Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b).

Several forms of immunotherapy are apparently effective in inducing clinical remissions in metastatic renal cancer, but their benefit on survival times have not been demonstrated so far. The present analysis was designed to assess the effects of concomitant application of renal cancer vaccine and cytokines on DTH skin responses to tumor cell challenge, clinical remissions and patients survival. 40 patients with advanced RCC, all with distant metastases in at least one organ, were entered after nephrectomy into a protocol involving multiple vaccinations with Newcastle disease virus (NDV)-infected autologous irradiated tumor cells, with subsequent repetitive 3 bi-weekly cycles of low dose interleukin-2 (r-IL-2) and interferon-alpha(2b)/rIFN-alpha(2) s.c. (1.5 million r-IL-2 Cetus units/m(2)/day and 3 million IFN-alpha IU/m(2)/day). In a pilot study the coadministration of a supplement of r-IL-2 proved to be important for augmentation of DTH responsiveness upon tumor cell challenge. Patients with aneuploid tumors vaccinated without r-IL-2 apparently developed an anergy to the vaccine throughout vaccination. In the main study, of the 40 evaluable RCC patients, 5 exhibited a complete response (CR), 6 displayed a partial remission (PR), 12 showed stable disease (SD, median 25 months) and 17 tumor progression. Survival distribution analysis predicted for all patients with stable disease a median survival of 31 months while CR+PR patients had a median survival >4 years. 23/40 (57.5%) patients (CR, PR and SD) appear to have a significant survival advantage compared to the patients with progressive disease during the treatment period and to a historic reference group. Further data analysis revealed that the number of metastatic sites was predictive of survival characteristics (p<0.05). A marked increase during 3 vaccinations of DTH anti-tumor reactivity predicted a survival advantage (35 vs 14 months), a correlation that was also significant by the Wilcoxon test. While the multi-modality treatment with autologous tumor vaccine and s.c. administration of IL-2 and IFN-alpha appears to be effective in advanced RCC, a randomized trial (ASI-IL-2/IFN-alpha vs IL-2/IFN-alpha without ASI) is now set up to help assess the role of ASI within the combined treatment regimen.

Localization of endogenous sugar-binding proteins (lectins) in tumors of the central and peripheral nervous system by biotinylated neoglycoproteins.

The carbohydrate part of cellular glycoconjugates - glycoproteins, glycoproteins, glycolipids and proteoglycans - and specific endogenous sugar receptors, i.e. lectins, can establish a system of biological recognition based on protein-sugar interactions on the cellular and subcellular levels. To gain insight into the role of proteins in this type of interaction, sections of surgically removed tumor specimens of central and peripheral nervous tissue were analyzed glycohistochemically, using biotinylated neoglycoproteins with different sugar part. A specific staining with this type of probe, exposing different sugar moieties as ligands, indicated the presence of sugar receptors in different types of meningiomas, glioblastomas, gangliocytomas, anaplastic and well-differentiated oligodendrogliomas and ependymomas as well as in neurinomas and neurofibromas of peripheral nerves. In comparison to the well-differentiated ependymomas, the anaplastic form of this tumor exhibited a generally higher capacity to specifically bind the neoglycoproteins, containing alpha- or beta-glucosides. Inverse intensity of the glycohistochemical reaction was observed with galactose-6-phosphate-, galactose-beta(1.3)-N-acetylglucosamine-N-acetyl-D-glucosamine- and mannose- (BSA- biotin), respectively, when anaplastic and differentiated oligodendrogliomas were compared with each other. Tumorously dedifferentiated neurons, i.e. in gangliocytomas, showed a changed spectrum of endogenous sugar receptors in comparison to neurons of normal cerebral cortex. Qualitative and quantitative differences of sugar receptors were observed among the distinct subtypes of meningiomas. Receptors for N-acetyl-D-galactosamine were present only in the anaplastic form, while glucuronic acid-specific receptors were only found in the meningotheliomatous meningiomas. Distinctions in binding spectrum of neoglycoproteins suggest the presence of a possible additional subtype of meningiomas, called submalignant meningioma. Analysis of the spectrum of endogenous sugar receptors can serve to distinguish between different cell populations composing a given tumor, as shown in neurofibromas in the cases of Schwann cells and fibroblastoid cells stained with N-acetyl-D-glucosamine-(BSA-biotin). The analysis of expression of endogenous sugar receptors, as part of an intercellular information code system, may represent a further way of studying the mechanism of tumor differentiation and propagation.

