Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery.

PURPOSE: Allogeneic blood transfusions have reportedly been associated with a poor prognosis in patients with curatively resected cancer. To control for immunosuppression induced by a speculatively causal allogeneic blood transfusion, we designed a randomized study in which the control group received autologous blood transfusions not related to any condition of immunosuppression. PATIENTS AND METHODS: One hundred twenty patients with potentially curative resectable colorectal cancer and the capability to predeposit autologous blood were randomly selected to receive either standard allogeneic blood transfusion or predeposited autologous blood. RESULTS: In curatively resected cancer patients, the number who needed allogeneic blood transfusions was reduced from 60% in the allogeneic blood group to 33% in the autologous blood group (P = .009). After a median follow-up duration of 22 months (range, 8 to 48) tumor recurrence was observed in 28.9% of the allogeneic blood group and 16.7% of the autologous blood group. Life-table analysis established a tendency toward a shorter tumor-free survival for the allogeneic blood group (log-rank P = .11). The problem with this analysis was the strong association of allogeneic blood transfusions with tumor recurrence, which interfered in 33% of patients in the autologous blood group who required additional allogeneic blood transfusions. Multivariate analysis of established risk factors for tumor recurrence and surgery-related variables reflecting potential immunosuppressive conditions showed that only pT stage (relative risk, 6.61; 95% confidence interval [CI], 1.82 to 23.99; P = .004), pN stage (relative risk, 8.39; 95% CI, 3.15 to 22.33; P < .001), and the need for allogeneic blood (relative risk, 6.18; 95% CI, 2.20 to 17.37; P < .001) were independent predictors of tumor recurrence. Subgroup analysis of patients who received a transfusion of < or = 2 U blood found a significantly higher risk of tumor recurrence in the allogeneic blood group (relative risk, 5.16; 95% CI, 1.13 to 23.62; P = .034), which was reduced to borderline significance (relative risk, 3.54; 95% CI, 0.76 to 16.51; P = .107) by adjustment for tumor (T) and node (N) stage. CONCLUSION: As indicated by these first results, the blood transfusion modality has a significant effect on tumor recurrence after surgical treatment of colorectal cancer. A change in the practice of blood transfusion might thus potentially surpass the impact of any recent adjuvant treatment strategies.

Prognostic significance of bone marrow micrometastases in patients with gastric cancer.

BACKGROUND: Monoclonal antibodies (mabs) against components of the cytoskeleton such as cytokeratins allow single disseminated epithelial carcinoma cells to be detected in the bone marrow. The aim of this study was to examine the prognostic relevance of these cells in patients with gastric cancer and to evaluate by multivariate analysis their predictive value compared with conventional risk factors. PATIENTS AND METHODS: A total of 1 x 10(6) cells from bone marrow aspirates were screened immunoctochemically for the presence and absolute number of disseminated tumor cells using mab CK2 to cytokeratin component no. 18. Patients were monitored prospectively for 30.6 +/- 15.2 months. RESULTS: Between one and 122 CK2-positive cells per 1 million mononuclear bone marrow cells were present in 95 of 180 patients (53%). A similar prevalence of 51% was found in curatively operated patients (55 of 109). Comparison with conventional prognostic risk factors showed a correlation of cell dissemination with pathohistologic tumor (pT) stage (P = .07) and Bormann classification (P = .022). Tumor-cell content in the bone marrow predicted disease-free and overall survival in curatively resected patients (P = .007 and P = .049, respectively). Multivariate analysis, which included established risk factors, showed that extent of tumor-cell dissemination was an independent prognostic parameter for disease-free survival in T1/2 tumors (P = .014; relative risk [RR], 1.84; 95% confidence interval [CI], 1.35 to 2.52), in intestinal type carcinomas according to Laurén (P = .008; RR, 1.62; 95% CI, 1.23 to 2.12), and in patients without lymph node involvement (P = .004; RR, 2.43; 95% CI, 1.22 to 4.82). CONCLUSION: Presence of disseminated tumor cells in bone marrow is indicative of systemic disease even in early-stage gastric cancer. The extent of tumor-cell presence in bone marrow correlates with prognosis in curatively resected patients. Therefore, a positive bone marrow finding may be a selection criteria for adjuvant treatment because of minimal residual tumor load.

[Assessment of quality of medical activities (author's transl)]. / Praxis der Qualitätsbeurteilung ärztlichen Handelns.

