Dietmar Schnorr

Improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (FloSeal)

OBJECTIVESnLong-term follow-up studies have demonstrated that effective local tumor control and long-term tumor-free progression rates can be achieved by nephron-sparing surgery. However, hemostasis is a major issue, and the lack of effective means of hemostasis has limited the wider use of the laparoscopic approach to nephron-sparing surgery.nnnMETHODSnBetween January 2001 and April 2002, 25 patients with renal cell carcinoma were treated with partial nephrectomy using a two-component tissue sealant (FloSeal). The median age was 54 years (range 42 to 71). The follow-up time was 1 to 12 months (median 3.5). The tumor diameter ranged from 2 to 5 cm (median 2.8). Fifteen cases were performed by open retroperitoneal surgery, and 10 cases were performed laparoscopically. The two-component tissue sealant (consisting of a gelatin matrix granula component and a thrombin component) was applied after resection of the tumor and before perfusion of the kidney. The following parameters were recorded: time until complete hemostasis was achieved; decrease in postoperative hemoglobin level; postoperative bleeding; and presence or absence of a perirenal hematoma 24 hours and 10 days postoperatively by ultrasonography.nnnRESULTSnAfter application of the tissue sealant for 1 to 2 minutes to the moist resection site, hemostasis was immediate in all cases. During the laparoscopically performed partial nephrectomies, a laparoscopic applicator was used to avoid wasting the tissue sealant within the dead space of the instrument. When reperfusion of the kidney was established, hemostasis was maintained. The decrease in postoperative hemoglobin level ranged from 0.3 to 1.2 points (median 0.7). None of the patients required blood transfusions. No postoperative bleeding occurred. The ultrasound examination 24 hours and 10 days postoperatively demonstrated the absence of a significant perirenal hematoma.nnnCONCLUSIONSnThe two-component tissue sealant FloSeal provided immediate and durable hemostasis in open and laparoscopically performed partial nephrectomies. The tissue sealant may provide a tool to expand the possibilities of laparoscopic nephron-sparing surgery.

Fluorescence endoscopy with 5-amino levulinic acid (ALA) reduces early recurrence rate in superficial bladder cancer

Purpose: Several investigators have demonstrated an approximately 20% higher tumor detection rate by ALA (5-aminolevulinic acid) based fluorescence endoscopy (AFE) compared to standard white light cystoscopy. These data suggest a reduction of residual and recurrent tumor following fluorescence guided transurethral resection (TUR) of bladder carcinoma. The present study was performed to test this hypothesis. Materials and Methods: In a prospective randomized multi-center study, 2 x 51 patients underwent TUR of bladder tumor(s) either with white light (current standard) or assisted by ALA-induced fluorescence. A 2nd look TUR with AFE was performed 6 weeks after the initial operation. Control cystoscopies were performed 3 and 6 months after initial tumor resection. Results: At 2nd look TUR (6 weeks post op) and at control cystoscopies 3 and 6 months following initial TUR in the white light group residual and/or recurrent carcinoma was detected in 20 of 51, in 24 of 48 and in 28 of 48 patients, respectively, and in the AFE group in 8 of 51, in 10 of 47 and in 17 of 47 patients, respectively. The differences were statistically significant (p=0.005, p=0.002 and p=0.01, respectively). Three patients in the white light and four patients in the AFE group were lost to follow up. Conclusions: AFE is a minimally invasive and inexpensive diagnostic procedure that significantly improves bladder tumor detection rates compared to standard white light endoscopy. In the present study AFE reduced the residual/recurrent tumor rate 6 weeks, 3 and 6 months after initial TUR by 59%, 58% and 38%, respectively.

