The prognostic value of p53 and c-erb B-2 immunostaining is overrated for patients with lymph node negative breast carcinoma: a multivariate analysis of prognostic factors in 613 patients with a follow-up of 14-30 years.

BACKGROUND: Approximately 30% of breast carcinoma patients with negative lymph nodes die of their disease. Biologic markers such p53 protein and c-erb B-2 have been related to tumor progression, but their prognostic value remains controversial. METHODS: Two large series of a total of 613 lymph node negative breast carcinoma patients from a single institution were analyzed with respect to tumor size, histologic grade, and immunohistochemical staining for p53, c-erb B-2, estrogen receptor (ER), and progesterone receptor (PgR). Interobserver variation in histologic grading was evaluated by Kappa statistics. The two series had different treatment modalities: 228 patients (SACGS group) were treated surgically with mastectomy and given 1 perioperative chemotherapy course, and 385 patients (HOST group) were treated with mastectomy and ovarian radiation and further randomized to receive postoperative treatment with radiotherapy or no adjuvant treatment. The follow-up ranged from 14-30 years. RESULTS: Immunoreactivities for p53, c-erb B-2, ER, and PgR did not differ significantly in the two series. p53 immunostaining was present in 187 of 613 tumors (29%), and c-erb B-2 immunoreactivity was present in 58 of the tumors (10%). Three hundred forty-eight tumors (57%) were positive for ER. Kappa statistics value of interobserver variation in the histologic grading of ductal carcinomas was 0.69, which is considered to be a substantial degree of agreement. No significant differences in survival were found when comparing p53, c-erb B-2, ER, and PgR positive and negative cases. However, both recurrence free survival rates and overall survival rates after 10 years were significantly better in the T1N0M0 group compared with the T2N0M0 group (81% vs. 67% [P < 0.0001] and 85% vs. 70% [P < 0.0001]). Ten-year recurrence free survival rates for patients with histologic Grade 1 versus Grades 2-3 (according to Elston and Ellis' modification of the Bloom and Richardson method) tumors were 90% and 70%, respectively (P < 0. 0001), and overall survival rates for the same groups were 94% and 81%, respectively (P=0.0002). After 30 years of follow-up, the overall survival rate for patients with tumors of histologic Grade 1 versus Grades 2-3 were 87% and 68%, respectively, and were 78% and 66%, respectively, for patients with tumors 20-50 mm. Approximately 35% of the patients with tumors of histologic Grades 2-3 and measuring > 20 mm were dead after 10 years of follow-up, contrary to 6% of the patients with tumors of histologic Grade 1 measuring

Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency. Islet LPL regulates insulin secretion.

Lipoprotein lipase (LPL) provides tissues with fatty acids, which have complex effects on glucose utilization and insulin secretion. To determine if LPL has direct effects on glucose metabolism, we studied mice with heterozygous LPL deficiency (LPL+/-). LPL+/- mice had mean fasting glucose values that were up to 39 mg/dl lower than LPL+/+ littermates. Despite having lower glucose levels, LPL+/- mice had fasting insulin levels that were twice those of +/+ mice. Hyperinsulinemic clamp experiments showed no effect of genotype on basal or insulin-stimulated glucose utilization. LPL message was detected in mouse islets, INS-1 cells (a rat insulinoma cell line), and human islets. LPL enzyme activity was detected in the media from both mouse and human islets incubated in vitro. In mice, +/- islets expressed half the enzyme activity of +/+ islets. Islets isolated from +/+ mice secreted less insulin in vitro than +/- and -/- islets, suggesting that LPL suppresses insulin secretion. To test this notion directly, LPL enzyme activity was manipulated in INS-1 cells. INS-1 cells treated with an adeno-associated virus expressing human LPL had more LPL enzyme activity and secreted less insulin than adeno-associated virus-beta-galactosidase-treated cells. INS-1 cells transfected with an antisense LPL oligonucleotide had less LPL enzyme activity and secreted more insulin than cells transfected with a control oligonucleotide. These data suggest that islet LPL is a novel regulator of insulin secretion. They further suggest that genetically determined levels of LPL play a role in establishing glucose levels in mice.