The efforts to measure the quality of medical activities have been described in the literature a great many times. In this respect, high blood pressure, urinary tract infections and cholecystectomy are great health problems which are most frequently the objects of the investigations. This is also to be seen in the choice of the qualitative measurements used. Whereas adaptable procedures to measure the quality of processes seem to be available, the search for suitable process-specific result measures is far from being concluded. But approximations can be made use of. Finally the quality of medical activities need not be measured exactly in order to be able to assure quality.

[Observations on the temporal sequence of reported pregnancy risks]. / Beobachtungen zur zeitlichen Aufeinanderfolge befundeter Schwangerschaftsrisiken.

A prospective study was conducted with 383 pregnant women concerning the occurrence in respect of time, the duration, and the mutual interactions of pregnancy risks. 35 per cent of the women with hemorrhages during early pregnancy later had premature labour pain (p less than 0.01). The relative risk of premature labour is greater by the factor 2.2 in pregnant women with hemorrhages during early pregnancy than in women without haemorrhages. There was no difference between the investigated groups in respect of onset and duration of these two risk factors. 54 per cent of the pregnant women in whom circular sature of the cervix according to Shirodkar had been performed, also had premature labour pain (p less than 0.001). After the performance of the Shirodkar suture, premature labour followed in 40% of the pregnant women during the further course of pregnancy, corresponding to a relative risk of 2.3 compared with the group without Shirodkar. Premature labour with subsequent Shirodkar cerclage occurred earlier (21st week) and lasted for a longer time (13 weeks) than with the reverse sequence or if premature labour occurred alone. If cervical insufficiency occurred first, followed by premature labour, the time of birth was definitely much earlier (36 weeks) than with the controls. There was no evident connection between the risks "infections of urinary tract" and "premature labour". On the other hand, 32 per cent of the pregnant women with urinary tract infections suffered an EPH gestosis, corresponding to a relative risk of 2 (p less than 0.001). The results show that clear and specific pointers towards the possible occurrence of other risks can be derived from the presence of certain pregnancy risks based on specific findings.

[Prognostic significance of risk factors in pregnancy. I. Observations of onset and duration of observed pregnancy risks]. / Die prognostische Bedeutung von Risikofaktoren während der Schwangerschaft. I. Beobachtungen zu Beginn und Dauer befundeter Schwangerschaftsrisiken.

In a prospective study 383 from 712 women attending our antenatal clinic were found on examination to have pregnancy risks. These were followed with regard to the time of first occurrence, duration and time of last occurrence, as well as their relation to other risk factors occurring in both history, examination or during labour. The method of delivery, necessity for postpartal intensive pediatric care and the perinatal mortality were considered. Risks included antepartal haemorrhage in the first trimester (median time of onset 11 weeks); in the second trimester: hypotension (20 weeks), cervical incompetence (21 weeks), anaemia (25,5 weeks), premature labour (29 weeks) and uterus size inappropriate to gestational age (34,5 weeks) in the third trimester. Antepartal haemorrhage tends to be episodic (median duration of bleeding one week). The average duration for a cerclage was 16 weeks. The other risk factors were observed to last between 3 and 8 weeks. The onset and duration of risk factors found on examination considered alone do not present a sufficient criterion to enable their gravidity to be judged.

[Prognostic significance of risk factors in pregnancy. II. Risk status at onset of labor]. / Die prognostische Bedeutung von Risikofaktoren während der Schwangerschaft. II. Der Risikostatus am Beginn der Geburt.

A group of 383 women with pregnancy risks were screened at the onset of labour. 70% of the EPH-Gestosis, 56% of the urinary tract infections and cervical incompetence, 48% of the anaemias, 38,6% of the premature labour, 11% of the hypotension and 4% of the antepartal haemorrhages were found still to be present at the onset of labour. In those women with EPH-Gestosis at the onset of labour, the risk of cesarean section was markedly higher. When the risks premature contractions and cervical incompetence were recorded, the resulting birth weights were lower and the necessity for intensive paediatric care higher than normal. EPH-Gestosis and urinary tract infections which were still present at the onset of labour were of a longer duration. If the risks premature contractions and cervical incompetence were present at the onset of labour one could imply a shorter period of gestation.

[Premature birth rate, incidence of cesarean section and perinatal mortality between 1945 and 1980. An analysis of 55,000 births]. / Frühgeburtenrate, Sektiofrequenz und perinatale Mortalität zwischen 1945-1980. Eine Analyse von 55000 Geburten.