Urinary markers of malignancy

Transitional cell carcinoma (TCC) is the second most common malignancy in the genitourinary tract. The majority of urothelial tumors are superficial when the patient first presents, but despite adequate resection of the primary lesion the recurrence rate is particularly high. In a small but significant group of patients the tumor is primary invasive or subsequently can progress and leads to death. Voided urine can be easily obtained and therefore diagnostic urine tests would be ideal for screening or follow up of TCC. Although many urinary markers have been described, none of them is used routinely in clinical practice. Promising tumor markers still need to be evaluated in multi-center clinical studies. Larger prospective trials are necessary in order to identify prognostic indicators that would help to predict disease progression or response to different treatment modalities (BCG, chemo-, radiotherapy, etc.). Hopefully, new diagnostic urine tests will allow to identify patients who will most benefit from early cystectomy with or without adjuvant treatment, bladder sparing protocols or systemic treatment. In this paper we have reviewed the literature and discuss, from the clinicians point of view, the current status of various diagnostic tests for urinary markers. [Lee SJ, Lee WE, Chang SG, Lee CH, Kim JI. A comparative study of telomerase, Lewis X, BTA, NMP22 and urinary cytology in bladder tumor. J Urol 1999;161(suppl):152.]

Verbesserung der Hämostase bei laparoskopischen und offenen Teilnephrektomien durch Gelatine-Thrombin-Matrix (FloSeal)

ZusammenfassungEine Reihe von Studien hat gezeigt, dass beim Nierenzellkarzinom eine effektive Kontrolle des Primärtumors und ein langzeitiges tumorfreies Überleben durch nierenparenchymschonende Eingriffe erzielt werden kann. Dabei ist eine schnell wirksame und dauerhafte Hämostase nach Resektion bei diesen Eingriffen von großer Bedeutung. Das Fehlen einer effizienter Hämostase hat dazu geführt, dass die Laparoskopie bei nierenparenchymschonenden Eingriffen bisher mit Zurückhaltung eingesetzt wurde.Zwischen Januar 2001 und August 2002 wurden 36xa0Patienten mit Nierenzellkarzinomen in unserer Klinik teilnephrektomiert, wobei der Gewebekleber FloSeal® eingesetzt wurde. Das mediane Alter der Patienten war 55,2 (34–71) Jahre. Der Nachsorgezeitraum umfasste 1–18 (Median 5,5) Monate. Die Tumordurchmesser waren 2–5 (Median 2,9) cm; 17xa0Patienten wurden retroperitoneal offen operiert 19xa0Patienten wurden laparoskopisch teilnephrektomiert. FloSeal® wurde in allen Fällen nach Resektion des Tumors und vor Reperfusion der Niere eingesetzt. Die folgenden Parameter wurden gemessen: Zeit bis zur kompletten Hämostase, Abfall des Serumhämoglobins (prä- vs. postoperativ), intraoperativer Blutverlust, postoperative Nachblutung und postoperativer Ultraschall nach 24xa0h und 10xa0Tagen zum Nachweis oder Ausschluss eines perirenalen Hämatoms.Nach Applikation von FloSeal® für 1–2xa0min auf die Resektionsoberfläche wurde in allen Fällen eine sofortige Blutstillung erzielt. Bei den laparoskopischen Eingriffen wurde ein spezieller Applikator eingesetzt. Nach Reperfusion der Niere kam es bei keinem der Fälle zu Nachblutungen. Der Abfall des Serumhämoglobins (prä- vs. postoperativ) war 0,3–1,2 (Median 0,8) mg/dl. Bei keinem der Patienten war die Gabe von Blutprodukten erforderlich. Es kam in keinem der Fälle zu postoperativen Nachblutungen. Die Ultraschalluntersuchung zeigte nach 24xa0h und 10xa0Tage keinen Hinweis auf signifikante perirenale Hämatome. Hinsichtlich der untersuchten Parameter war zwischen offenen und laparoskopischen Teilnephrektomien kein statistisch signifikanter Unterschied nachzuweisen.Der Gewebekleber FloSeal® ermöglicht eine sofortige und dauerhafte Hämostase bei offenen und laparoskopischen Teilnephrektomien und könnte dadurch dazu beitragen, die Möglichkeiten der Laparoskopie bei nierenparenchymschonenden Eingriffen weiter auszubauen.AbstractLong-term follow-up studies have demonstrated that effective local tumor control and long-term tumor-free progression rates can be achieved by nephron-sparing surgery. However, hemostasis is a major issue and the lack of effective means of hemostasis has limited a wider use of the laparoscopic approach to nephron-sparing surgery.Between January 2001 and August 2002, a total of 36 patients with renal cell carcinomas were treated by partial nephrectomies using a two-component tissue sealant (FloSeal®). The median age was 55.2xa0years (range: 34–71xa0years). Follow-up time was 1–18xa0months (median: 5.5xa0months). The tumor diameter ranged from 2 to 5xa0cm (median: 2.9xa0cm). Open retroperitoneal surgery was performed in 17 cases and laparoscopic partial nephrectomy in 19 cases. The two-component tissue sealant (consisting of a gelatin matrix with granular and thrombin components) was applied after resection of the tumor and before perfusion of the kidney. The following parameters were recorded: (1) time until complete hemostasis was achieved, (2) decrease in postoperative hemoglobin level, (3) postoperative bleeding, and (4) presence or absence of a perirenal hematoma 24xa0h and 10xa0days postoperatively by ultrasound.After application of the tissue sealant for 1–2xa0min to the moist resection site, hemostasis was immediate in all cases. During the laparoscopic partial nephrectomies, a laparoscopic applicator was used that avoided wasting the tissue sealant within the dead space of the instrument. When reperfusion of the kidney was established, hemostasis was maintained. The decrease in postoperative hemoglobin level ranged from 0.3 to 1.2 points (median: 0.8 points). None of the patients required blood transfusions. There were no cases of postoperative bleeding. An ultrasound examination 24xa0h and 10xa0days postoperatively demonstrated the absence of a significant perirenal hematoma.The two-component tissue sealant FloSeal® provided immediate and durable hemostasis in open and laparoscopic partial nephrectomies. The tissue sealant may provide a tool to expand the possibilities of laparoscopic nephron-sparing surgery.

