Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes.

The therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-alpha) correlates with the occurrence of CD4(+) lymphocytes identified by fine-needle aspirates from melanoma metastases (Håkansson et al, 1996). The present investigation studies a possible correlation between tumour-infiltrating CD4(+) lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m(2) d.1-3, DTIC 250 mg/m(2) d.1-3 i.v. and IFN-alpha 2 b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumour-infiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4(+) lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4(+) lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-alpha therapy alone, there seems to be a need for CD4(+) lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs.

Complications of laparoscopic cholecystectomy as recorded in the Swedish laparoscopy registry.

The Swedish laparoscopy registry prospectively recorded 11,164 laparoscopic cholecystectomies during the years 1991-1993 with the aim of monitoring bile duct injuries and other complications of the new technique. In total 57 bile ducts were injured; 35 of these were merely incision of the common bile duct. Serious injuries with tissue loss occurred in 11 cases and clipping or electrocautery damage in another 11.

On down-regulation of the immune response to metastatic malignant melanoma.

Treatment of metastatic malignant melanoma with interferon alpha (IFNalpha) results in objective remission in approximately 15% of patients. In a previous investigation, we found that about 50% of the patients achieved at least minor or short-lived remissions. In some tumours extensive areas of regressive tumour change occurred. However, even in these areas remnants of tumour cells were generally found. The short duration of the immune response in some patients and the incomplete eradication of the tumour can be due either to selection of non-immunogenic tumour cells or to down-regulation of the immune reactivity to the tumour. In the present paper, the expression of the zeta chain of the T cell receptor in CD3+ lymphocytes and the expression of CD28 in CD3+, CD4+ and CD8+ lymphocytes was studied in resectable melanoma metastases from 20 treated (IFNalpha or IFNalpha in combination with cisplatinum and dacarbazine) and 16 untreated patients. A double-staining technique was used, and the occurrence and distribution of lymphocytes showing down-regulation of the zeta chain or CD28 were separately registered in different areas of the metastases: close to the tumour cells in areas of unaffected tumour growth, in areas with regressive tumour changes, in areas with marked fibrosis and in stromal areas with densely packed lymphocytes. CD3+ zeta lymphocytes were found in all metastases, but their number and distribution varied considerably. Down-regulation of the zeta chain was most often found in areas of regressive changes. In contrast, T lymphocytes infiltrating close to the tumour cells had a stronger expression of the zeta chain (P = 0.016). Down-regulation was also found in stromal areas of densely packed lymphocytes and in areas of fibrosis. The pattern of down-regulation of CD28 in various subsets of lymphocytes was similar to that of zeta chain. The same pattern of down-regulation of CD28 and the zeta chain was found in both untreated and treated patients, indicating that the down-regulation is not due to treatment but to the release of immunosuppressor factors from areas with high tumour cell density or extensive destruction of tumour cells. These results concur well with the view that IFNalpha treatment can result in immune-mediated tumour cell destruction early in the treatment period and that this immune response to the tumour can be followed by immunosuppression within a few weeks.

Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumor-infiltrating mononuclear cells and regressive tumor changes.

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in cell to cell interactions. In malignant melanoma, ICAM-1 expression correlates with malignant behavior. We used monoclonal antibodies, anti-ICAM-1, anti-CD4+, anti-CD8+, and anti-CD11c+ to study the effect of interferon-alpha (IFN-alpha) on the expression of ICAM-1 by melanoma cells in regional metastases and its correlation to the occurrence of CD4+, CD8+, and CD11c+ cells close to tumor cells and in the tumor stroma. We also estimated the expression of ICAM-1 and regressive changes in malignant melanoma metastases, correlating the duration of treatment to these effects of IFN-alpha. Twenty-three IFN-alpha-treated and 10 untreated patients with regional metastatic malignant melanoma were studied. The duration of IFN-alpha treatment influenced the expression of ICAM-1. In metastases from patients treated for 1 week only, 1 of 5 showed high expression of ICAM-1 compared with 6 of 11 of those treated for 3 weeks (p = 0.01, chi-square test for trend comparing untreated patients and patients with various durations of IFN-alpha treatment). In IFN-alpha-treated patients with low expression of ICAM-1, none of 7 metastases showed CD4+ cells infiltrating close to tumor cells, in contrast to 6 of 10 metastases expressing high amounts of ICAM-1 (p = 0.03). Similarly, the expression of ICAM-1 was found to correlate with the occurrence of CD8+ cells close to the tumor cells (p = 0.04). We also showed a correlation between ICAM-1 expression and histologic evidence of tumor regression (p = 0.02).

[Survey among 90 surgical departments. Laparoscopic cholecystectomy in Sweden 1991]. / Enkät bland nittio kirurgiska kliniker. Laparoskopisk cholecystektomi i Sverige 1991.

According to a recent questionnaire study, laparoscopic cholecystectomy has been rapidly adopted at surgery departments in Sweden, 68 per cent of which either use the technique already or intend to introduce it in the near future. The procedure has aroused great optimism regarding improved treatment for patients and economic gain to the community in terms of shorter periods of sick-certification. Swedish surgery departments are interested in collaborating over a national registry with a view to the identification and follow-up of any disadvantages that may be associated with the procedure. The laparoscopic cholecystectomy technique places new demands on surgical skill, and thus on specialist training.

Indomethacin and pancreatic blood flow. An experimental study in pigs.