Glycogen supercompensation masks the effect of a traininginduced increase in GLUT-4 on muscle glucose transport.

Endurance exercise training induces a rapid increase in the GLUT-4 isoform of the glucose transporter in muscle. In fasted rats, insulin-stimulated muscle glucose transport is increased in proportion to the increase in GLUT-4. There is evidence that high muscle glycogen may decrease insulin-stimulated glucose transport. This study was undertaken to determine whether glycogen supercompensation interferes with the increase in glucose transport associated with an exercise-induced increase in GLUT-4. Rats were trained by means of swimming for 6 h/day for 2 days. Rats fasted overnight after the last exercise bout had an approximately twofold increase in epitrochlearis muscle GLUT-4 and an associated approximately twofold increase in maximally insulin-stimulated glucose transport activity. Epitrochlearis muscles of rats fed rodent chow after exercise were glycogen supercompensated (86.4 +/- 4.8 micromol/g wet wt) and showed no significant increase in maximally insulin-stimulated glucose transport above the sedentary control value despite an approximately twofold increase in GLUT-4. Fasting resulted in higher basal muscle glucose transport rates in both sedentary and trained rats but did not significantly increase maximally insulin-stimulated transport in the sedentary group. We conclude that carbohydrate feeding that results in muscle glycogen supercompensation prevents the increase in maximally insulin-stimulated glucose transport associated with an exercise training-induced increase in muscle GLUT-4.

Rapid reversal of adaptive increases in muscle GLUT-4 and glucose transport capacity after training cessation.

Previous studies have shown that when exercise is stopped there is a rapid reversal of the training-induced adaptive increase in muscle glucose transport capacity. Endurance exercise training brings about an increase in GLUT-4 in skeletal muscle. The primary purpose of this study was to determine whether the rapid reversal of the increase in maximally insulin-stimulated glucose transport after cessation of training can be explained by a similarly rapid decrease in GLUT-4. A second purpose was to evaluate the possibility, suggested by previous studies, that the magnitude of the adaptive increase in muscle GLUT-4 decreases when exercise training is extended beyond a few days. We found that both GLUT-4 and maximally insulin-stimulated glucose transport were increased approximately twofold in epitrochlearis muscles of rats trained by swimming for 6 h/day for 5 days or 5 wk. GLUT-4 was 90% higher, citrate synthase activity was 23% higher, and hexokinase activity was 28% higher in triceps muscle of the 5-day trained animals compared with the controls. The increases in GLUT-4 protein and in insulin-stimulated glucose transport were completely reversed within 40 h after the last exercise bout, after both 5 days and 5 wk of training. In contrast, the increases in citrate synthase and hexokinase activities were unchanged 40 h after 5 days of exercise. These results support the conclusion that the rapid reversal of the increase in the insulin responsiveness of muscle glucose transport after cessation of training is explained by the short half-life of the GLUT-4 protein.

Insulin resistance of muscle glucose transport in rats fed a high-fat diet: a reevaluation.

Rats fed a high-fat diet develop skeletal muscle insulin resistance. There is disagreement regarding whether a decrease in the GLUT4 isoform of the glucose transporter is responsible. We found that feeding rats a high-fat diet that reduced the responsiveness of glucose transport to insulin in skeletal muscles by approximately 25-45% in 4 weeks, had no significant effect on muscle GLUT4 content. There is also controversy regarding whether the contraction/anoxia activated pathway of glucose transport stimulation is affected by fat feeding. We found that stimulation of muscle glucose transport by either swimming, in situ contractions, or anoxia was depressed to a similar extent as insulin responsiveness in high-fat-fed rats. It has been suggested that the muscle insulin resistance caused by a high-fat diet is due to increased fat oxidation and glucose-fatty acid cycle activity. However, we found that insulin-stimulated glucose transport was reduced by approximately 40% when muscles of fat-fed rats were incubated under anoxic conditions under which fatty acid oxidation should not occur. Rats maintained on the high-fat diet up to 32 weeks developed the characteristics of the abdominal obesity syndrome, including insulin resistance, hyperinsulinemia, hyperglycemia, elevated LDL cholesterol and VLDL triglycerides, and marked visceral obesity. We conclude that 1) in rats fed a high-fat diet the muscle insulin resistance is not due to a decrease in total GLUT4 content or to increased fat oxidation, 2) fat feeding also results in resistance of muscle glucose transport to stimulation via the contraction/anoxia pathway, and 3) rats fed a high-fat diet may be a useful model of the abdominal obesity syndrome.