Nutzung von artifiziellen neuronalen Netzwerken zur Risikoabschätzung eines Prostatakarzinoms

ZusammenfassungIn einer prospektiven Studie über 5xa01/2xa0Jahre wurde die diagnostische Wertigkeit eines artifiziellen neuronalen Netzwerkes (ANN) mit den 5 Eingangsvariablen PSA, %fPSA, Prostatavolumen, rektaler Tastbefund und Patientenalter im PSA-Bereich von 2–20xa0µg/l als Prostatabiopsieindikator evaluiert. Daten von 944 Prostatakarzinom- und BPH-Patienten wurden in einem ANN ausgewertet. Die Ermittlung der Biopsieindikationen erfolgte in den verschiedenen PSA-Bereichen 2,0–4,0; 4,1–10,0 und 10,1–20,0xa0µg/l an den jeweiligen 90%- und 95%-Spezifitäts- oder Sensitivitätsgrenzwerten.Während im PSA-Bereich 2–4xa0µg/l eine 95%ige Spezifität des ANN-Wertes empfohlen wird, sollte im PSA-Bereich 4,1–10,0xa0µg/l eine 95%ige Sensitivität (ANN-Wert) als Biopsieindikation zugrunde gelegt werden. Eine 95%ige Sensitivität wird als Biopsieindikation für eine Wiederholungsbiopsie im PSA-Bereich 10,1–20,0xa0µg/l empfohlen. Die jeweiligen Sensitivitäts- und Spezifitätswerte verbessern sich an den 95%igen Grenzwerten um ca. 9–39% im Vergleich zur alleinigen %fPSA-Nutzung. Eine verfeinerte Biopsieindikation mittels zusätzlicher klinischer Parameter im ANN kann somit zur Erhöhung der Karzinomentdeckungsrate pro Biopsie führen.AbstractIn this prospective study covering 5.5xa0years we evaluated the diagnostic power of an artificial neural network (ANN) based on PSA, %fPSA, and clinical data in the PSA range 2–20xa0µg/l as prostate biopsy indicator. A total of 944 patients with prostate cancer or benign hyperplasia (BPH) were analyzed. The calculation of the individual patients risk before prostate biopsy was performed at the 90% and 95% specificity and sensitivity levels within the PSA ranges 2–4, 4.1–10, and 10.1–20xa0µg/l.For the low PSA range 2–4xa0µg/l, we recommend a first time biopsy at an ANN specificity level of 95%. For PSA range 4.1–10xa0µg/l, we recommend a first time biopsy at an ANN sensitivity level of 95%. A rebiopsy at the PSA range 10.1–20xa0µg/l should be performed based on a 95% sensitivity level. The use of an ANN at PSA 2–20xa0µg/l enhances the specificity and sensitivity of %fPSA by 9–39%. The application of an ANN based on %fPSA and clinical data improves the diagnostic performance compared to %fPSA only.

