoma. We continue to recommend adjuvant abdominal irradiation for patients with Stage IA, IIA completely resected stomach lymphoma and Stage IA completely resected small bowel lymphoma. We recommend combined modality therapy for patients with completely resected Stage IIA small bowel lymphoma and all other localized gastrointestinal lymphoma where visible residual disease is present.

Prognostic factors in patients with stage I epithelial ovarian cancer.

We analyzed factors predictive of relapse risk in patients with stage I invasive epithelial ovarian cancer: 252 patients from the Princess Margaret Hospital provided a data base for hypothesis generation, and data on 267 patients from the Norwegian Radium Hospital were used for hypothesis testing. The outcomes in most analyses in the two series were very similar, validating the following conclusions. Differentiation (grade) was the most powerful predictor of relapse, followed by dense adherence (which resulted in outcomes equivalent to those in stage II) and, finally, large-volume ascites. When the effects of these three factors were accounted for, then none of the following were prognostic: bilaterality (stage Ib), cyst rupture (stage Ic), capsular penetration (stage Ic), tumor size, histologic subtype, patient age, year of diagnosis, and postoperative therapy. These results allow simplification of stage I substaging, as only differentiation, dense adherence, and large-volume ascites (? peritoneal cytology) need be considered. The 5-year relapse-free rate was 98% in patients with grade 1 tumors in whom both dense adherence and large-volume ascites were absent. These patients are adequately treated by operation alone. Although the relapse risk was high enough in the remaining patients to warrant postoperative treatment, a significant benefit could be shown only for a small subset of patients, namely those with densely adherent tumors treated with abdominopelvic radiotherapy. In grades 2 and 3, none of the therapies used in either series was superior to pelvic radiotherapy or operation alone.

Patterns of disease in localized extranodal lymphomas.

The site of origin of lymphoid tissue is an important determinant of lymphocyte migration patterns. The association of gastrointestinal (GI) and Waldeyer's ring lymphoma and the unique lymphocyte migration pattern of gut-associated lymphoid tissue (GALT) have been previously described. To establish whether predictive clinical patterns of disease occur in localized Non-Hodgkin's lymphoma, survival and relapse patterns for 496 patients with stage I and II non-Hodgkin's lymphoma (NHL) treated with loco-regional irradiation (XRT) alone were examined. We identified 139 patients with GALT lymphoma (defined as arising from primitive gut and including Waldeyers' ring, thyroid, and GI lymphomas) and 87 patients with extranodal non-gut-associated lymphoma (ENL). Survival and relapse data were assessed in multifactorial analysis to correct for previously identified other prognostic variables. GALT lymphomas (GALT-L) have a survival advantage compared with other ENL (P = .017) independent of stage and histology. A difference in distant relapse (DR) rate between GALT-L and other ENL (P = .0002) was also identified. The presentation site of localized extranodal NHL is predictive of clinical behavior and is an independent determinant of outcome. This may be an expression of lymphocytic origin and determinants of migration patterns.

Role of radiation therapy in localized non-Hodgkin's lymphoma.

Relapse occurs in 50% of patients receiving radiation for clinical stage (C.S.) I and II nodal and extranodal non-Hodgkin's lymphoma (N.H.L.). Prior to the introduction of intensive chemotherapy those failing primary control with irradiation and most of those who relapsed died of their disease with a resultant overall mortality of 50%. An analysis of Princess Margaret Hospital results with radiation for C.S. I and II N.H.L. between January 1967 and December 1978 revealed that tumour bulk, age, stage and histology were of independent prognostic significance. It was possible to group patients using combinations of these attributes so that each group encompassed only patients with similar outcomes. Such prognostic groups were identified separately within the low grade and the intermediate plus high grade categories of the Working Formulation. Patients with a high probability of cure with radiation were so defined. Also those patients in whom chemotherapy would be optimal initial therapy were also defined. Such patients were in the intermediate plus high grade histology groups. Thirty percent of all patients with low grade histology lymphoma had an actuarial survival of 83%, and relapse-free rate of 63% at 10 years. By implication, approximately 20% of all patients with these histologies seen at the Princess Margaret Hospital for the same time period achieved prolonged relapse-free survival by localized therapy. This is at variance with the implications of staging from studies where laparotomy and multiple bone marrow biopsies have been used. Such aggressive staging procedures suggest truly localised disease in only 5-6% of patients with low grade lymphoma. A significant relationship between radiation dose and disease control was demonstrated only for patients with intermediate and high grade lymphoma of medium or large bulk. A minimum tumour dose of 30 Gy was required for optimal local control with radiation.