Effect of endurance exercise training on muscle glycogen supercompensation in rats.

The purpose of this study was to test the hypothesis that the rate and extent of glycogen supercompensation in skeletal muscle are increased by endurance exercise training. Rats were trained by using a 5-wk-long swimming program in which the duration of swimming was gradually increased to 6 h/day over 3 wk and then maintained at 6 h/day for an additional 2 wk. Glycogen repletion was measured in trained and untrained rats after a glycogen-depleting bout of exercise. The rats were given a rodent chow diet plus 5% sucrose in their drinking water and libitum during the recovery period. There were remarkable differences in both the rates of glycogen accumulation and the glycogen concentrations attained in the two groups. The concentration of glycogen in epitrochlearis muscle averaged 13.1 +/- 0.9 mg/g wet wt in the untrained group and 31.7 +/- 2.7 mg/g in the trained group (P < 0.001) 24 h after the exercise. This difference could not be explained by a training effect on glycogen synthase. The training induced approximately 50% increases in muscle GLUT-4 glucose transporter protein and in hexokinase activity in epitrochlearis muscles. We conclude that endurance exercise training results in increases in both the rate and magnitude of muscle glycogen supercompensation in rats.

Systemic pneumococcal disease after staging splenectomy for Hodgkin's disease 1969-1980 without pneumococcal vaccine protection: a follow-up study 1994.

We surveyed, during 1994, all 325 patients who underwent staging laparotomy with splenectomy for Hodgkin's disease in Norway 1969-80, before pneumococcal vaccine was available in this country. The patients were thus not immunized preoperatively. Of 162 patients (49.8%) who died before 1994, 8 (2.4% of the total study) died from pneumococcal septicaemia and 16 (6.2%) from infections totally. Of 163 patients (50.2%) who were alive in 1994, 158 cooperated and filled in a questionnaire: 22 had been hospitalized for serious infections; 2 with pneumococcal septicaemia, and 6 with pneumonia, although lacking a specified microbiological diagnosis. We observed 325 patients representing 4420 patient-years, 3066 patient-years among survivors and 1354 patient-years among the dead. This resulted in an incidence rate of systemic pneumococcal disease of 226 per 100,000 patient-years, which is a relative risk of 20.5 compared to the general Norwegian population during 1994. Septicaemia for these patients most often had an abrupt clinical start even for relapse-free individuals and occurred from 2 to 17 yr after splenectomy (mean 10 yr). The risk of developing an overwhelming pneumococcal septicaemia with high case-fatality in asplenic patients seems to persist for these patients at about the same level even 15-20 yr after splenectomy. Only 12.7% of the survivors had been given pneumococcal vaccine in the autumn of 1993. Despite the fact that medical journals and media in Norway focused upon the problem of pneumococcal disease in asplenic individuals in the autumn of 1993 and spring of 1994, a substantial proportion of these patients (55.3%) still remained unimmunized when interviewed in the autumn of 1994. None of our systemic pneumococcal disease patients was vaccinated. Our data underline the need for prophylactic immunization with effective vaccines against pneumococcal infection in splenectomized Hodgkin's disease patients.

[Tumor size and histological grading of stage 1 breast cancer. Prognostic and therapeutic significance]. / Tumorstørrelse og histologisk gradering ved cancer mammae stadium 1. Prognostisk og terapeutisk betydning.

