Monitoring the response to primary medical therapy for breast cancer using three- dimensional time-resolved optical mammography.

Primary medical therapy is used to reduce tumour size prior to surgery in women with locally advanced breast cancer. Optical tomography is a functional imaging technique using near- infrared light to produce three-dimensional breast images of tissue oxygen saturation and haemoglobin concentration. Its advantages include the ability to display quantitative physiological information, and to allow repeated scans without the hazards associated with exposure to ionising radiation. There is a need for a non-invasive functional imaging tool to evaluate response to treatment, so that non-responders can be given the opportunity to change their treatment regimen. Here, we evaluate the use of optical tomography for this purpose. Four women with newly diagnosed breast cancer who were about to undergo primary medical therapy gave informed and voluntary consent to take part in the study. Changes in physiological and optical properties within the tumour were evaluated during the course of neoadjuvant chemotherapy. Optical imaging was performed prior to treatment, after the first cycle of chemotherapy, halfway through, and on completion of chemotherapy. Images of light absorption and scatter at two wavelengths were produced, from which images of total haemoglobin concentration and oxygen saturation were derived. All patients that showed a good or complete response to treatment on MRI showed a corresponding recovery in the haemoglobin concentration images. Changes in mean tumour total haemoglobin concentration could be seen four weeks into treatment. The tumour oxygen saturation was low compared to background in three out of four patients, and also showed a return to baseline over treatment. Optical imaging of the breast is feasible during primary medical therapy and can be used to assess response to treatment over six months.

Significance of prostaglandin E2 in acute necrotising pancreatitis in rats.

Acute necrotising pancreatitis in rats was induced by injecting 5% sodium taurocholate into the pancreatic duct. Prostaglandin E2 (100 micrograms/kg subcutaneously twice) decreased the mortality rate from 100% to 60% (NS). When treatment with prostaglandin E2 was combined with simultaneous administration of either dazmegrel (UK 38,485, 50 mg/kg bodyweight) or Sibelium (Flunarizine R 14,950, 0.2 mg/kg body weight) a significant decrease in the mortality rate (p less than 0.05) was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and prevents the formation of thromboxane A2. Flunarizine (a calcium entry blocker) decreases thromboxane A2 formation and also inhibits the effects of raised thromboxane A2 concentrations. As plasma thromboxane B2 (the stable metabolite of thromboxane A2) concentrations increase and the plasma prostaglandin E2 concentrations decrease in acute necrotising pancreatitis in rats, the results of the present study indicate that these prostaglandins play a role in the pathophysiology of the disease. It is suggested that restoration of the balance in prostanoid concentrations will have a beneficial effect on the course of acute necrotising pancreatitis.

Consequences of blood loss on growth of artificial metastases.

Previous studies have shown that lung metastases from a nonimmunogenic sarcoma (LS175) in BN (homozygous for RTln) rats were stimulated by blood transfusions. Enhanced growth was also observed after abdominal surgery combined with allogeneic blood transfusions while syngeneic blood transfusions had no effect. These experimental findings have been confirmed in retrospective clinical studies. The allogeneic blood transfusion effect may be avoided in cancer patients by autologous blood transfusions although this implies blood donation before surgery. The aim of the present study was to investigate the effect of blood loss before surgery on formation ('take') of lung colonies, and on the outgrowth of established metastases in the BN rat model. These aspects of tumour behaviour were also investigated in rats undergoing surgery, or receiving blood transfusion, or both, after blood loss. The results indicate that blood loss has a profound stimulating effect on the growth of established metastases, but not on the 'take' of tumour cells. This stimulating effect was also present when blood loss was combined with surgery, while previously surgery alone was found to have no effect. Allogeneic and syngeneic transfusions in combination with blood loss both had a strong stimulating effect on growth of established lung metastases. The results indicate that blood loss may be an important factor in determining the outcome of metastatic growth.

Prostanoid imbalance in experimental acute necrotizing pancreatitis in rats.

