Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects.

The International Breast Cancer Study Group (IBCSG, formerly the Ludwig Group) is currently conducting several trials to improve available adjuvant therapies for operable breast cancer. Within the framework of clinical trials, treatment is available for several subpopulations of patients with operable disease. Two trials for patients with node-negative breast cancer question the efficacy of the combination of chemotherapy and endocrine manipulation. Four trials for patients with node-positive disease investigate questions of chemoendocrine therapy and of delayed reintroduction of chemotherapy after an initial cytotoxic treatment. One trial for elderly patients investigates the role of axillary lymph node dissection in terms of treatment outcome and quality of life. The ongoing trials are based on the results of past investigations by the Group: seven clinical trials, conducted since 1978, tested hypotheses of timing, duration, and the combined use of chemo- and endocrine therapies. Several ancillary studies were conducted using the database amassed from these trials, including pathological findings in node-negative disease, significance of micrometastases detected by serial sectioning of axillary nodes, importance of c-erbB-2 oncogene expression for prediction of treatment responsiveness, patterns of relapse, and assessing the impact of adjuvant treatment for breast cancer on the patients' quality of life. This report presents updated results of the seven IBCSG trials conducted from 1978 to 1993 and describes the trials currently open to patient accrual.

Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.

PURPOSE An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.

A correlative cytologic and histologic study of 40 cases of histologically highly pleomorphic malignant fibrous histiocytoma (MFH) is presented. The fine-needle aspiration biopsy was performed preoperatively, and a diagnosis of malignant soft-tissue tumor could be established in all cases. The cytologic and histologic features corresponded well with each other. The two main cell types were mono- and multinucleated, large polymorphic, often bizarre, histiocyte-like cells and atypical fibroblast-like cells. For a correct diagnosis of pleomorphic MFH, it is important to recognize atypical large polymorphic tumor cells showing signs of phagocytosis: prominent cytoplasmic vacuolization, cell debris or even well-preserved cells within the tumor cell cytoplasm. Phagocytic activity was easily demonstrated in air-dried and May-Grünwald Giemsa-stained material. The differential diagnosis of MFH as opposed to other soft-tissue sarcomas and pleomorphic carcinomas is discussed.

The prognostic significance of histologic tumor grade has been evaluated in 1537 women entered into the Ludwig Trials I-IV of adjuvant therapy for node-positive breast cancer. Tumor grade was determined on histologic review of primary tumor sections by two central review pathologists using a modification of the Bloom and Richardson grading system. The 5-year overall survival rates (+/- SE) were: Grade 1, 86% +/- 2; Grade 2, 70% +/- 2; and Grade 3, 57% +/- 2 (P less than 0.0001). This survival difference was seen in both premenopausal (P less than 0.0001) and postmenopausal (P less than 0.0001) women. Significant differences in disease-free survival (DFS) by tumor grade were also observed (P less than 0.0001). The tumor grade determined by the 75 contributing local clinic pathologists was also highly significant for predicting DFS and overall survival. Tumor grade remained a statistically significant prognostic factor for DFS (P less than 0.0001) and overall survival (P less than 0.0001) in multivariate analyses controlling for nodal status, tumor size, estrogen receptor status, menopausal status, age, peritumoral vessel invasion, and treatment assigned. In postmenopausal patients for whom adjuvant treatment was compared with no adjuvant therapy, the prognostic significance of tumor grade was modified by the effect of treatment. The presence of vessel invasion by primary tumor cells was a stronger predictor of early recurrence than was increasing tumor grade in postmenopausal patients who received no adjuvant therapy. The higher failure rates for patients with high-grade tumors was due to a larger number of failures in regional and visceral sites. Tumor grade can be determined by any pathologist and allows for selection of a subpopulation of breast cancer patients at high risk for early mortality.

Spontaneous diabetes in the domestic pig, an animal suitable for metabolic and endocrine studies and for experimental surgery, is extremely rare. In this study we have compared the diabetogenic response of various doses of streptozotocin in comparison to surgically induced diabetes. Streptozotocin in a low dose, 35 mg/kg body weight did not influence glucose metabolism while an intermediate dose, 85 mg/kg, resulted in a transient diabetic reaction. Streptozotocin, 100-150 mg/kg body weight, caused a complete and permanent diabetes. Animals made diabetic by means of pancreatectomy did not survive more than 10 days due to their poor general condition and diabetes. Streptozotocin induced diabetic animals survived with insulin treatment up to seven months. The results show that juvenile pigs made diabetic with 100-150 mg/kg body weight of streptozotocin may be useful in experimental work on glucose-, insulin- and C-peptide-metabolism in a large animal. Therefore it is potentially useful in pancreatic transplantation research.