Systemic adjuvant therapy can improve the prognosis for breast cancer patients. In node negative disease most patients have a good prognosis with local therapy only. Therefore, identification of subgroups with higher risk of relapse is warranted in order to avoid overtreatment of a large number of patients. A total of 399 tumours from patients without axillary metastases, operated on in the years 1964-72, were measured preoperatively and graded according to a modified Scharff-Bloom-Richardson scheme. Patients with T2 (UICC) tumours and histologic grade 2 and 3, had a 3.3-fold relative risk of mortality from breast cancer compared with the rest of the patients. These patients should receive adjuvant systemic therapy.

The relationship of strength to function in the older adult.

Reduced lower extremity strength has been associated with reduction in gait speed, balance, stair-climbing ability, and getting up from a seated position. The relationship of lower extremity strength and the ability to accomplish selected functional activities was examined in 16 healthy but frail older adults ranging in age from 75 to 88 years (mean = 80.9 years). The following measures were obtained for each subject: preferred gait speed under laboratory and free walking conditions, 5 timed chair stand-ups, and time to complete an obstacle course. Strength measures of the hip extensors, hip abductors, knee extensors, planter flexors, and dorsiflexor muscle groups were obtained using a hand-held dynamometer. The relationship between the time to complete the functional activities and each of the strength variables was determined using Pearson product moment correlations. In addition, performance was examined in relation to various combinations of strength measures (e.g., hip and knee extension). Weak, nonsignificant hip, knee and ankle strength/functional activity relationships were found for all of the variables examined. When hip extension, knee extension, and ankle plantar flexion strength values were combined and normalized to body weight, a significant strength-to-functional activity relationship was found for 14" chair stand-ups (r = .636, p < .01). When values for quadriceps strength and gait speed for 35 adults ranging in age from 60-72 years were compared to those for 75-88 year olds, marked differences emerged. A more significant relationship between knee extension force and gait speed was observed for the younger adults (r = .528 vs r = .353).(ABSTRACT TRUNCATED AT 250 WORDS)

Scapular taping in the treatment of anterior shoulder impingement.

The purpose of this case report is to describe how taping designed to promote proximal scapular stability was used in conjunction with other physical therapy interventions to manage a patient with anterior shoulder impingement. The taping technique is described in detail. The evaluation and treatment of a patient with an 8-month history of shoulder pain are described as an example of when this type of taping procedure may be indicated. This case report demonstrates that a patient was able to return to all of his regular overhead sports activities without pain following scapular taping used in combination with a home exercise program. Presumably, the improved resting position of the scapula corrected faulty scapulothoracic joint movements.

[Infrastructure for clinical research in a hospital]. / Infrastruktur for klinisk forskning i et sykehus.

Clinical research in hospitals involves many partners. In Norway, the doctors are allocated little time for clinical research. Furthermore, complicated laws and directives have to be followed. The authors describe the organisation of clinical research and a software collection, including CD-ROM. We conclude that clinical research in large hospitals demands both a strong organisation and extensive use of modern information technology. The problems can be solved at acceptable cost.

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.

PURPOSE: To examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial. PATIENTS AND METHODS: We studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified. RESULTS: The increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials. CONCLUSION: The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.

Host markers and prognosis in recurrent rectal carcinomas treated with radiotherapy.

The value of blood tests as prognostic factors in patients with recurrent rectal carcinomas treated with radiotherapy was studied in one retrospective (n = 114, 1976-1984) and one prospective (n = 100, 1985-1989) group of patients. The retrospective group was used for validation of the results from the prospective group. In univariate survival analyses, 19 of totally 38 variables significantly correlated to the survival. Of 13 significant blood parameters, lactate dehydrogenase (LD), erythrocyte sedimentation rate (ESR), alpha 1-, alpha 2-globulin, fibrinogen, carcinoembryonic antigen (CEA), C-reactive protein (CRP), haptoglobin, granulocytosis and thrombocytosis were the most important ones (p < or = 0.01). In the multivariate analyses (Cox regression) of the prospective group, LD, alpha 1-globulin, diagnosed liver metastases and CEA were found to be significant predictors of survival. A prognostic index was derived from the prospective group including ESR, LD and relapse-free interval. This clearly separated the patients in the retrospective group into one low- and one high-risk group.

