M. Betzler

Activation and Signaling Status of Human Lamina Propria T Lymphocytes

In this study, proliferative responses of human lamina propria T lymphocytes were examined in vitro. The response of lamina propria T lymphocytes to Sepharose-bound anti-CD3 antibody plus interleukin 2 was significantly lower than the response of autologous peripheral blood T lymphocytes, whereas the responses of lamina propria T lymphocytes to anti-T11(2/3) antibodies plus sheep erythrocytes or anti-CD28 antibody plus interleukin 2 were largely preserved. After coculture with mucosa supernatant, peripheral blood T lymphocytes showed a similar pattern of reactivity as lamina propria T lymphocytes. This reduced reactivity to T-cell antigen receptor stimulation appears to exist at the level of signal transduction, because triggering of CD3 induces low amounts of intracellular inositol 1,4,5-triphosphate and no free calcium increase in lamina propria T lymphocytes when compared with peripheral blood T lymphocytes. This study indicates that the antigen receptor-dependent activation pathway of lamina propria T lymphocytes for proliferation is down-regulated by intestinal mucosa derived factor(s) and that the alternative pathways mediated by CD2 or CD28 are largely preserved. Based on previous data that lamina propria T lymphocytes can provide help to B cells, it is possible that these alternative activation pathways play an important role in T-B cell interaction in the gut.

Current Practice Patterns in Pancreatic Surgery: Results of a Multi-institutional Analysis of Seven Large Surgical Departments in Germany With 1454 Pancreatic Head Resections, 1999 to 2004 (German Advanced Surgical Treatment Study Group)

Despite decreasing mortality rates, morbidity is still high after pancreatic head resection. Comparative data in the United States and Europe show a relationship between hospital volume and mortality. Treatment strategies vary frequently, partially because of the lack of evidence-based data. We performed a multi-institutional analysis in Germany evaluating current numbers, indications, techniques, and complication rates of pancreatic head resection. Questionnaires were completed by seven high-volume surgical departments regarding quantitative and qualitative aspects of pancreatic head resections in the period from 1999 to 2004 (five prospective and two retrospective institutional databases). A total of 1454 pancreatic head resections (944 for malignancy) were reported. Mean annual hospital volume ranged from 14 to 52 (10 to 43 in malignancy). Mortality was between 1.1% and 4.8%, morbidity was between 24% and 46%, and pancreatic leakage was between 9% and 20%. In malignant disease, all centers perform standard lymphadenectomy and regard arterial infiltration as a contraindication for resection. However, the rate of portal vein resection varied from 0% to 28%. No consensus is seen on the type of surgery for malignancy and chronic pancreatitis. After resection for pancreatic cancer less than one fourth of the patients receive adjuvant therapy. The results of our analysis in Germany confirm that pancreatic head resection can be performed with low mortality in specialized units. Variations in indications, operative technique, and perioperative care may demonstrate the lack of evidence-based data and/or personal and institutional experience. The low number of patients receiving adjuvant therapy after resection of pancreatic cancer suggests that more efforts must be made to establish novel adjuvant therapies under randomized study conditions.

Diagnostic evaluation, surgical technique, and perioperative management after esophagectomy: consensus statement of the German Advanced Surgical Treatment Study Group

PurposeCorrect diagnosis, surgical treatment, and perioperative management of patients with esophageal carcinoma remain crucial for prognosis within multimodal treatment procedures. This study aims to achieve a consensus regarding current management strategies in esophageal cancer by questioning a panel of experts from the German Advanced Surgical Treatment Study (GAST) group, comprised of 9 centers specialized in esophageal surgery, with a combined total of >220 esophagectomies per year.Materials and methodsThe Delphi method, a systematic and interactive, evidence-based approach, was used to obtain consensus statements from the GAST group regarding ambiguities and disparities in diagnosis, patient selection, surgical technique, and perioperative management of patients with esophageal carcinoma. After four rounds of surveys, agreement was measured by Likert scales and defined as full (100% agreement), near (≥66.6% agreement), or no consensus (<66.6% agreement).ResultsFull or near consensus was obtained for essential aspects of esophageal cancer staging, proper surgical technique, perioperative management and indication for primary surgery, and neoadjuvant treatment or palliative treatment. No consensus was achieved regarding acceptability of minimally invasive technique and postoperative nutrition after esophagectomy.ConclusionThe GAST consensus statement represents a position paper for treatment of patients with esophageal carcinoma which both contributes to the development of clinical treatment guidelines and outlines topics in need of further clinical studies.

