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677Long term experience with carboplatin monotherapy for clinical stage 1 seminomas
978
677 LONG TERM EXPERIENCE W I T H CARBOPLATIN MONOTHERAPY FOR CLINICAL STAGE 1 SEMINOMAS
LONG TERM RESULTS OF LAPAROSCOPIC R E T R O P E R I T O ~ E M , LYMPH NODE DISSECTION IN CLINICAL STAGE 1 NSGTC
Miiller T. 1, Hobisch A . 2, Rein R 2, Aufderklamm j.3, Akkad TJ, Gozzi C. ~, Bartsch G?, Steiner H. 1
Steiner H. 1, Peschel R. 1, Miiller T), Gozzi C. 1, Bartsch G. 1, Hobisch A.2
tMedical University Innsbruck, Urology, Innsbruck, Austria, 2LKH Feldkirch, Urology, Feldkirch, Austria, 3KH Meran, Urology, Meran, Italy INTRODUCTION & OBJECTIVES: Radiotherapy is the standard treatment of patients with clinical stage I seminoma. Carboplatin has been advocated as an effective treatment alternative to avoid well known late effects of radiotherapy (including second malignancy and gastrointestinal toxicity) and the high recurrence rate of surveillance. Since carboplatin mouotherapy was initiated at our department more than 14 years ago, we evaluate the long term oncological effectiveness and morbidity.
~Medical University Innsbrnck, Urology, Irmsbruck, Austria, 2LKH Feldkirch, Urolog3, Feldkirch, Austria INTRODUCTION & OBJECTIVES: In clinical stage I testicular tumouv, retroperitoneal lymph node dissection (RPLND) is the most sensitive and spedfiz diagnostic modality for detecting occult lymph node metastases. To reduce th~ morbidity of these procedures we have replaced open surgery by laparoscopy 1~ geaIs ago. MATERIAL & METHODS: Between August 1992 and September 2004, laparos :opic RPLND (L-RPLND) was performed 132 times in 131 patients with clinical !;tage I nonseminoma gema cell turnout, in case of pathological stage II 2 cycles of adjuvarLt cisplatin based chemotherapy were administered.
RESULTS: In all patients carboplatin was well tolerated associated with only mild gastrointestinal complaints. Leukocytopenia developed in 31 patients (19.1%) including 3 patients with leukocyte levels between 1.5x109/L and 2.0x109/L. No patient developed neutropenic fever. Thrombocytopenia was observed in 47 patients (29.0%) with thrombocyte levels below 20x109/L in two patients (1.2%) after the second treatment cycle. Carboplatin was not associated with neurotoxicity, ototoxicity or nephrotoxicity. During mean follow-up of 73 months (range 2-187) three patients (1.8%) developed recurrent paraaortic tumour within the first year, these patients received 2 courses cisplatin-based chemotherapy as successful salvage therapy (follow-up of 2, 108 and 147 months). Currently, all patients are alive with no evidence of disease.
RESULTS: Once the learning curve had been overcome, mean operatiw~ time decreased significantly from 399 to 186 rain (first and last 20 pts.). L-RPLND coLld be completed as planned in all but 7 patients in whom conversion to open surge~3' w~s performed (bleeding in 4 patients, renal artery injury in 2 patient, positive lymph node in 1 of our first patiants). Renal artery and colon injury were major complications in 3 patients (2.2%); minor postoperative complications such as asymptomatic lymphoceles (17 pts.) and chylous ascites (9 pts.) resolved with conservative me asnr~ s in all patients but one (laparoscopic incision of a persisting lymphocele). Mean post-cp hospital stay was 4.2 days, respectively. 24 patients were identified as pathological stage II and underwent 2 cycles of cisplatin-based chemotherapy. Antegrade ejaculation was preserved in all patients. Mean follow-up is currently 66.0 months. Over this period no recurrence occurred in 24 pathological stage II patients, while 6 pulmonary recurrences and 1 tumour marker recurrence were observed in pathological stage i patients (5.3%); In additional 1 patiant (0.7%) contralateral retroperitoneal recurrence occurred because of false negative histological report of lymphadenectomy specimen resulting in lack of adjuvant treatment. In orchiectomy specimen of all but one patient with recurrence either vessel invasion, more than 90 % embryonal carcinoma or both features were l~resert. All patients were salvaged by cisplatin-based chemotherapy and additional surgery :n 2 patients). All other patients have remained free of relapse; no patient died of Lttmour progression.
CONCLUSIONS: In stage I seminoma two cycles of carboplatin monotherapy were found highly effective from an oncologic standpoint and associated with only minimal morbidity.
CONCLUSIONS: Open and L-RPLND depend on an experienced urolog!st and pathologist; the diagnostic accuracy of L-RPLND was as good as that of the open procedure published in literature, while the morbidity is significantly lower. Tumour control was not compromised by the laparoscopic approach.