Role of color-coded Doppler sonography in the assessment of internal ureteral stent patency.

OBJECTIVE: To evaluate the role of color-coded Doppler sonography (CCDS) in the assessment of internal ureteral stent patency. PATIENTS AND METHODS: We compared micturating cystography (MC) and CCDS in 48 patients with internal ureteral stents. Forty-five of these patients had pyelocaliectasis on renal sonography. RESULTS: In all of the 48 patients, the distal end of the internal ureteral stent could be seen sonographically in the bladder. The color images of 30 patients showed typical flow from the distal holes of the stent. Micturating cystography demonstrated patency of the stents in 36 patients. The two procedures showed the same results in 42 of 48 patients. Six patients had no detectable flow by CCDS, but the MCs showed patency of the stents. CONCLUSION: The CCDS is a valid noninvasive method for the assessment of internal ureteral stent patency with a sensitivity of 100%, a specificity of 83%, a positive predictive value of 67%, and a negative predictive value of 100%.

Effects of carbon dioxide pneumoperitoneum in pigs with impaired pulmonary function.

The objective of our study was to investigate the possible adverse hemodynamic effects of a CO2 pneumoperitoneum in an experimental model in pigs with impaired pulmonary function. Thirteen animals were anesthetized with azaperon/ketamine and ventilated with 67% nitrous oxide in oxygen. By intravenous injection of dextran microspheres, a capillary pulmonary embolism was induced. After embolization, three animals served as controls (Group 1), five underwent open nephrectomy (Group 2), and five underwent laparoscopic nephrectomy (Group 3). Intra-abdominal pressure was kept constant at 15 mm Hg. At intervals, hemodynamic parameters were measured, and blood gas measurements were performed. Data were analyzed using a general linear model analysis of variance for differences between groups, and a paired t-test was applied for differences within groups from one condition to the next. The groupwise comparison revealed a significant rise of cardiac output in the laparoscopy group compared with the open nephrectomy group. No differences were noted for heart rate, systemic arterial pressure, central venous pressure, mean pulmonary arterial pressure, or pulmonary arterial wedge pressure. Impairment of pulmonary function caused no negative hemodynamic effect during laparoscopic nephrectomy.

[Therapy of ureteral tumor]. / Die Therapie des Harnleitertumors.

Nephroureterectomy is the standard treatment of tumors in the upper and middle third of the ureter. Whereas, resection of the distal ureter and uretercystoneostomy is the treatment of choice of tumors in the lower third, as long as there is enough renal function which is worthwhile to be preserved. Lymphadenectomy should be performed in all patients suspicious for invasion of the ureteral wall since already 10% of patients with pT1 and pT2 tumors will present with metastases to the lymphnodes. In case of functional or anatomic single kidney therapy has to be adapted to the patient and tumor appropriately. Endoscopic resection, partial or complete resection of the ureter with substitution by ileum or autotransplantation with pyelovesicostomy are the operative options. Elective endoscopic treatment of ureteral tumors should be done in patients with G1 tumors only. However, the recurrence rate is as high as 30 to 60% and the mean interval to recurrence is about 9 months. Regular followup by means of cytology and endoscopy is mandatory. Laparoscopic nephroureterectomy is still a experimental treatment at present time and should be not considered in the treatment of ureteral tumors because of the complexity of the procedure and the risk of tumor spillage.

[Renal cell carcinoma with vena cava involvement. Surgical strategies and results]. / Nierenzellkarzinome mit V.-cava-Befall. Operative Strategien und Ergebnisse.

The elaboration of new operative procedures established in the last decade has led to an improved prognosis in patients with renal cell carcinoma with vena caval extension. We report on our personal operative experience in over 100 patients and present the current analysis of 76 patients with renal carcinoma with vena caval extension seen in our institution between 1985 and 1996. Sixty-six patients underwent nephrectomy and removal of vena caval tumor thrombi. Actuarial 5-year survival for patients without metastasis was 38%. For patients with tumor stages between I and III, 5-year survival was between 40 and 50% and was not significantly related to the rostral extent of the tumor thrombus. The relatively poor outcome for patients with tumor thrombi invading the right atrium was caused by a high perioperative mortality (50%). For patients with distant metastases, medium survival time was 10.5 months, implying that radical surgery is useless in cases of distant metastases.