56,686 single births between 1945 and 1980 were evaluated in a retrospective study. The results reflect the change which has taken place in obstetrics. Perinatal mortality dropped in a straight line from 48.50/00 to 17.20/00. At the same time, the frequency of Caesarian section increased in non-linear progression from an initial value of 1.9% (1945-1949) to 14.0% (1975-1980). The rate of early births dropped in the first ten years only from 10.6% to 7.3%, followed by an approximately constant value up to 1969. From 1970 onwards, there is a rising tendency (6.7% to 7.7%) which was found in all weight categories. The share of early births in perinatal mortality dropped during the first years only, from 77% to 63%, and has since remained constant. If we compare the periods 1945 to 1959 and 1970 to 1980 with regard to indications for Caesarian section, assuming a birth weight of more than 2500 g, the indication of cessation of labour would rise from the 4th rank to the 1st position, whereas disproportion and asphyxia of the newborn continue to occupy the 2nd and 4th ranks, respectively, despite a relative increase. Meanwhile, the indication "condition after Caesarian section" now occupies the 3rd rank. In newborn weighing less than 2500 g, the prominent indications are early birth, asphyxia, desire to have a child and breech presentation, whereas emergency indications were previously the most important ones.(ABSTRACT TRUNCATED AT 250 WORDS)

[Economic aspects of intensive care medicine--cost and reimbursement according to diagnosis related grouping]. / Okonomische Aspekte in der Intensivmedizin: Kosten und Reimbursement unter DRG-Bedingungen 2004.

We analyse relevant modifications of the new German diagnosis related reimbursement system for 2004. It is difficult to judge the consequences of financing intensive care systems by such flat rates. In our surgical ICU total treatment costs were 1 050.-euro /day and 11 530.-euro /patient. Comparison of our total costs and German federal calculation 2003 for long-term ventilation revealed that our costs resulting from a tertiary unit topped the average by 36-60 %. Already the present reimbursement was not cost rewarding. Evaluation according to the 2003 criteria resulted in profound further deterioration to a cost covering of only 49 %. The 2004 system, however, allows for better differentiation of patients and should result in improved reimbursement of long-term ventilation. Further professional analysis of the DRG system is essential for its "learning" development.

Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart.

BACKGROUND: In severe human heart failure, an increase in frequency of stimulation is accompanied by a reduced force of contraction in vivo and in vitro. The present study was aimed to investigate whether inotropic stimulation influences the inverse force-frequency relationship in failing human myocardium. METHODS AND RESULTS: The effects of the cAMP-independent positive inotropic agents ouabain (0.01 mumol/L) and BDF 9148 (0.1 mumol/L) as well as the beta-adrenoceptor agonist isoprenaline (0.01 mumol/L and 0.1 mumol/L) on the force-frequency relationship in electrically driven papillary muscle strips from nonfailing (brain death, n = 5) and terminally failing (NYHA class IV, heart transplants, dilated cardiomyopathy, n = 22) human myocardium were studied. For comparison, we examined the effect of elevation of the extracellular Ca2+ concentration (3.2 mmol/L and 6.2 mmol/L). In nonfailing myocardium, force of contraction, peak rate of tension rise, and peak rate of tension decay increased, whereas time to peak tension and time to half relaxation decreased following an increase of stimulation frequency. In NYHA class IV, force of contraction gradually declined followed by changes of other parameters of isometric contraction. Moderate stimulation of contractility by isoprenaline (0.01 mumol/L) partly reversed the negative force-frequency relationship in NYHA class IV and preserved the positive force-frequency relationship in nonfailing myocardium. The addition of ouabain and BDF 9148 together restored completely the force-frequency relationship in NYHA class IV. In contrast, high concentrations of isoprenaline (0.1 mumol/L) and an elevation of the extracellular Ca2+ concentration enhanced the decline in force of contraction in the presence of higher stimulation frequencies. CONCLUSIONS: It is concluded that functionally important changes occur in the intracellular Ca2+ handling, leading to the negative force-frequency relationship in terminally failing human myocardium. Interestingly, the negative force-frequency relationship can be restored by agents producing positive inotropic effects by elevation of the intracellular Na+ concentration. These findings suggest that hitherto unknown changes in the intracellular ionic homeostasis occur in the failing human heart. Even though increasing [Ca2+]i in failing heart cells may be detrimental, increasing [Na+bdi may be beneficial through a mechanism independent of an increase in [Ca2+]i.