Adjuvant chemo(immuno-)-therapy of primary breast cancer with adriamycin-cyclophosphamide (and levamisole)—Six-year evaluation

In a phase II-type study 52 patients with no signs of metastases but with a high risk of recurrence were treated with 6 courses of adriamycin-cyclophosphamide as adjuvant systemic therapy following modified radical mastectomy of primary breast cancer. Half of the patients were randomized to receive additional immunotherapy with levamisole for 2 yr. The scheduled dose and time regimen could be achieved in over 90% of patients. A comparison of the actuarial disease-free and overall survival with data reported in the literature indicates a similar positive effect of adjuvant systemic therapy as described in adjuvant studies using polychemotherapy regimens. Immunotherapy with levamisole has no effect on disease-free and overall survival but added to general toxicity. Particular attention was paid to psychological consequences of adjuvant systemic therapy; consistent attention by one specifically trained physician during the whole therapy and follow-up period was effective in coping with the emotional problems. The difficulties in treating recurrences after adjuvant therapy became apparent. A high rate of loco-regional recurrences and of cerebral metastases was noted.

Assessment of Crohn's disease activity and α1-antitrypsin in faeces

The case-fatality ratio for patients over 65 years of age was 40%; all but 1 of the adult deaths occurred in this group. The ratio was similar for the patients with risk factors (41 %) compared with those without (40%); 29% and 31 %, respectively, of those patients with high dependency or advanced malignancy were included. This series reflects the known higher incidence and mortality of pneumococcal disease in elderly people. 64% of the cases over 65 did not have risk factors that would have led to their being offered pneumococcal vaccination had the UK guidelines been followed. The mortality for those with and without risk factors was similar. 7 of the 47 patients had a poor quality or expectation of life before pneumococcal infection. However, most probably had a reasonable quality of life, and so the pneumococcus would not have been for

Retrospektive Analyse von anterioren Rectumresektionen und abdomino-perinealen Rectumexstirpation bei Patienten mit Rectumcarcinom*

SummaryEighty-seven patients with an abdomino-perineal extirpation of the rectum and 75 patients with an anterior resection of the rectum could be analysed retrospectively. The mean observation period was 36 months for anterior resection and 38 months for abdomino-perineal extirpation. The rate of recurrences, mortality, and postoperative complications of each surgical method was correlated to tumor-localization, -staging, and -grading. The poor prognosis of patients with abdomino-perineal extirpation was mainly due to relatively more cases in advanced tumor stage. In rectal cancer above 7 cm anterior resection should be performed.ZusammenfassungIn einer retrospektiven Analyse wurden Patienten, bei welchen wegen eines Rectumcarcinoms eine anteriore Rectumresektion oder eine abdomino-perineale Rectumexstirpation vorgenommen wurde, erfaßt. Dabei wurde für jedes Operationsverfahren die Rate der Operationsletalität, der postoperativen Komplikationen, der Wiedererkrankung (loco-regionäre Rezidive, Fernmetastasen) und der Mortalität in Korrelation zu der Tumorlokalisation, dem Tumorstaging und dem Tumorgrading gesetzt. Gleichzeitig wurde unter diesen Aspekten ein Vergleich zwischen diesen beiden Operationsverfahren bei Carcinomen des mittleren Rectumdrittels (7–11 cm) vorgenommen. Es zeigte sich, daß im Gesamtkrankengut wie auch bei den Patienten mit einem Carcinom im mittleren Rectumdrittel die Rate an Wiedererkrankungen und postoperativen Komplikationen bei den anterioren Rectumresektionen niedriger war als bei den abdomino-perinealen Rectumexstirpationen, was jedoch auf die unterschiedliche Verteilung der Tumorstadien zurückgeführt werden muß.