[The role of surgery in renal cell carcinoma]. / Die chirurgische Therapie des Nierenzellkarzinoms.

Renal cell carcinoma accounts about three percent of all adult neoplasms. This review provides a current status about the surgical management of renal cell carcinoma. In localised carcinomas radical nephrectomy is still the standard treatment and provides 5 Year survival rates up to 98 %. As nephron-sparing surgery in mandatory indications can achieve similar survival doubt can be expressed whether lymphadenectomy or adrenalectomy are necessary in every case. Nephron-sparing surgery is associated with a higher rate of operative complications up to 40 % and probably with a higher risk of local recurrence. However, parenchymal-sparing surgery in elective indications is possible for small tumors, if long term follow up is guaranteed. But there is no convincing advantage of nephron-sparing surgery to recommend this procedure as a general approach in patients with a normal contralateral kidney. Radical surgery in renal carcinomas invading to the vena cava still remains a challenging surgical intervention. Nevertheless, in selected patients surgery can realise long term survival in over a third of cases. Palliative nephrectomy in metastatic renal carcinomas is only justified in real palliative indications (bleeding, pain) or in clinical trials investigating cytoreductive surgery before immunotherapy. In highly selected patients with metastatic renal carcinoma a radical surgical approach including nephrectomy and complete metastasectomy can achieve long term survival.

[Status of organ preserving surgery in renal cell carcinoma]. / Stellenwert der organerhaltenden Chirurgie beim Nierenzellkarzinom.

Nephron-sparing surgery in renal cell carcinoma is an accepted approach in patients with bilateral carcinomas, solitary kidneys and in patients with chronic renal failure in whom radical nephrectomy would necessitate immediate renal replacement therapy (mandatory indications). Because of the improvement of operative techniques-like renal perfusion in hypothermia or work-bench surgery-over 95% of patients can spared dialysis even if multiple tumors or locally advanced renal cancer is present. Based on the excellent outcome of nephron-sparing surgery in mandatory indications (5-year survival rates over 80%), several centers advocate extending the use of partial nephrectomy to selected patients with a normal opposite kidney (elective indications). Several reports on nephron-sparing surgery in elective indications with a median follow-up time of 40 months document similar survival rates compared to radical nephrectomy. Nevertheless, due to the low incidence of bilateral renal carcinomas (under 2%), only 2 of 100 patients would benefit from this approach. Furthermore, local recurrence after nephron-sparing surgery occurs mostly after 4 years (late recurrence); therefore, it seems doubtful whether the short follow-up times really reveal the the true recurrence rate. The prognosis after development of a local recurrence is poor.

[Spontaneous kidney rupture after delivery due to an urothelial carcinoma]. / Spontanruptur einer Niere post partum aufgrund eines urothelialen Karzinoms. Bedeutung für die bildgebende Diagnostik.

The case of a spontaneous kidney rupture due to an urothelial carcinoma one week after delivery is presented. Diagnosis was made during operation. In comparison to the carcinoma, which is diagnosed and treated in time, the prognosis is poor. The patient deserved continuous gynecological follow-up and showed the classic symptoms of an urothelial carcinoma for six months. In spite of regular sonographic controls during pregnancy the tumor was not diagnosed. Diagnosis and management of renal carcinomas during pregnancy are discussed.

[Local recurrence after organ saving kidney tumor surgery]. / Lokale Rezidive nach organerhaltender Nierentumorchirurgie.

Although excellent survival rates for nephron-sparing surgery in mandatory indications (solitary kidney, bilateral renal neoplasms) have been documented, parenchymasparing surgery in elective indications (normal contralateral kidney) is a point of controversy. Local tumor recurrence is the most important argument against this approach. From January 1971 to December 1989, 107 patients suffering from renal cell carcinoma in solitary kidneys or bilateral renal carcinoma underwent nephron-sparing surgery. Thirteen patients (12%) suffered from local recurrence between 4 and 112 months after tumor resection. A high proportion of these recurrences were seen within the first 2 years after resection, followed by a almost linear increase thereafter. Thus-there are possibly two different entities for local recurrence. A correlation between tumor grade and interval from resection to local recurrence could be found, with a long average interval for grade 1 tumors--longer than the published follow-up times for patients undergoing elective tumor resections. Although most of the patients described in this report do not fulfil the surgical criteria for elective resection, we cannot recommend parenchyma-sparing surgery in elective indications.