The failing human heart is unable to use the Frank-Starling mechanism.

There is evidence that the failing human left ventricle in vivo subjected to additional preload is unable to use the Frank-Starling mechanism. The present study compared the force-tension relation in human nonfailing and terminally failing (heart transplants required because of dilated cardiomyopathy) myocardium. Isometric force of contraction of electrically driven left ventricular papillary muscle strips was studied under various preload conditions (2 to 20 mN). To investigate the influence of inotropic stimulation, the force-tension relation was studied in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured after stretching the preparations to 150% of the resting length. To evaluate the length-dependent activation of cardiac myofibrils by Ca2+ in failing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction gradually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle length, or cross-sectional area of the muscles between both groups. Pretreatment with ouabain (0.02 mumol/L) restored the force-tension relation in failing myocardium and preserved the force-tension relation in nonfailing tissue. In skinned-fiber preparations of the same hearts, developed tension increased significantly after stretching only in preparations from nonfailing but not from failing myocardium. The Ca2+ sensitivity of skinned fibers was significantly higher in failing myocardium (EC50, 1.0; 95% confidence limit, 0.88 to 1.21 mumol/L) compared with nonfailing myocardium (EC50, 1.7; 95% confidence limit, 1.55 to 1.86 mumol/L). After increasing the fiber length by stretching, a significant increase in the sensitivity of the myofibrils to Ca2+ was observed in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing human myocardium. On the subcellular level, this phenomenon might be explained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.

Hepatitis C virus infection as a possible risk factor for ductopenic rejection (vanishing bile duct syndrome) after liver transplantation.

Irreversible ductopenic rejection (DR) after orthotopic liver transplantation (OLT) is a major cause of late hepatic allograft failure. A variety of risk factors for DR have been postulated, but they are controversial. All transplant recipients at our institution with graft survival of more than 1 month (n = 120) were examined retrospectively with a view to possible risk factors for DR. These factors included age, sex, underlying liver disease, hepatitis B and C infections, donor-recipient CMV status, post-OLT CMV infections, immunosuppressive regimen, ABO blood type, and HLA class I and class II mismatches. Statistical analysis was performed with the univariate chi-square test or the two-tailed Fischer's exact test. Ten patients (8.3%) developed DR. Seventeen patients had HCV infections after OLT. In this group, the incidence of DR was highest (4 of 17, or 23.5%). This was significantly higher than for all other OLT groups (6 of 103 patients, or 5.8%; P < 0.03). The other factors analyzed did not reach statistical significance, including those that other authors found important for the development of DR. It may well be that hepatitis C infection predisposes one to the development of DR after OLT.

Beneficial effect of autologous blood transfusion on infectious complications after colorectal cancer surgery.

Homologous blood transfusion has been associated with an increased risk of postoperative infectious complications. To test the clinical consequences of this apparently immunosuppressive effect of homologous blood in a controlled trial, we designed a study in which the control group deposited autologous blood before their operations for use should transfusion be needed. We enrolled 120 patients with apparently curable colorectal cancer who were able to predeposit autologous blood (haemoglobin > 12.5 g/dL). 62 patients were assigned to receive homologous blood if blood transfusions were needed during operation, and the other 58 to receive their own predeposited blood followed, if necessary, by homologous blood [corrected]. Despite the similarity between the groups in factors known to affect the risk of postoperative infections, there was a significant difference in postoperative infection rate between the homologous and autologous blood groups (17 [27%] vs 7 [12%], p < 0.05; unadjusted odds ratio 2.75 [95% CI 1.07-7.11). The rates of non-infectious complications were similar Probably because their preoperative blood depositing caused the autologous blood patients to have lower haemoglobin concentrations, they were more likely to require transfusion than were the homologous blood group (53 [91%] vs 37 [60%], p < 0.001; relative risk 1.53 [1.24-1.89]). 20 (35%) required homologous as well as autologous blood. To adjust for the many infection-related factors, we did multivariate regression analysis; tumour location, preoperative ASA index, and study group assignment were the only significant risk factors. The odds ratio for postoperative infections adjusted for these factors was 2.84 (1.02-7.98, homologous vs autologous). Testing of delayed-type hypersensitivity responses before and after surgery showed decreases in both mean diameter and number of positive reactions in recipients of homologous blood and slight increases in those who received autologous blood. This study shows the clinical potential of blood-transfusion-mediated immunomodulation, which may be important also in tumour immunology.