Quantitative and Functional Studies of Lymphocyte Subpopulations During Adjuvant Chemo(immuno)therapy in Patients with Breast Cancer

One of the major problems of chemotherapy is that virtually all cytotoxic drugs are immunosuppressive. While there is general agreement that intermittent chemotherapy allows for a certain degree of recovery of immune functions, or even temporary “rebound overshoot” reactions, reliable immune parameters for a rational design of chemotherapy are lacking. In this study, an attempt was made to describe and evaluate in vitro immune parameters in patients with breast cancer undergoing mastectomy and adjuvant chemo(immuno)therapy.

Untersuchungen zum zellulären Immunstatus bei Normalpersonen, Nichtmalignom- und Malignompatienten

Die Verteilung der lymphatischen Subpopulationen bei Malignompatienten wurde in 2 Untersuchungsschritten untersucht. Zunachst wurden die Befunde bei 39 Normalpersonen und 101 Malignompatienten in verschiedenen Tumorstadien sowie 34 Patienten mit fortgeschrittenen Karzinomen verglichen. Es fand sich eine signifikante Verminderung der T-Lymphozyten bei Malignomen, welche besonders ausgepragt in den fortgeschrittenen Tumorstadien war. In einem zweiten Untersuchungsschritt sollte der Einflus der Tumorresektion auf die Verteilung der lymphatischen Subpopulationen untersucht werden; dabei wurden 26 kurativ operierte Tumorpatienten mit 23 operierten Nichtmalignompatienten verglichen. Bei den Nichtmalignompatienten ergaben sich zwischen den pr-a und postoperativen Kontrollen keine signifikanten Abweichungen zwischen den T- und B-Lymphozytenzahlen. Nach Resektion des Tumors zeigten Tumorpatienten eine signifikante Zunahme der prozentualen wie absoluten T-Lymphozytenzahl. Die moglichen pathophysiologischen Grundlagen fur die durch die operative Tumorresektion hervorgerufene reversible Verminderung der T-Zellen werden diskutiert.

Einfluß der Darmresektion auf das Verhalten der mononucleären Subpopulationen bei Morbus Crohn