[Brain metastases in renal cell carcinoma. Results of treatment and prognosis]. / Hirnmetastasierung beim Nierenzellkarzinom. Behandlungsergebnisse und Prognose.

Brain metastases develop as a late manifestation of renal cell cancer (RCC) and pose an increasing challenge to urologists as a result of the more frequent prolonged survival of patients with advanced RCC. Therapeutic options, including surgical resection and radiotherapy, were analyzed retrospectively to assess survival and to identify factors influencing prognosis in a group of 90 patients treated either by brain metastasectomy (n = 64) or radiotherapy (n = 26). The analysis confirmed that the overall median survival was a disappointing 461 days and the 1-year survival rate was 31% for patients treated by surgical resection and 310 days and 15% respectively for patients treated by radiotherapy. However, a subgroup of patients who, benefitted significantly from aggressive treatment of metastases could be defined. The following favorable prognostic factors showed a trend toward improved survival: (1) metachronous appearance of brain metastases more than 1 year after nephrectomy (P < 0.0001), (2) good patient performance (Karnofsky > 70) (P < 0.0002), (3) patient's age under 50 years (P < 0.05), (4) solitary lesions (P < 0.05), (5) minimal or no neurological deficit (P < 0.05), and (6) the absence of/or minimal extracranial metastases (P < 0.05). No influence of lesion size and localization (infratentorial vs supratentorial) on survival was detected. Surgical treatment of recurrent brain tumors (n = 17) yielded and additional median survival advantage of 8 months as compared to untreated patients (n = 16). Our results suggest that, especially in patients with good prognostic criteria, a radical metastasectomy plus vigorous surgery of local recurrences and, if required, subsequent systemic immuno- or chemoimmunotherapy should be performed. In patients with poor prognosis, stereotactic radiosurgery is recommended for palliation and survival prolongation.

[Magnetic resonance urography. First clinical results]. / Die Magnetresonanzurographie. Erste klinische Ergebnisse.

We report our preliminary results using a new magnetic resonance imaging technique for visualization of the urinary tract. Using the paramagnetic contrast medium gadolinium diethylene triamine penta-acetic acid (DTPA), we were able to obtain images of the urinary tract comparable to those obtained by conventional excretory urography. The major advantage of our technique is that besides good morphologic visualization, the excretion of gadolinium-DTPA can be studied simultaneously. We demonstrate our preliminary results in selected cases.

[Repetitive immuno-embolization of inoperative liver metastases of renal cell carcinoma. Method characterization and preliminary results]. / Repetitive Immunembolisation inoperabler Lebermetastasen beim Nierenzellkarzinom. Methodencharakterisierung und vorläufige Ergebnisse.

Interleukin 2 (IL2)-based immunotherapy is effective in a subgroup of patients with metastatic renal cancer, but cure from liver metastases is very rare and even the selection of patients to be treated is very much limited by the toxicity of IL2. To reduce this toxicity and to augment the efficacy of intrahepatic IL2 application, a protocol of combined rIL2 (3 mg/day) and Lipiodol (2-5 ml/day according to tumour size), via a catheter inserted percutaneously into the hepatic artery, was implemented. As an adverse reaction, moderate fever (WHO) grade I and II was noted. A partial remission was seen in one patient and stable disease in four patients over a period of 2-6 years (median 32.2 month). It seems that immuno-embolisation of otherwise intractable liver metastases of renal cancer is well tolerated and its efficacy may be augmented by optimisation of the therapeutic protocol.

[Spontaneous kidney ruptures--a complication of panarteritis nodosa]. / Spontane Nierenrupturen--eine Komplikation der Panarteriitis nodosa.

Besides renal cell carcinomas and angiomyolipomas panarteritis nodosa (PAN) is a common underlying disorder for spontaneous perirenal hematomas (SPH). Herein we report on 3 cases with PAN associated kidney ruptures where diagnosis of PAN was not known before in 2 instances. The hematoma was identified by computerized tomography (CT) in all patients, nevertheless CT failed to reveal the underlying disorder in any case. In this situation angiography was extremely valuable visualizing multiple renal microaneurysms that are typical for PAN. Operative exploration and drainage of the hematoma was necessary in two patients because of hemodynamic instability. In one patient bleeding could be controlled after an immediate immunosuppressive therapy with prednisone and cyclophosphamide. Due to the high incidence of PAN associated spontaneous perirenal hematomas angiography should be performed in all cases with unclear SPH after CT evaluation. In our opinion an immediate surgical intervention is only indicated in cases with hemodynamic instability. Otherwise a conservative approach including immediate immunosuppression seems justified. Nephrectomy should be avoided whenever possible.