Indomethacin has been reported to decrease pancreatic blood flow. The drug has been used as an analgesic in acute pancreatitis. As decreased blood flow to the pancreas may detrimentally affect the outcome of acute pancreatitis, we investigated the effects of indomethacin on blood flow in the normal porcine pancreas. Regional blood flows, with special reference to the pancreatic flow, were studied with radioactively labelled microspheres in ketamine-anesthetized pigs before and after intravenous administration of indomethacin 2 mg/kg during 10 min. A transient decrease of cardiac output was seen during the infusion. Basal pancreatic blood flow was significantly increased 10 and 30 min after administration of indomethacin. No significant changes were found in small-intestinal or renal blood flow. We conclude that indomethacin does not reduce blood flow in normal porcine pancreas.

Pathobiochemistry and early CT findings in acute pancreatitis.

Extrapancreatic findings at computed tomography (CT), performed within 24 h in 42 consecutive episodes of acute pancreatitis, were classified according to a scoring system (EP score) and were correlated to Ranson's prognostic signs, to duration of hospital stay, biochemical changes in plasma and pancreatic ischaemia found at CT with contrast enhancement. Increasing EP score was found to be related to increasing number of positive Ranson's signs, longer hospital stay and pancreatic ischaemia. Plasma levels of immunoreactive cationic trypsin and amylase were not proportional to EP score. alpha 1-protease inhibitor, antichymotrypsin but not immunoreactive pancreatic secretory trypsin inhibitor increased proportionally to EP score. No changes related to EP score were seen in alpha 2-macroglobulin levels. Serum levels of trypsin-alpha 1-protease inhibitor complex were maximal after 3 days and most pronounced in cases with high EP scores. Plasma levels of factor X, alpha 2-antiplasmin and C1-esterase inhibitor were found to be inversely proportional to EP score.

Early diagnosis and classification in acute pancreatitis. A comparison of clinical outcome with findings at computed tomography and Ranson's prognostic signs.

The clinical outcome in 52 consecutive episodes of suspected acute pancreatitis was compared with Ranson's prognostic signs and findings on noncontrast and contrast-enhanced computed tomography (CT) scans performed within 24 h of patient admission. The predictive value of CT scan for diagnosis was 95% for positive results and 53% for negative results. In providing an accurate prognosis of a single attack, scoring of extrapancreatic signs was as good as that of Ranson's prognostic signs. CT with contrast medium revealed pancreatic ischaemia in 3 cases of 4 with clinically severe disease. The risk of developing severe pancreatitis was 23% in first attacks and 6% in relapses. Early CT scan is recommended in most patients with suspected pancreatitis to confirm diagnosis and to predict the severity of an attack.

Interactions in vitro and in vivo between anionic and cationic porcine trypsin and porcine plasma proteinase inhibitors.

A method for purifying porcine anionic and cationic trypsin is presented. Reaction mixtures with increasing amounts of the two porcine trypsins and porcine serum were studied in vitro to evaluate the relative importance of alpha 1-macroglobulin and alpha 2-macroglobulin as well as alpha 1-proteinase inhibitor in the rapid binding of porcine anionic and cationic trypsin. Porcine cationic trypsin was preferentially bound to alpha 1-macroglobulin, while anionic trypsin exhibited equal binding to both alpha-macroglobulins. Both trypsins were also bound by the alpha 1-proteinase inhibitor but not until alpha 1-macroglobulin approached saturation. Trypsin-alpha-macroglobulin complexes were cleared from plasma with a half-life of 6 min. For trypsin-alpha 1-proteinase inhibitor-complexes the half-life was 120 min. These findings are in accordance with results for other mammalian species, including man.

Ganglion of the hip--an unusual cause of soft tissue swelling of the groin.

Soft tissue swellings of the groin can be a problem for diagnosis and treatment. One case of a ganglion connected to the hip joint capsule is presented.

Protease-antiprotease imbalance, hemodynamic and regional blood flow changes in experimental pancreatitis.

Pathologic proteolysis in pancreatitis is an important clue to understand the pathophysiology in pancreatitis. Impairment of pancreatic circulation is also important in the development of severe pancreatitis. In an attempt to study some of the biochemical and circulatory events in experimental pancreatitis in the pig the following experiments were undertaken. Pancreatic and splanchnic blood flow were studied in severe and mild pancreatitis with the microsphere method, together with cardiac output and mean arterial pressure. Kininogen, alpha-2-macroglobulin and alpha-1-proteinase inhibitor were measured in plasma and in peritoneal fluid. In severe pancreatitis consumption of kininogen in the peritoneal cavity was demonstrated together with a final lowering of the plasma protease inhibitors. This was accompanied by a rapid reduction of cardiac output and finally mean arterial blood pressure. Pancreatic blood flow was profoundly diminished in this group. No such changes were found in mild pancreatitis. It is concluded that pancreatic ischemia in pancreatitis is associated with protease-antiprotease imbalance.

Major gastrointestinal haemorrhage as a complication of cholecystoduodenal fistula in gallstone disease. Report of three cases.

Three patients with cholecystoduodenal fistulae due to gallstone penetration, resulting in major gastrointestinal haemorrhage are presented. Diagnosis and treatment of this condition are discussed.

Transmesenteric hernia in the meso-appendix with gangrene of the small bowel.

Reviewing the literature, transmesenteric hernias were found to be rare. A case with herniation in the meso-appendix, intestinal obstruction and gangrene of the small bowel is presented. Surgery was performed and the outcome was uneventful.