SummaryThe literature data about the distribution of mononuclear cells in Crohns disease are still contradictory. In 50 surgical C.D. patients, clinically classified corresponding to the Crohns Disease Activity Index (CDAI), the T-lymphocytes and their subsets helper-T- and suppressor-T-lymphocytes (TH/TS) were therefore determined by use of monoclonal antisera, the B-lymphocytes by F(a b)-anti human Ig and the macrophages by uptake of latex microparticles. 37 C.D. patients underwent diseased bowel removal. Blood was drawn from the Crohn-draining mesenteric vein for analysis. Further investigations were performed at the 10th p. op. day as well as after an average period of 7 months (2–18). In comparison the mononuclear cell distribution was examined in 14 patients suffering from chronic osteitis and in 14 patients without any inflammatory disease as controls. C.D. patients showed preoperatively a significantly decreased TH/TS-ratio as well as a significantly increased proportion of macrophages. There was a lymphocytopenia in the peripheral differential blood count. Whereas the distribution of mononuclear subpopulations in the mesenteric blood was identical to the peripheral blood, significant lymphocytosis in the differential blood count of mesenteric blood was found. On the 10th p. op. day the TH/TS-ratio rose almost up to normal, which continued during the follow-up period. The macrophages remained constantly increased in all stages of investigation although during the follow-up none of the patients had signs of disease recurrence. Osteitis patients showed a similar distribution as C.D. patients, even if the changes compared to controls were not as distinct. The proportion of B-lymphocytes was the same in all groups examined. The individual TH/TS-ratios and proportions of macrophages of C.D. patients did not correlate to their clinical data. The changes within the T-cell-subpopulations seem to reflect less M. Crohns disease itself than its inflammatory complications. Further studies have to be undertaken concerning the impact of the constant increase in macrophages, even after resection of the Crohn bearing bowel segment.ZusammenfassungDie Berichte über die Verteilung mononucleärer Zellen bei Morbus Crohn sind in der Literatur weiterhin widersprüchlich. Es wurden deshalb bei 50 chirurgischen M.C.-Patienten, welche klinisch nach dem Crohns Disease Activity Index (CDAI) eingestuft wurden, die T-Lymphocyten und ihre Untergruppen T-Helfer und T-Suppressor-Lymphocyten (TH/Ts) mit monoklonalen Antiseren analysiert. Die B-Lymphocyten wurden durch ein F(a b)-anti-Human Ig und die Makrophagen durch Aufnahme von Latexmikropartikeln identifiziert. 37 M.C.-Patienten kamen zur Resektion des Crohn-befallenen Darmanteils. Dabei wurde auch Blut aus der Crohn-drainierenden Mesenterialvene zur Analyse gewonnen. Nachuntersuchungen erfolgten am 10. postop. Tag und nach durchschnittlich 7 Monaten (2–18). Zum Vergleich wurde die mononucleäre Zellverteilung bei 14 Patienten mit chronischer Osteitis, sowie bei 14 Patienten ohne entzündliche Erkrankungen als Kontrollkollektiv untersucht. Präoperativ zeigten die M.C.-Patienten einen signifikant erniedrigten TH/TS-Quotienten, sowie einen signifikant erhöhten Makrophagenanteil bei einer Lymphocytopenie im peripheren Differentialblutbild. Während die Verteilung der mononucleären Subpopulationen des mesenterialen Blutes im Vergleich mit dem peripheren Blut identisch war, fand sich im mesenterialen Differentialblutbild eine signifikante Lymphocytose. Bis zum 10. postop. Tag zeigte der TH/TS-Quotient eine weitgehende Normalisierung, der noch zum Zeitpunkt der Nachuntersuchung anhielt. Die Makrophagen waren zu allen Untersuchungszeiten konstant erhöht, obgleich alle Patienten zum Zeitpunkt der Nachuntersuchung klinisch keinen Anhalt für ein Crohn-Rezidiv zeigten. Die Osteitis-Patienten wiesen eine dem M.C. ähnliche, wenn auch nicht so stark vom Kontrollkollektiv abweichende Zellverteilung auf. Der B-Lymphocytenanteil war in allen untersuchten Kollektiven gleich. Für die individuellen TH/TS-Quotienten und Makrophagenanteile der M.C.-Patienten ließen sich keine Korrelationen zu klinischen Daten finden. Die Veränderungen innerhalb der T-Lymphocyten-Untergruppen scheinen weniger Ausdruck des Morbus Crohn selbst, als vielmehr seiner entzündlichen Komplikationen zu sein. Einer weiteren Klärung bedarf die Bedeutung der konstanten Makrophagenerhöhung, auch nach Resektion des Crohntragenden Darmsegmentes.

Postoperative individuelle Verlaufskontrollen der natürlichen Killerzell-Aktivität und der CEA-Werte bei Patienten mit gastrointestinalen Carcinomen

Die naturlichen Killerzellen (NK), eine lymphatische Subpopulation, konnen spontan, d.h. ohne vorherige Sensibilisierung, Targetzellen zerstoren; dieser Vorgang wird spontane „Zellvermittelte Cytotoxizitat“ genannt. Vor allem tierexperimentelle Untersuchungen weisen darauf hin, das die NK-Zellen bei der Anti-Tumor-Reaktion, insbesondere bei der Vernichtung kleiner Tumormengen, beteiligt sind (2, 3). Es konnte bereits gezeigt werden, das die NK-Aktivitat bei Malignompatienten gegenuber gesunden Probanden deutlich herabgesetzt ist (1). In der vorliegenden Untersuchung sollte uberpruft werden, ob sich durch die regelmasige Bestimmung der NK-Aktivitat ahnlich wie durch die Bestimmung des carcinoembryonalen Antigens (CAE) prognostisch relevante Aussagen uber den Verlauf der Erkrankung bei Patienten mit gastrointestinalen Carcinomen machen lassen.