MATERIAL & METHODS: From February 1990 until August 2004, 162 patients received two adjuvant cycles of single-agent carboplatin (400mg/m2 bodysurface, day 1 and day 22) two weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once weekly until the nadir occurred after the second treatment cycle.
0i~
~NEYiUM~USS! BASiC~ES~CHD~6No$is~NDTRFATMENT
679
680
RAPID IDENTIFICATION OF RENAL CELL CARCINOMAS BY MULTICOLOUR F I S H
H E M A T O G E N O U S VERSUS LYMPHATIC DISSEMINATION: THE ROLE OF THE VASCULAR E N D O T H E L I A L G R O W T H FACTOR (VEGF) FAMILY IN THE METASTATIC PROCESS OF CLEAR CELL RENAL CELL CARCINOMA
Junker K. ~, Sanjmyatav J J, Hindermama W.z, Ilse B. 1, Hartmann A. 3 , Schubert J.] aKlinikum der Friedrich-Schiller-Universit/it, Dept. of Urology, Jena, Germany, 2Kliniknm der Friedrich-Schiller-Universit~it, Institute of Pathology, Jena, Germany, SUniversity of Regensburg, Institute of Pathology, Regensburg, Germany
Seiler D., Leppert J., Lam J., Yu H., Seligson D., Dong J., Horvath S., Pantuck A., Fi~lin R., Belldegmn A. University of California Los Angeles, Urology, Santa Monica, United States
INTRODUCTION & OBJECTIVES: An accurate differentiation of renal cell carcinoma (RCC) on the basis of histopathological features alone is some times difficult, especially on biopsies. Earlier genetic studies have shown that each RCC subtype is characterized by a specific genetic pattern. FISH on interphase nuclei has been shown to be an efficient method for detecting genetical alterations in tumour cells. The aim of the study was to develop a rapid FISH test set for differentiation of RCC based on known genetic alterations and to verify the suitability of this test for practical
INTRODUCTION & OBJECTIVES: The Vascular Endothelial Growth Factor qVEGF) superfamily includes distinct pathways to signal either angiogenesis or lymphangiogenesis. The relative expressionof these pathwaysis thought to determine a mmour's ability to spread via hematogenousor lymphatic pathways. We compared the protein expressionof the VEGF family with the pattern of spread of clear cell renal cell carcinoma (RCC).
MATERIAL & METHODS: We composed 2 multi-colour FISH test sets using 6 eentromere specific and 2 region specific DNA probes. The test set 1 contains the centromere probes of chromosomes 1, 2, 6 and 9 labelled by 4 different fluorescence dyes. For the test set 2 we have chosen 3p25 and 3p21 regions as well as centromere probes of chromosomes 7 and 17. Interphase nuclei of tumour specimens and normal renal samples were prepared from 50 pm frozen tissue sections and fixed on the slides. Both sets were hybridized simultaneously on the same slide side by side.
MATERIAL & METHODS: A tissue microarray was constructed from paraffin-embedded clear cell (N=340) RCC specimens from patients treated with nephrectomy. inununohistochemistrywas perfomaedwith monnclonalantibodies directed againstVEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3. The percentage of tumour cells expressing each marker was scored in 3 locations and averaged. Expression of the receptors was also scored in tumour associated endothelium. The Kruskal-Wallis test was used to compare the expressionof each marker with the TNM staging system. Spearmanco~xelation coefficients (sp) were determined for each marker and clinical variable. Logistic regression was used to determine the ability of a marker to predict the presence of lymphatic or hematogenous metastases.
RESULTS: 25 RCC of different histological types (clear cell, papillary, chromophobe RCC, oncocytoma) were evaluated by this method and the results were compared with CGH findings and pathological reports. Analysing normal renal samples cut-offs were defined for each DNA probe. The genetic alterations of mmour samples detected by this test correlated with the CGH results. 22 Analyzed tumours could be identified correctly analysing 50-100 cells. In 3 samples, no alterations were detected by FISH and CGH. In three cases, the histopathological diagnosis was corrected after FISH analysis. Furthermore, biopsies from 3 patients with renal mmour were accurately classified as clear cell and papillary RCC, respectively.
RESULTS: Markers found to be over expressedin patients with metastatic disease included: VEGF-A (sp-0.12, p=0.03), VEGFR-1 (sp=0.18, p=0.0009), VEGFR-2 (sp=0.15, p=0.008) and endothelial expressionof VEGFR-1 (sp=0.13, p=0.02). Hematngenousspread correlated with over expression of VEGFR-I (sp=0.14, p=0.009), VEGFR-2 (sp 0.15, p=0.0053) and VEGFR-1 expression in tumour endothelium (sp 0.14, p 0.008). VEGFR-1 (p=0.006) and VEGFR-2 (p=0.02) were significant predictors of distant metastases by logistic regression. Lower expression of VEGFR-3 within the tumour endothelium correlated with lymphatic spread in all patients with clear cell RCC (sp:-0.21, p=0.00019) and in patients with no evidence of distant metastasis (sp--0.17, p=0.026). In logistic regression, VEGFR-3 expressionwas a significantpredictor of lymph node positive disease (p=0.00028).