CATHEPSINS B, H, L AND CYSTEINE PROTEINASE INHIBITORS IN RENAL CELL CARCINOMA : NO EVIDENCE FOR DYSREGULATED PROTEOLYTIC BALANCE

Sir, In a recent paper published in this journal, Kirschke et al. (1997) reported that renal cell carcinomas contained lower concentrations of cathepsins B, C, H, L and S than normal kidney parenchyma. The author demonstrated decreased levels both by activity measurements and protein determinations, such as enzyme-linked immunoassays and immunoblotting. It was pointed out that no tumour other than renal cell carcinoma has been described so far as showing lower cathepsin values than those in the corresponding normal tissue. However, the authors did not answer the question whether the balance between proteases and their inhibitors was altered. It has been suggested that the balance between proteases and their endogenous inhibitors, in the case of cathepsins the so-called cysteine protease inhibitors (CPI), determines the invasive and metastatic characteristics of tumour cells (Twining 1994). We therefore read the publication of Kirschke et al. (1997) with great interest because our research is engaged in the same ®eld. Since we have carried out experiments measuring both cathepsins and CPI, we will soon report on them to complement the data and conclusions of Kirschke et al. (1997). We measured cathepsins B, H and L as well as CPI levels in 12 paired tissue specimens of normal kidney and renal cell carcinoma. The cathepsins were extracted by a two-step homogenisation procedure with 0.25% Triton X-100 solution in 10 mM phosphate bux80er, pH 7.46, and 10 mM CaCl2, using a Wheaton homogeniser. Fluorimetric assays similar to those described by Kirschke et al. (1997) were applied, but with ®nal substrate concentrations of 5 lM for all the three enzymes and a ®nal inhibitor concentration of 0.5 lM Z-PhePhe-CH2 for the determination of cathepsin L. Heatstable CPI were determined in supernatants of samples heated at 100°C for 10 min (Lah et al. 1992) by testing their inhibitory capacities against puri®ed cathepsin B from human placenta. The tumour stage was assigned to each patient according to the TNM system and the histological grade of the cancer was classi®ed as 1, 2 or 3 (UICC 1992). The use of human tissues for research purposes was approved by the Ethical Committee of the Charite University Hospital, Berlin. Figure 1 shows the individual values of each cathepsin related to protein, and the respective medians. The median values of the cathepsins and the CPI were lower in cancerous than in non-cancerous samples; however, that tendency did not reach statistical signi®cance (U-test according to Mann-Whitney: P > 0:05). The enzyme activities did not correlate with the staging and grading of the tumour (Spearman rank correlation coex81cient: P > 0:05). Our data con®rm the results presented by Kirschke et al. (1997) that renal cell carcinomas did not show higher cathepsin activities than the corresponding normal tissue specimens. We made additional calculations of the ratios of each cathepsin to CPI as that ratio seems to be more important than the level of the respective individual component alone (Liotta and Stetler-Stevenson 1991). For example, reduced concentrations of metalloproteinases and their corresponding tissue inhibitors (TIMP) were found more in cancerous than in non-cancerous prostatic tissue samples (Jung et al. 1997). However, compared to the metalloproteinase activities, the decrease of the TIMP level in cancerous prostatic tissue was even more distinct so that the ratio of metalloproteinase to TIMP was increased in cancerous samples above that of the noncancerous samples, indicating a proteolytic dysbalance. In the present data on renal cell carcinoma, no dix80erences in the ratio of cathepsins to CPI were found when cancerous and non-cancerous tissue samples were compared (P > 0:05). Thus, an expected imbalance could not be established. J Cancer Res Clin Oncol (1998) 124: 60±61 Ó Springer-Verlag 1998