In an investigation of the pathogenesis of acute necrotizing pancreatitis (ANP) the plasma levels of TXB2, 6-keto-PGF1 alpha, and PGE2 were measured in rats. After induction of ANP by injection of 5% sodium taurocholate into the pancreatic duct, a marked increase in TXB2 levels and a slight increase in 6-keto-PGF 1 alpha levels were found. PGE2 levels decreased. Mortality was 100% within 30 h. Pretreatment with chloroquine, a phospholipase A2 inhibitor, led to a inhibition of TXB2 production, whereas 6-keto-PGF1 alpha and PGE2 levels showed a surprising slight elevation in the first 6 h. Pretreatment with chloroquine decreased mortality by 30%. Pretreatment with FPL 55712, a leukotriene synthesis blocker, caused an increase in TXB2 and PGE2 levels, whereas the formation of 6-keto-PGF1 alpha remained unaltered. Two out of nine animals survived after pretreatment with FPL 55712. The results of the present study indicate that arachidonate end products are involved in ANP. The significance of the high TXB2 levels, decreased PGE2 levels, and only slightly elevated 6-keto-PGF1 alpha levels during ANP requires further investigation. The thromboxane A2 to prostacyclin ratio may be important.

Raised plasma thromboxane B2 levels in experimental acute necrotizing pancreatitis in rats. The effects of flunarizine, dazoxiben, and indomethacin.

The possible role of thromboxane A2 (TXA2) in acute necrotizing pancreatitis (ANP) was investigated in rats. After ANP was induced by injecting sodium taurocholate (5% w/v) into the pancreatic duct, the thromboxane B2 (TXB2) levels in plasma increased significantly. The effects of indomethacin, a general blocker of prostaglandin synthesis, on survival time and on plasma TXB2 levels were compared with those of dazoxiben, a more specific blocker of TXA2 synthesis, and Flunarizine, a calcium entry blocker known to inhibit the effects of TXA2. In a test group without any treatment, all animals died within 30 h of ANP induction. Although TXB2 levels were lowered by the administration of indomethacin, dazoxiben, and Flunarizine, survival times were not significantly altered. Indomethacin pretreatment had no beneficial effect, whereas 30% and 40% of the animals survived for 36 h after treatment with Flunarizine and dazoxiben, respectively. The results of the present study indicate that inhibition of TXA2 synthesis alone does not dramatically alter survival time. However, a potential role for other arachidonate metabolites in ANP cannot be ruled out by this study.

Enhanced growth of artificial tumor metastases following blood transfusion: the effect of erythrocytes, leukocytes and plasma transfusion.

Clinical and experimental investigations have shown that allogeneic blood transfusions may modulate the growth of tumors. Dependent on the tumor model used in animal studies, the effects observed ranged from inhibition to stimulation of tumor growth. We have demonstrated previously that allogeneic blood transfusions gave rise to enhanced growth of a transplantable sarcoma (LS 175) in BN rats. In the experiments reported here the effect of transfusion of different allogeneic blood constituents on the growth of artificial LS 175 lung metastases was investigated. Erythrocytes and leukocytes were found to promote tumor growth to a similar degree as whole blood transfusions, plasma transfusions had no effect.

Omega-3 fatty acids inhibiting the growth of a transplantable rat mammary adenocarcinoma.

BN/Bi inbred female rats fed diets containing different amounts of polyunsaturated fatty acids, either of the omega-3 or omega-6 type, each received an implant of a syngeneic mammary adenocarcinoma. When the diameter of the tumors reached 20 mm, they were surgically removed; 2 weeks thereafter the animals were sacrificed and lung metastases were counted. Cellular immune response was determined before tumor inoculation; certain prostaglandin values in plasma and platelet aggregation were measured before and after tumor inoculation. Plasma prostaglandin E2 and thromboxane B2 values were significantly decreased in those rats fed a diet containing menhaden oil. 6-Keto-prostaglandin F1 alpha, cellular immune response, and platelet function were not significantly different in either one of the diet groups. Tumor growth in the groups of rats receiving the omega-3 fatty acids in their diet was significantly inhibited in comparison with that in the rats receiving the omega-6 fatty acids. However, the number of metastases was not significantly altered.

Growth of an implanted fibrosarcoma in rats is associated with high levels of plasma prostaglandin-E2 and thromboxane-B2.

Growth of BN175, a malignant fibrosarcoma, was correlated with high plasma TXB2 and PGE2 levels. This statistically significant increase was first detected 17 days after inoculation of the tumor, at which time the tumors were 20 mms in diameter. A further increase in tumor size was associated with still higher PGE2 and TXB2 values. At the same time, progressive alterations in platelet function, as measured by ADP-induced platelet aggregation, were observed. 6-keto-PGF1 alpha levels remained normal throughout the whole experiment. It was concluded that tumor growth was associated with changes in PG synthesis and platelet function, although it remains unclear whether these changes were caused by some host immunological response towards the tumor or were predominantly the result of tumor PG-synthesis.