[Hodgkin's disease or lymphogranulomatosis. New views on prognosis, complicating conditions and complications after treatment]. / Hodgkins sykdom eller lymfogranulomatose. Nyere synspunkter på prognose, følgetilstander og komplikasjoner etter behandling.

Between the years 1968-85, 1,177 patients started treatment for Hodgkins disease at the Norwegian Radium Hospital. In this unselected material from Norway the age distribution was bimodal with the highest incidence between 20-40 years of age. Survival is dependent on age, stage and histology, and was better between the years 1980-85 as compared with the period 1974-79. During the last ten years, treatment has been decentralized in Norway, and all centres cooperate by using the same protocol for staging and treatment. The article summarizes the results of the treatment, and related complications.

[New cancer disease after treatment of Hodgkin's disease]. / Ny kreftsykdom etter behandling for Hodgkins sykdom.

The risk of a second cancer was assessed in 1,152 patients with Hodgkins disease who were treated at the Norwegian Radium Hospital from 1968-85. 68 patients developed a second cancer more than one year after the diagnosis of Hodgkins disease. These included nine acute non-lymphocytic leukemias, eight non-Hodgkins lymphomas and 51 solid tumours, including 11 lung cancers. The overall relative risk (observed/expected ratios) of developing a second cancer was 1.86. After 18 years the cumulative risk of developing a second cancer was 14.4% +/- 2.9%, of which 11.2% +/- 2.6% referred to solid tumours. The cumulative risk of leukemia appeared to reach a plateau level of 1.5% after 12 years while the risk of non-Hodgkins lymphomas and lung cancer continued to rise with time to 2.1% and 3.3% respectively after 18 years. The risk of developing leukemia increased after treatment with alkylating agents and Procarbazine. The risk of non-Hodgkins lymphoma was not related to any specific type of therapy. Excess lung cancer risk was noted in patients treated with radiotherapy, and the cancers appeared within the treated areas.

Blood tests and prognosis in bladder carcinomas treated with definitive radiotherapy.

The value of some commonly recorded blood tests as prognostic factors in patients with bladder carcinomas treated with definitive radiotherapy has been assessed. This study included 202 consecutive patients (T2, n = 46; T3, n = 82 and T4, n = 74) treated during the period 1980-1987. The median total dose received was 56 Gy [50-67] and the median cumulative radiation effect was 1750 reu (radiation effect unit) (1515-1823). The blood tests examined in survival analyses were erythrocyte sedimentation rate (ESR), hemoglobin (Hb), leucocyte and thrombocyte count, alkaline phosphatase (ALP), gamma-glutamyltransferase (GT), lactate dehydrogenase (LD), creatinine and albumin. In the univariate survival analyses six blood tests were significant prognostic factors (ESR, albumin, creatinine, Hb, ALP and GT). In the multivariate analysis of all 202 patients, the following five variables were significantly associated with shorter survival: T4 tumors, ESR > 30 mm/h, albumin < 35 g/l, LD > 400 U/I and age > 75 years. Our conclusion is that several commonly recorded blood tests are powerful prognostic factors in bladder cancer treated with definitive radiotherapy. These tests can replace other more expensive laboratory investigations used for prognostication.

Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time, and age.