[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany]. / Gemcitabin/Cisplatin vs. MVAC. 5-Jahres-Ergebnisse der Phase-III-Studie zur Chemotherapie des fortgeschrittenen Urothelkarzinoms in Deutschland.

Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.

Percutaneous radiofrequency ablation of renal cell carcinoma: preliminary results.

PURPOSE: To report early results in percutaneous radiofrequency ablation (RFA) of renal cell carcinoma with an expandable RF probe. MATERIAL AND METHODS: In 14 patients (9 male, mean age 67.9 +/- 9.9 years) CT-guided percutaneous radiofrequency ablation of 15 renal cell carcinomas was performed using an expandable LeVeen probe (diameter 2-4 cm) and a 200-watt generator under general anesthesia and CT control. Tumors exceeding a diameter of 3 cm (n=6) were embolized within 24 h prior to RFA. Average tumor size was 3.0 +/- 1.0 cm. RESULTS: RFA was technically successful in all patients, resulting in a mean size of necrosis of 3.7 +/- 0.7 cm. With the exception of one reno-cutaneous fistula, which was successfully treated conservatively, no major complications were observed. No local recurrence was observed (follow-up: 13.9 +/- 12.4 months) while extrarenal tumor progression occurred in four patients. CONCLUSION: Our preliminary data suggest that nephron sparing percutaneous RFA of renal tumors with an expandable RF probe is safe and effective.

The role of radical surgery for renal cell carcinoma with extension into the vena cava.

PURPOSE: New operative technologies, such as the bypass procedures that have become established in the last decade, have led to improved prognosis in patients with renal cell carcinoma and vena caval thrombi. We report the outcome of stage dependent surgical strategies in patients with renal cell carcinoma extending into the vena cava. MATERIALS AND METHODS: From January 1987 to August 1998, 93 patients with renal cell carcinoma invading the inferior vena cava were seen at our institution. Of the patients 79 underwent radical nephrectomy, phlebotomy and thrombus extraction, including 74 who underwent surgical treatment with cardiopulmonary bypass and deep hypothermic circulatory arrest. In 2 patients with retrohepatic thrombi we placed a pump driven femoro-axillary shunt during surgical resection of the retrohepatic tumor portion. RESULTS: Distant metastases and lymph node involvement proved to be highly significant prognostic factors for survival, while the cranial extent of the tumor thrombi had no prognostic impact. Patients without distant metastases had a 5-year survival rate of 34%, which improved to 39% if regional lymph nodes were not involved. There were 5 perioperative deaths (6.3%) and the highest perioperative mortality rate (40%) was seen in patients with supradiaphragmatic thrombi. CONCLUSIONS: Radical surgery for renal cell carcinoma extending to the vena cava is justified when the tumor thrombus does not extend beyond the level of the diaphragm in the cranial direction. In view of the high perioperative mortality decisions about radical surgery must be made individually in patients with level IV thrombi, even if long-term survival is possible.

[Vena cava invasion in kidney carcinoma--a typical example of multidisciplinary surgery]. / Der Cavazapfen beim Nierenkarzinom--ein typisches Beispiel zum multidisziplinären chirurgischen Vorgehen.

Between 1987 and 1998, a total of 79 patients with renal cell carcinoma and venal caval thrombus underwent radical nephrectomy with removal of the tumor thrombus. Of these patients, nine had atrial thrombus extension. Actuarial 5 year survival for patients without metastasis was 39%. For patients with tumor thrombi not invading the right atrium (state I-III) the 5 year survival rate was up to 50% and was not related to the cranial extent of the tumor thrombus. We conclude that an aggressive multispeciality surgical approach is justified as it provides prolonged survival even in patients with large vena caval thrombi.

Variations in lectin localization in different parts of the bovine heart.

In order to study the distribution of endogenous sugar-binding proteins (lectins) in various areas of the adult bovine heart, we used a battery of biotinylated neoglycoproteins. These tools expose carrier-immobilized carbohydrate moieties as ligands for receptor detection. Characteristic staining patterns depending on the type of carbohydrate ligand were observed in all constituents examined. Comparison to data obtained for lectin distribution in the respective areas of the human heart indicate that the localization of certain types of endogenous sugar receptors can exhibit species-dependent variations.