Comparison of endoscopic retrograde pancreatography with functional and histologic changes in chronic pancreatitis.

The findings from endoscopic retrograde pancreatography (ERP) and secretin-CCK test data were compared in 69 patients: 36 with chronic pancreatitis, 9 with possible chronic pancreatitis, and 24 without chronic pancreatic disease. The ERP findings were also compared with the histologic changes in pancreatic tissue in 18 patients who underwent pancreatic surgery for chronic pancreatitis. ERP films were reviewed according to the criteria proposed by Kasugai et coll. with special attention paid to the side branches. Secretin-CCK test data were interpreted using the discriminant analysis. A good correlation between bicarbonate and chymotrypsin output and ductular changes at ERP was found. The results of ERP and the secretin-CCK test were compatible in 86 per cent of the patients. The relationship between ERP findings and histologic changes was not straightforward. It was concluded that ERP and the secretin-CCK test are complementary in the diagnosis of chronic pancreatitis. ERP does not necessarily represent the histology in chronic pancreatitis.

Conversion of diets at tumor induction shows the pattern of tumor growth and metastasis of the first given diet.

In a previous study, significant differences in the growth rate of a transplantable mammary adenocarcinoma were observed between rats receiving a diet rich in saturated fatty acids (lard, diet A), and rats on a diet in which the saturated fat was partly replaced by polyunsaturated fatty acid of the omega-3 type (Menhaden oil, diet B). In the present investigation, it was our aim to study tumor growth in rats on diet A and B, as well as in rats that had, at tumor inoculation, a change of diets, from diet A to diet B. Tumor growth of rats receiving diet A throughout the whole experiment was the same as in those rats that had a conversion of diets. The data shows that the observed inhibiting effect of diet B on tumor growth could not be obtained when this diet was given exclusively after tumor inoculation.

Calibration of stenosis of the small intestine with marbles.

A simple and reliable method for the calibration of stenoses in intestinal Crohn's disease, using a marble, is presented. With this procedure, unnecessary resection or stenoplasty can be avoided and adequate passage of intestinal contents throughout the whole length of the small intestine is secured.

Abrogation of the tumor promoting effect of allogeneic blood transfusion by polyadenylic-polyuridylic acid (poly A-poly U).

Studies from several centers have shown an immunosuppressive effect of surgical procedures, whilst others have shown blood transfusion in association with cancer surgery to have an adverse effect on ultimate prognosis. We have previously demonstrated enhanced growth of tumor metastases, in rats following allogeneic blood transfusion and surgery. Polyadenylic-polyuridylic acid (poly A-poly U) has been reported to stimulate immune responses. In this report, we have investigated the effectiveness of poly A-poly U as an adjuvant to blood transfusion and surgical procedures in BN rats bearing artificial lung metastases. Significantly reduced tumor growth was observed, following poly A-poly U adjuvant treatment. These results lead to serious contemplation of the use of this drug as adjuvant therapy in blood transfused and surgically treated patients.

Per-operative topical administration of ZK 36 374 (Iloprost) acts favorably on patency of small artery anastomoses in rats.

Aspirin (group I, 20 mg/kg, 0.5 hour preoperatively, ip, xylocaine (group II, topical administration of 1 ml of a 2% solution), and ZK 36,374 (Iloprost) either pre- or per- or postoperatively (group III, 10 micrograms/kg 0.5 hour peroperatively iv; group IV, topical administration of 1 ml of a solution containing 25 micrograms/ml peroperatively; and group V, 10 micrograms/kg 0.5 hour postoperatively iv) were given to groups of BN female rats in order to improve the patency rate of small artery (less than 0.5 mm) anastomoses. The rats in group VI received saline peroperatively by topical application, this group served as a control. The patency was established by means of arteriography and macroscopical examination. Neither aspirin nor xylocaine improved the number of successful anastomoses. However, Iloprost administered topically, while performing the anastomosis, substantially improved the patency rate when compared with group VI, the control group. In the control group only five out of 21 animals showed patent anastomoses, whereas in group IV (Iloprost, topical administration) seven out of ten operations were successful. The results suggest that Iloprost applied locally could be helpful in clinical microsurgery for elective operations as well as in replantation surgery.