Details of a female infant, who was born after 29 weeks gestation and who died within minutes of birth, are presented. The infant was hydropic, showed macroglossia and had very short limbs with normal sized hands and feet. Apart from a preductal aortic coarctation the pathological findings were confined to the skeleton. The radiographical and histological findings are described in detail; they differ from those of previous studies of similar conditions.

In the transplantation of vascularized pancreatic grafts severe problems are related to the exocclusion is an improved alternative to duct ligation in producing atrophy of the exocrine pancreas while leaving the endocrine pancreas intact. Fractional growth rate in duct-ligated and duct-occluded animals was reduced to 1/3 - 1/4 of that of sham operated controls. Fasting blood glucose, fasting insulin, sum of blood glucose and glucose elimination rate during an intravenous glucose tolerance test remained normal in the duct-ligated and Ethibloc-occluded animals. There was a diminished insulin response to a maximal glucose load. In spite of this, the glucose tolerance remained virtually normal. The volume of the pancreas was reduced to 1/3 of its normal size after both experimental procedures. Histologically, the islets appeared to remain normal, while the exocrine portion of the gland was replaced by fibrous tissue. No traces of the active compound, Ethibloc, remained after 4 weeks. This study shows that pancreatic duct occlusion with Ethibloc results in impairment of endocrine function. Consequently, Ethibloc duct occlusion does not seem to be a superior alternative to other methods of producing exocrine atrophy in organs intended for transplantation.

This study examined pancreatic allograft function in transplanted diabetic juvenile pigs. The grafts were transplanted with ligated, occluded (Ethibloc) or open ducts. No immunosuppression was used. Irreversible and permanent diabetes was induced by streptozotocin. Graft function was assessed by measuring glucose tolerance and insulin production during an i.v. glucose tolerance test. The fractional growth rate of the transplanted host was used to evaluate the long-term consequence of transplantation. Normal glucose tolerance was achieved in 50%, and a slight impairment in 10% of the animals. In 35%, no detectable graft function was observed. Duct-ligated and Ethibloc-occluded grafts had a significantly lower function rate within the first week compared with grafts with open ducts. The fractional growth rate was significantly decreased in animals receiving grafts with occluded ducts. This was probably not due to different insulin production. No graft failures were observed within the first week in open-duct graft transplantations. Graft failures were associated with elevated serum alpha-amylase and were probably due to vascular impairment. Normal glucose tolerance in transplanted pigs was associated with elevated levels of normal insulin and C-peptide in peripheral blood, concomitant with low levels of proinsulin. Our results show that a pancreatic graft should be transplanted with open ducts. Obstructed ducts lead to an increased frequency of graft failure, while the transplanted hosts with such functioning grafts show retarded growth due to unidentified factors.

The morphological findings of duct-ligated pancreas grafts in streptozotocin-induced diabetic hosts were studied using inbred AGUS and WAG rats with a major histocompatibility complex difference. AGUS to AGUS pancreas isografts survived indefinitely. Morphologically, islet tissue was partly dispersed and showed about 75% granulated β cells. Fibrosis was minimal and inflammatory cells generally absent. WAG to AGUS allografts were quickly rejected and showed severe pancreatitis with a polymorphonuclear and mononuclear infiltrate. Islet destruction lagged behind that of exocrine tissue and vascular thrombosis was a late event. In the last group, AGUS recipients first received WAG spleen allografts which survived spontaneously. Three to 5 months later they were removed and WAG pancreas allografts inserted. Sixty-eight percent of these pancreas allografts survived. Four to 10 months later they were characterized by severe dense fibrosis surrounding islet tissue. Capillaries were always present between islet cells, about 75% of which showed β granules. A mild to moderate mononuclear cell infiltrate and vascular intimal proliferation were also part of the picture. We conclude that pancreatitis after duct-ligated pancreas allografts is not a sequel of duct ligation but results from rejection and can be prevented with adequate immunosuppression. Fibrosis does not have a detrimental effect on islet cell function as a result of the feasibility of insulin secretion by β cells into adjacent capillaries and thence to larger vessels traversing through the dense fibrosis.

