Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).

We conducted a prospectively randomised clinical trial to investigate the role of adjuvant outpatient immunochemotherapy administered postoperatively in high-risk patients with renal cell carcinoma. In total, 203 renal carcinoma patients' status post radical tumour nephrectomy were stratified into three risk groups: patients with tumour extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), patients with locoregional lymph node infiltration (pN+), and patients after complete resection of tumour relapse or solitary metastasis (R0). Patients were randomised to undergo either (A) 8 weeks of outpatient subcutaneous interleukin-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen (Atzpodien et al, 2004) or (B) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58% in the treatment arm, and 91, 76, and 66% in the observation arm (log rank P=0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39% in the treatment arm, and at 62, 49, and 49% in the observation arm (log rank P=0.2398). Stage-adapted subanalyses revealed no survival advantages of treatment over observation, as well. Our results established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immunochemotherapy compared to observation in high-risk renal cell carcinoma patients following radical tumour nephrectomy.

Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group.

PURPOSE: To compare mantle-cell lymphomas (MCLs) and follicle-center lymphomas (FCLs) for their features of clinical presentation, response to chemotherapy, and prognosis on the basis of a prospective randomized clinical trial. PATIENTS AND METHODS: Patients with MCL and FCL who entered onto the prospective randomized comparison of cyclophosphamide, vincristine, and prednisone (COP) versus prednimustine and mitoxantrone (PmM) followed by a second randomization for interferon (IFN) maintenance versus observation only. RESULTS: One hundred sixty-five of 234 patients had FCL and 45 of 234 patients had MCL. With FCL, both sexes were equally affected (men, 47%); patients with MCL were predominantly men (78%; P < .0004) and had a higher median age (64 v 53 years; P < .0001). Patients with MCL also had more widespread disease, reflected by the proportion of patients with two or greater extranodal manifestations (43% v 21%; P < .005) and nine or greater involved nodal areas (64% v 45%; nonsignificant [NS]). Response to chemotherapy was significantly lower in patients with MCL (complete remission [CR] + partial remission [PR], 69% v 88%; P < .05) and occurred at a slower pace. Patients with MCL also had a shorter event-free interval (median, 8 v 24 months; P < .0001) and overall survival (median, 28 v 77 months; P < .0001). In both subtypes, however, patients with less than two residual lymphoma manifestations in remission experienced a relatively good prognosis with an estimated 5-year survival of greater than 60% for MCL and greater than 75% for FCL. CONCLUSION: MCL and FCL differ substantially in their features of presentation, response to chemotherapy, and long-term prognosis. The extent of residual disease after completion of chemotherapy discriminates patients with different prognosis and may be used for the stratification of postremission strategies.

[Pseudoleukocytosis in cryoglobulinemia type I]. / Pseudoleukozytose bei Kryoglobulinämie Typ I.

During routine clinical and laboratory examinations of a symptom-free 54-year-old man a leukocytosis was repeatedly noted, but no cause found. 11 months later a painful spontaneously disappearing cyanosis occurred in two fingers of his right hand. Serum analysis demonstrated monoclonal type IgG-kappa immunoglobulin and an antinuclear antibody titre of 1:160. Skin biopsy suggested scleroderma. 4 months later, after exposure to cold, extensive acral haemorrhages occurred. Serum cryoglobulin concentration in serum was found to be 800 mg/dl. Comparative manual and electronic counts on warm and cooled blood identified the previously diagnosed leukocytosis as a typical artefact associated with cryoglobulinaemia. Treatment with chlorambucil (10-20 mg/d) and prednisolone (25 mg/d), for 14 days every 4 weeks, and finally interferon alpha-2b (5 mill. IU/d) reduced the cryoglobulin concentration to 150 mg/dl. Acral cyanosis and haemorrhages have not recurred since then. No cause of the cryoglobulinaemia has been found.

Inhibitory effect of partial cystectomy on experimental carcinogenesis in the urinary bladder.