Prognostic groups for management of localized Hodgkin's disease.

Two hundred fifty-two patients receiving radical irradiation for clinical stages I and II Hodgkin's disease between 1968 to 1977 had an actuarial ten-year survival rate of 78% and a relapse-free rate of 61%. Sixty-seven patients receiving chemotherapy followed by radiation had a 78% survival rate and a 63% relapse-free rate. Independent prognostic factors for survival and relapse were age, stage, and histology. Disease bulk was predictive only of relapse. Neither site of presentation above or below the diaphragm nor presence of mediastinal involvement was predictive for survival or relapse; however, patients with large mediastinal masses (greater than or equal to 10 cm absolute diameter) had a significantly higher intrathoracic failure rate with conventional mantle irradiation. Analysis of failure, according to age, clinical stage, and histologic type, showed three groups of patients defined according to the risk of relapse with radiation therapy: those with isolated upper cervical stage IA disease (group 1, relapse rate 8%), younger patients with localized stages I and II disease of favorable histologic type (group 2, relapse rate 35%), and older patients with extensive or symptomatic stages I and II disease of less favorable histologic type (group 3, relapse rate 70%). Subsequent analysis of radiation treatment volume indicates that the use of upper abdominal irradiation for patients in group No. 2 could yield results equivalent to those achieved with radiation therapy for surgically staged patients.

Ovarian cancer: contribution of radiation therapy to patient management. Erskine memorial lecture, 1983.

Ovarian cancer may be treated with radiation therapy, surgery, chemotherapy, or a combination. To evaluate the contribution of radiation therapy to patient management the cure rate must be estimated; data are presented suggesting that the 5-year survival rate provides a reasonable estimate of the cure rate. Multiple prognostic factors have been shown to affect outcome. A study of patients treated since 1971 showed that stage and postoperative residuum could be used to divide patients into two subgroups, a "poor prognosis" group and a "good prognosis" group; a multifactorial grouping of patients in the good prognosis group who were treated postoperatively with radiation therapy only was further able to divide patients into low-risk, intermediate-risk, and high-risk groups. Studies of radiation therapy for different subgroups are discussed; abdominopelvic irradiation has been shown to improve survival for approximately one-third of patients with cancer of the ovary.

Quality assurance in radiation therapy: clinical and physical aspects. Quality assurance: past and present in Canada.

Quality assurance in any clinical field must involve the three components of clinical care: (a) diagnosis and evaluation of patients; (b) medical decision making and treatment; and (c) outcome analysis. Nationally, there have been five annual reviews of outcome from all cancer centers following radiation therapy for cancer at various sites. These reviews are voluntary and organized through the Canadian Association of Radiologists. The objective is to determine if there are any major differences in outcome across the country, and if so, can such differences be related to the population treated or technique used. So far no major differences have been noted, although the reviews have led to improved communication between centers and constructive discussions of dose and technique. There is a National Tumour Reference Centre funded by the National Cancer Institute of Canada (NCIC) to provide assistance in establishing diagnostic criteria in pathology. Ontario has been active through the Ontario Cancer Treatment & Research Foundation and the Ontario Cancer Institute in establishing UICC TNM staging and reporting, together with an evaluative program for this staging system. All other quality assurance programs take place at the level of local centers.

Quality assurance in radiation therapy: clinical and physical aspects. Future plans: clinical.

On a national scale in Canada, the members of the Canadian Association of Radiologists, Section of Radiation Oncology, plan to continue their outcome analyses. Nevertheless, there is considerable activity within many of the cancer centers in establishing quality assurance for all aspects of clinical practice, not just related to the technique of radiation therapy. Studies from the Princess Margaret Hospital will be used as examples to illustrate the need for quality assurance in: (a) diagnosis and evaluation of patients; (b) decision making with respect to treatment; (c) technical components of radiation therapy; and (d) outcome analysis, particularly an analysis of failures. For the future, there are two major objectives related to quality assurance. One is related to those patients with cancers who have a high probability of being cured. In this situation, achieving optimal treatment must be the objective and quality assurance must be directed at determining what is optimal treatment. For those patients in whom cure is still not commonly reached, the objective will be to determine why failures are occurring and whether radiation therapy technique can decrease the relapse rate.