PURPOSE: In the period 1968 through 1988, The Norwegian Radium Hospital (NRH) treated an unselected population of 1,152 patients with Hodgkin's disease (HD) that comprised more older patients (mean age, 43 years) than most other institutions. We considered it important to evaluate these patients for development of second cancers (SCs). PATIENTS AND METHODS: The Norwegian Cancer Registry identified previously untreated patients with HD treated at NRH who had developed a SC more than 1 year after diagnosis of HD. The relative risk ratio (RR) (observed/expected cases) and the cumulative risk were calculated. RESULTS: Sixty-eight patients had developed a SC, including nine acute nonlymphocytic leukemias (ANLLs), eight non-Hodgkin's lymphomas (NHLs), and 51 solid tumors, including 11 lung cancers. The RR of SC and leukemia was 1.86 (95% confidence interval [CI], 1.4 to 2.4) and 24.3 (95% CI, 11.1 to 46.2), respectively. The RR of SC was highest in younger patients (< 41 years, RR = 3.8). No significant association between splenectomy and development of ANLL was found. The influence of treatment and follow-up time on the development of SC agrees with data from other large cancer institutions. CONCLUSION: (1) The low RR of developing a SC in this study is probably due to the number of older patients included, who have a lower RR of developing a SC due to less aggressive treatment, shorter follow-up time, and higher incidence of cancer in the expected background population. (2) The low RR and cumulative risk of developing ANLL may be due to the limited use of extensive chemotherapy (CT) in our hospital in the earlier years.

Follow-up of breast cancer patients stage I-II: a baseline strategy.

In 430 stage I-II breast cancer patients the cost-benefit of investigations during follow-up have been studied. Median follow-up time was 8 years and 128 patients had relapsed, 91 with metastatic disease. High costs of routine chest X-ray, limited skeletal X-ray and bone scan examinations were associated with low incidence of diagnosed relapses not suspected otherwise. In the eight blood analyses examined, increases of more than 10 mm/h in erythrocyte sedimentation rate (ESR), 20 U/l in gamma-glutamyltransferase (GT) or 60 U/l in alkaline phosphatase (ALP) resulted in a combined sensitivity of 55% and specificity of 91% for relapses with distant metastases. Elevation of at least two blood tests gave a combined sensitivity of 31% and a specificity of 98%. The importance of using individual reference values in screening for recurrences is emphasised. Symptomatic relapse or relapse detected at interval visits were not independent prognostic factors. The blood tests ALP, ESR and GT were strong predictors of survival measured from relapse which increase their legitimacy in follow-up. A more frequent follow-up for patients with 4+ involved nodes is proposed: three visits annually the first 5 years vs. two visits annually for the others. We conclude that history, clinical examination, ALP, ESR and GT are sufficient as a baseline screening for relapse in breast cancer patients.

Chemotherapy with or without high-dose medroxyprogesterone acetate in oestrogen-receptor-negative advanced breast cancer. Norwegian Breast Cancer Group.

In a randomised study 142 patients with advanced oestrogen-receptor-negative breast cancer in the tumour tissue received chemotherapy alone or chemotherapy combined with high doses (1000 mg daily) of oral medroxyprogesterone acetate (HD-MPA). Of the 126 fully evaluable for response, the response rates were 46% for chemotherapy alone and 73% for chemotherapy with HD-MPA (P = 0.005). There was no significant difference with regard to duration of response. Of the 138 patients evaluable for survival and toxicity, survival was shorter in the combined treatment group; median survival of 9 versus 13 months (P less than 0.05). Considerable toxicity was seen from HD-MPA, especially weight gain and fluid retention. The present study provides evidence that in concordance with preclinical studies an interaction between chemotherapy and HD-MPA may exist in breast cancer normally resistant to hormone therapy. The side-effects from MPA were substantial, however, and the survival data are of great concern.

Post-mastectomy megavoltage radiotherapy: the Oslo and Stockholm trials.

The ability of adjuvant radiotherapy to prevent distant metastasis and to prolong survival in patients with early breast cancer is much debated. The paper presents a joint analysis of long-term results (13-16 years' follow-up) from the Oslo and Stockholm randomised trials of post-operative megavoltage radiotherapy versus surgery alone. Among node-positive patients there was a significant 37% relative reduction of distant metastases with radiation (P less than 0.01) and an overall survival difference in favor of the irradiated patients which corresponded with a 22% relative reduction of deaths of borderline significance (P less than 0.06). No significant benefit with radiation in terms of distant metastasis-free survival or overall survival was observed among node-negative patients. The results show that effective local treatment can prevent distant dissemination in some patients and contradict the contention that node-positive breast cancer invariably is a systemic disease already at primary diagnosis.