It was our aim in the present animal experiments to study the influence of stimulation of proliferative activity on carcinogenesis in the urinary bladder. Stimulation of urothelial proliferation was achieved by a one-third resection of the bladder. N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN), which was used as a carcinogen, was administered by gavage in three fractionated doses when proliferative activity was highest at 30, 45, and 70 h postoperatively. Contrary to our working hypothesis, the incidence of urinary bladder tumors proved to be significantly reduced by partial cystectomy. After administration of a low total dose of BBN (300 mg/kg bodyweight) and an experimental period of 6, 12, and 18 months, only 2.6% of the rats with a partial cystectomy, but 12.6% of the control animals with an intact bladder had developed papillomas and noninvasive papillary transitional cell carcinomas. Following administration of BBN at a higher total dose (1,300 mg/kg bodyweight), bladder tumors occurred after an induction period of 4, 6, and 12 months in 27.4% of the partially cystectomized and 48.1% of the nonoperated rats. Multiple tumors were found more frequently in the controls than in the operated animals. The reduction in the tumor incidence following one-third resection of the bladder evidently does not depend on a prolongation of the latency period or induction time. From findings in analogous experimental models it is conceivable that the observed inhibition of experimental bladder carcinogenesis is brought about by an increased capacity of the proliferating urothelial cells to repair carcinogen-induced DNA damage. Further studies are required to elucidate the significance of a stimulated proliferation for the repair system and neoplastic transformation of the urothelium.

Absence of a complete carcinogenic effect of phenacetin on the quiescent and proliferating urothelium stimulated by partial cystectomy. A 2-year feeding study in rats.

It was the object of the present animal experiments to test whether phenacetin (PH) exerts a complete solitary carcinogenic effect on the quiescent and rapidly proliferating urothelium of the lower urinary tract of the rat. In order to stimulate proliferative activity resection of one-third of the urinary bladder was performed which is known to induce intensive reparative regeneration in the stump. PH was administered either continuously with the diet or by gavage in three single doses when proliferative activity was highest. After an experimental period of 2 years 74-83% of the animals receiving PH continuously and 49-52% of the rats after limited gavage feeding had developed uni- and bilateral hyperplasia of the epithelium of the renal papilla. Histologically, the papillary hyperplasia exhibited urothelial differentiation and a typical endophytic growth pattern. It was always associated with healed or, rarely, fresh micronecroses of the subjacent papillary tissue. The urothelial hyperplasia of the renal papilla has to be considered not a true preneoplastic, but rather a reactive proliferative lesion in the sense of a reparative hyperregeneration due to toxic necroses. There was no evidence for a complete solitary carcinogenic action of PH on the urothelium of the entire lower urinary tract. It seems most likely that a metabolite of PH realizes tumor growth only as cocarcinogen with initiation-stimulating and/or initiation-promoting effects acting together with other causative factors during multifactorial multistage carcinogenesis. Based upon the experimental findings reported here, the concept of PH as a solitary complete urothelial carcinogen for man should be reassessed.

[Pulmonary damage caused by cytostatics and paraquat (author's transl)]. / Lungenschäden durch Zytostatika und Paraquat.

Pulmonary damage induced by cytostatics is a rare, although clinically important complication in the chemotherapy of tumours. Early recognition of this partly toxically and partly hypersensitively conditioned processes is of great prognostic importance, since in many cases the unchecked progress of the damage, eventually resulting in pulmonary fibrosis with respiratory insufficiency, can be prevent only by discontinuing the treatment well in time. Examinations of the pulmonary function enable a very early detection of functional disturbances in a lung which has been damaged by cytostatics. Since even the later roentgenological findings are non-specific, final confirmation of the diagnosis is possible by pulmonary biopsy only. Lungs damaged by cytostatics show histologically characteristic patterns, which, however, are non-specific and can become manifest in the same manner, inter alia, in shock and in intoxication by paraquat, since the basic principle of damage underlying these processes is very similar.

Cell cycle kinetics of regenerating urothelial cells of the rat urinary bladder after partial cystectomy.