In vivo optical coherence tomography in endoscopic diagnostics of bladder disease

Purpose: OCT is a new imaging method which produces a 3 mm wide x 2.5 mm deep 2D picture with a resolution of 15 μm. Materials and Methods: We utilised the Tomograph Sirius 713, developed at the Medical Laser Centre in cooperation with 4-Optics AG, Lubeck, Germany. This apparatus uses a special Super-Luminescence-Diode (SLD) that produces light within the near infrared wavelength, with a central wavelength of 1300 nm and spectral width of 45 nm. The coherence length is reduced to 15 μm. The light is introduced into a fibreglass optic which is a couple of meters long and is easy to handle. To measure the depth of invasion and position of urothelial bladder tumours, the fibreglass optic is attached to a regular endoscope (Wolf, Knittlingen, Germany) via a OCT adapter. That way, in parallel to the regular endoscopic view of the bladder mucosa with or without pathologic findings, an OCT picture of the superficial as well as the deeper muscle layers is visible online. OCT was used to obtaine 275 images from the bladder of 30 patients. Results: OCT of normal bladder mucosa produces an image with a cross section of up to 2.5 mm. It is possible to distinguish transitional epithelium, lamina propria, smooth muscles and capillaries. In cystitis the thickness of the mucosa is constant, but the distinction between the different layers is blurred. In squamous metaplasia there is thickening of the epithelial layer, with preservation of lamination of the lower layers. In transitional cell carcinoma there is a complete loss of the regular layered structure. Thus, the border between tumour and normal bladder tissue can be easily distinguished. Conclusions: This method can provide valuable information on tumour invasion and extension in real time and therefore influence therapeutic strategies

[Renal carcinoma with invasion of the suprahepatic vena cava (Staehler stage III and IV): surgical treatment and results].

ZusammenfassungDie operative Behandlung von Patienten mit Nierenzellkarzinomen (NZK) und suprahepatisch-infradiaphragmalem oder supradiaphragmalem Vena-cava-Befall (Stadium III und IV nach Staehler) stellt nach wie vor eine interdisziplinäre Herausforderung dar. Die potenziell hohe Komplikationsrate und der enorme operationstechnische Aufwand müssen individuell mit dem zu erwartenden Nutzen für den Patienten in Einklang gebracht werden.In dieser Studie haben wir die operativen Ergebnisse von 24 Patienten ausgewertet und diese Patienten in der Nachbeobachtung und anschließenden Chemoimmuntherapie bei Auftreten von Metastasen mit einer Kontrollgruppe von 75 Patienten retrospektiv verglichen.Die perioperative Mortalität bei den 24xa0Patienten betrug 4%; 4xa0Patienten hatten zum Zeitpunkt der Operation Metastasen, 14xa0Patienten entwickelten Metastasen im weiteren Verlauf bei einer medianen Nachbeobachtungszeit von 23,5xa0Monaten. Das mediane Überleben betrug 45xa0Monate bei einer 1-, 3- und 5-Jahres-Überlebensrate von 92, 57 und 33%. In einer multivariaten Analyse erwiesen sich lediglich das Auftreten von Fernmetastasen (p=0,002) und marginal die Durchführung einer Immuntherapie (p=0,1), nicht jedoch das Vorhandensein des V.xa0-cava-Befalls (p=0,259) oder ein positiver Lymphknotenstatus (p=0,624) als signifikante Prognosefaktoren.Für Patienten mit NZK und V.xa0-cava-Zapfen im Stadiumxa0III und IV stellt die Kombination von aggressivem chirurgischem Vorgehen und Immuntherapie bei Auftreten einer Metastasierung eine realistische Therapieoption mit einer akzeptablen Überlebensrate dar.AbstractThe operative treatment of patients with renal cell carcinoma (RCC) and suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion (Staehler stage III and IV) is still an interdisciplinary challenge. The potential high complication rate and the enormous operative-technical efforts have to be brought into line with the individual benefit for the patient.In this study, we have retrospectively analyzed the operative results of 24 patients. We have further compared the patients during follow-up and immunotherapy due to metastasis with a control group of 75 patients without vena cava invasion.Perioperative mortality in the 24 patients was 4%. Four patients had metastasis at presentation and 14 further patients developed metastatic disease during median follow-up of 23.5xa0months. Median survival was 45xa0months with a 1-, 3-, and 5-year survival rate of 92, 57, and 33%, respectively. In a multivariate analysis, only the presence of metastasis (p=0.002) and marginal immunotherapy (p=0.1), but not vena cava invasion (p=0.259) or a positive lymph node status (p=0.624) were significant predictors of a poor survival.For patients with RCC and suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion (Staehler stage III and IV), the combination of an aggressive surgical treatment combined with subsequent immunotherapy in the presence of metastatic disease offers a realistic therapeutic option with reasonable survival rates.