An ultrastructural study of 10 liposarcomas is reported. Four of the liposarcomas were wholly or predominantly of well‐differentiated, lipoma‐like or fibrosing type, 3 of myxoid type, 2 of round cell type and 1 of pleomorphic type. The well‐differentiated, lipoma‐like liposarcomas showed cells with a few, large lipid droplets, few organelles and a peripherally located, fairly large nucleus. The well‐differentiated liposarcomas of fibrosing type revealed mostly spindle‐shaped, fibroblast‐like cells, with abundant rough endoplasmic reticulum and inconspicuous lipid inclusions, surrounded by collagen. One well‐differentiated liposarcoma contained an area which was similar to brown adipose tissue and hibernoma. The spindle and stellate shaped cells of the myxoid liposarcomas showed abundant rough endoplasmic reticulum and large smooth‐membraned vacuoles filled with moderately dense amorphous material, which appeared to be extruded extracellularly by rupture of the vacuoles. Cytoplasmic lipid droplets were seen in most cells but were much less prominent than in the well‐differentiated lipoma‐like liposarcomas. Ultrastructurally there were many similarities between the myxoid and round cell liposarcoma, indicating a close relationship between the two types. The pleomorphic liposarcoma revealed cells with one or more large, irregular nuclei, numerous large vacuoles after dissolved lipids, abundant dilated cisternae of rough endoplasmic reticulum and rounded, electron‐dense bodies corresponding to PAS‐positive hyalin globules seen in the light microscope. The ultrastructural study suggests that the variegated cellular appearance of the different subtypes of liposarcoma reflects the wide cellular spectrum seen during the differentiation of adipose tissue and supports the view that al liposarcomas histogenetically represent a single entity.

Two cases of primary malignant histiocytoma of bone after irradiation are reported. One tumour developed in the left ileal bone ten years after irradiation for cystadenocarcinoma of the left ovary. The other developed in the left mandible 26 years after irradiation for a »semi‐malignant« mixed tumour of the left parotid gland. Both tumours had a light microscopic picture of malignant fibrous histiocytoma as described in soft tissues. Fascicular, spindle‐cell areas resembling leiomyosarcoma were found in both tumours. Ultrastructurally the pelvic tumour was found to be composed of histiocytic and fibroblastic cells and some spindle‐shaped cells with abundance of myofilaments with dense body‐like structures, indistinguishable from spindle‐cells of leiomyomatous tumours. The light and electron microscopic observations suggest that a relationship exists between fibroblastic, histiocytic and leiomyomatous cell elements of bone and soft tissue tumours.

A new technique for transplanting duct-ligated rat pancreas grafts, rather similar to the technique for spleen grafting in rats, is presented. Inbred AGUS and WAG rats with a strong Ag-B incompatibility were used. Duct-ligated pancreas AGUS to AGUS isografts survived indefinitely in streptozotocin-induced diabetic hosts while WAG to AGUS allografts were quickly rejected. However, when WAG spleen and pancreas were transplanted en bloc to AGUS rats, endocrine pancreas graft function persisted for up to 6 weeks. This finding of a transient protection of pancreas allografts by donor-strain spleen allografts led to further experiments. AGUS recipients first received WAG spleen allografts which then were removed after 3 to 5 months, at which time WAG pancreas allografts were inserted. Sixty-eight per cent of these grafts survived and cured their hosts of streptozotocin-induced diabetes.

In a recent in vitro study, mechanical vibration was shown to facilitate, considerably, both the passing of a basket catheter beyond an artificial ureteral stone as well as the extraction of a calculus. Therefore, a device by which vibration can be transmitted to the basket of a modified stone extractor was developed for clinical application. The basket moves to and fro with an amplitude of 2-4 mm and a frequency of 40-60 Hz. An experimental follow-up study was performed in dogs to find out whether the vibration procedure as such induced injuries to the ureters. Modified stone extractors were passed up bilaterally into the ureters of 11 dogs. Vibration was applied in a standardized manner to one side, the other non-vibrated side served as a control. Postoperatively, 5 dogs were followed during 4-5 weeks with repeated urographies. Specimens of the ureters were examined microscopically when the dogs were sacrificed. No complications which could be ascribed to the vibration procedure as such were observed. The vibration technique was tried also in a pilot study comprising 14 patients with distal ureteral stones; in 9 patients, the stones were successfully extracted. Of the remaining 5 patients in whom the stone extraction failed, 3 passed the stone spontaneously and in 2 ureterolithotomies were performed. No complications were encountered.