The cell cycle kinetics of bladder urothelial cells regenerating after partial cystectomy were investigated in 96 female Wistar rats using the percentage labelled mitoses method. In the area of resection a mean cell cycle time (TC) of 15 h was determined. The DNA synthesis phase (TS) lasted 6 h and the premitotic-postsynthetic phase together with the mitosis phase (TG2 + M) 1.5 h, thus giving a presynthetic-postmiotic phase (TG1) of 7.5 h. Similar values were found for the urothelial cells in the stump: the mean cycle time measured 14 h, the TS-phase 6 h, the TG6 + M-phase 2 h and the TG1-phase 6 h. These data are discussed with respect to known cell cycle parameters of bladder urothelium regenerating in response to cytotoxic agents and of neoplastic urothelial cells. The reported findings provide a basis for further investigations using weak carcinogens and threshold doses of potent carcinogens to test the working hypothesis that stimulation of proliferation following partial cystectomy is capable of initiating, accelerating and/or potentiating carcinogenic cell transformation in the urinary bladder.

[Valve lesions of the right heart associated with use of indwelling pulmonary artery catheters (author's transl)]. / Klappenschäden des rechten Herzens nach Anwendung von Pulmonalarterienverweilkathetern.

Pulmonary artery chatheterisation by means of flow-directed balloon-tipped catheters has proved a valuable aid in assessing haemodynamic parameters of critically ill patients. Serious complications are reported to be uncommon. On postmortem examination of 8 patients, in whom flow-directed balloon-tipped catheters were employed, and whose catheters were dissected in situ, there were 5 instances of non-bacterial thrombotic endocarditis (NBTE) and 4 of focal valvular bleeding. This is a much more frequent incidence of valvular lesions than has been reported previously. The pathogensis of NBTE is briefly disicussed, and attention is drawn to potential long-term complications. We suppose that valvular diseases of the right side of the heart will gain in significance due to the increasing use of flow-directed balloon-tipped pulmonary artery catheters.

[Stimulating effect of partial cystectomy on regeneration of rat bladder urothelium and its significance for carcinogenesis (author's transl)]. / Die reparative Regeneration des Rattenurothels nach partieller Cystektomie und ihre Bedeutung für die Carcinogenese.

Cell proliferation kinetics of the urinary bladder urothelium have been analyzed in a total of 218 female Wistar rats after partial cystectomy. After one-third resection of the bladder DNA synthesis started 15 h postoperatively in the bladder stump and reached its maximum at 25 h with a mean 3H-TdR index of 10.1%. In the area of resection the proliferative activity increased after 20 h and the highest 3H-TdR index was found to be 24.7% after 45 h. In the case of hemicystectomy the labeling index in the stump increased 15 h postoperatively and the highest 3H-T-dR index was determined at 20 h with 16.6%. The urothelial cells in the area of resection began to proliferate synchronously with those in the stump and the maximum of DNA synthesis was measured 35 h postoperatively with an 3H-TdR index of 24.2%. After 2 weeks the proliferative activity within the stump and operative region corresponded to that of the control urothelium. The basal cells showed absolutely the highest proliferative activity, the suprabasal cells exhibited on the other side the highest regenerative potential compared with the control urothelium. Partial cystectomy might possibly serve as an experimental model for testing low potential carcinogens, in the case where carcinogenic effects would be initiated, potentiated and accelerated via stimulation of the DNA synthesis.

[Cardiac tamponade after perforation of ventricle by central venous catheters and transvenous pacemakers (author's transl]. / Herzbeuteltamponade nach Ventrikelperforation durch zentrale Venenkatheter und Reizsonden.

Two cases of cardiac tamponade after perforation of the right ventricle by central venous catheter and transvenous pacemaker are reported. The apex of the right ventricle represents a "locus minoris resistentiae" for a perforation because of its thin wall and frequent infiltration of fat with relaxation of the small muscle bundle. An analysis of 41 heart perforations by central venous catheters and 47 by transvenous pacemakers from the literature demonstrates the particularly high mortality of the perforation by a central venous catheter referring to the possible production of hydropericardium. We think that extreme carefulness in the use of catheters, knowledge of the danger and vigorous treatment could reduce the mortality.