Nierenzellkarzinom mit suprahepatischem V. -cava-Befall (Stadium III und IV nach Staehler): Operative Therapie und Ergebnisse

ZusammenfassungDie operative Behandlung von Patienten mit Nierenzellkarzinomen (NZK) und suprahepatisch-infradiaphragmalem oder supradiaphragmalem Vena-cava-Befall (Stadium III und IV nach Staehler) stellt nach wie vor eine interdisziplinäre Herausforderung dar. Die potenziell hohe Komplikationsrate und der enorme operationstechnische Aufwand müssen individuell mit dem zu erwartenden Nutzen für den Patienten in Einklang gebracht werden.In dieser Studie haben wir die operativen Ergebnisse von 24 Patienten ausgewertet und diese Patienten in der Nachbeobachtung und anschließenden Chemoimmuntherapie bei Auftreten von Metastasen mit einer Kontrollgruppe von 75 Patienten retrospektiv verglichen.Die perioperative Mortalität bei den 24xa0Patienten betrug 4%; 4xa0Patienten hatten zum Zeitpunkt der Operation Metastasen, 14xa0Patienten entwickelten Metastasen im weiteren Verlauf bei einer medianen Nachbeobachtungszeit von 23,5xa0Monaten. Das mediane Überleben betrug 45xa0Monate bei einer 1-, 3- und 5-Jahres-Überlebensrate von 92, 57 und 33%. In einer multivariaten Analyse erwiesen sich lediglich das Auftreten von Fernmetastasen (p=0,002) und marginal die Durchführung einer Immuntherapie (p=0,1), nicht jedoch das Vorhandensein des V.xa0-cava-Befalls (p=0,259) oder ein positiver Lymphknotenstatus (p=0,624) als signifikante Prognosefaktoren.Für Patienten mit NZK und V.xa0-cava-Zapfen im Stadiumxa0III und IV stellt die Kombination von aggressivem chirurgischem Vorgehen und Immuntherapie bei Auftreten einer Metastasierung eine realistische Therapieoption mit einer akzeptablen Überlebensrate dar.AbstractThe operative treatment of patients with renal cell carcinoma (RCC) and suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion (Staehler stage III and IV) is still an interdisciplinary challenge. The potential high complication rate and the enormous operative-technical efforts have to be brought into line with the individual benefit for the patient.In this study, we have retrospectively analyzed the operative results of 24 patients. We have further compared the patients during follow-up and immunotherapy due to metastasis with a control group of 75 patients without vena cava invasion.Perioperative mortality in the 24 patients was 4%. Four patients had metastasis at presentation and 14 further patients developed metastatic disease during median follow-up of 23.5xa0months. Median survival was 45xa0months with a 1-, 3-, and 5-year survival rate of 92, 57, and 33%, respectively. In a multivariate analysis, only the presence of metastasis (p=0.002) and marginal immunotherapy (p=0.1), but not vena cava invasion (p=0.259) or a positive lymph node status (p=0.624) were significant predictors of a poor survival.For patients with RCC and suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion (Staehler stage III and IV), the combination of an aggressive surgical treatment combined with subsequent immunotherapy in the presence of metastatic disease offers a realistic therapeutic option with reasonable survival rates.