CONCLUSIONS: The results of this study demonstrate that the performed test set allows the identification of most frequent RCC types in one hybridization step. Therefore, FISH represents a highly effective method for rapid detection and classification of RCC. In the futm-e, this new technique could represent an additional or an alternative method to the classical histo-pathological evaluation in cases with uncertain diagnosis or in cases of small sample size like biopsies.
CONCLUSIONS: Increased expression of the angiogenesissignalling pathway (VEGF-A, VEGFR-1 and VEGFR-2) is associated with hematogenous spread of clear cell RCC. Decreased expressionof the lymphangiogenesisreceptor (VEGFR-3) in tumour endothelium is related to the spread of tumour to the lymphatic system.The expressionof the VEGF family of ligands and receptors offers a molecular explanation for the pattern of spread of clear cell RCC.
use.
European Urology Supplements 4 (2005) No. 3, pp. 172
677 LONG TERM EXPERIENCE W I T H CARBOPLATIN MONOTHERAPY FOR CLINICAL STAGE 1 SEMINOMAS
LONG TERM RESULTS OF LAPAROSCOPIC R E T R O P E R I T O ~ E M , LYMPH NODE DISSECTION IN CLINICAL STAGE 1 NSGTC
Miiller T. 1, Hobisch A . 2, Rein R 2, Aufderklamm j.3, Akkad TJ, Gozzi C. ~, Bartsch G?, Steiner H. 1
Steiner H. 1, Peschel R. 1, Miiller T), Gozzi C. 1, Bartsch G. 1, Hobisch A.2
tMedical University Innsbruck, Urology, Innsbruck, Austria, 2LKH Feldkirch, Urology, Feldkirch, Austria, 3KH Meran, Urology, Meran, Italy INTRODUCTION & OBJECTIVES: Radiotherapy is the standard treatment of patients with clinical stage I seminoma. Carboplatin has been advocated as an effective treatment alternative to avoid well known late effects of radiotherapy (including second malignancy and gastrointestinal toxicity) and the high recurrence rate of surveillance. Since carboplatin mouotherapy was initiated at our department more than 14 years ago, we evaluate the long term oncological effectiveness and morbidity.
~Medical University Innsbrnck, Urology, Irmsbruck, Austria, 2LKH Feldkirch, Urolog3, Feldkirch, Austria INTRODUCTION & OBJECTIVES: In clinical stage I testicular tumouv, retroperitoneal lymph node dissection (RPLND) is the most sensitive and spedfiz diagnostic modality for detecting occult lymph node metastases. To reduce th~ morbidity of these procedures we have replaced open surgery by laparoscopy 1~ geaIs ago. MATERIAL & METHODS: Between August 1992 and September 2004, laparos :opic RPLND (L-RPLND) was performed 132 times in 131 patients with clinical !;tage I nonseminoma gema cell turnout, in case of pathological stage II 2 cycles of adjuvarLt cisplatin based chemotherapy were administered.
RESULTS: In all patients carboplatin was well tolerated associated with only mild gastrointestinal complaints. Leukocytopenia developed in 31 patients (19.1%) including 3 patients with leukocyte levels between 1.5x109/L and 2.0x109/L. No patient developed neutropenic fever. Thrombocytopenia was observed in 47 patients (29.0%) with thrombocyte levels below 20x109/L in two patients (1.2%) after the second treatment cycle. Carboplatin was not associated with neurotoxicity, ototoxicity or nephrotoxicity. During mean follow-up of 73 months (range 2-187) three patients (1.8%) developed recurrent paraaortic tumour within the first year, these patients received 2 courses cisplatin-based chemotherapy as successful salvage therapy (follow-up of 2, 108 and 147 months). Currently, all patients are alive with no evidence of disease.
RESULTS: Once the learning curve had been overcome, mean operatiw~ time decreased significantly from 399 to 186 rain (first and last 20 pts.). L-RPLND coLld be completed as planned in all but 7 patients in whom conversion to open surge~3' w~s performed (bleeding in 4 patients, renal artery injury in 2 patient, positive lymph node in 1 of our first patiants). Renal artery and colon injury were major complications in 3 patients (2.2%); minor postoperative complications such as asymptomatic lymphoceles (17 pts.) and chylous ascites (9 pts.) resolved with conservative me asnr~ s in all patients but one (laparoscopic incision of a persisting lymphocele). Mean post-cp hospital stay was 4.2 days, respectively. 24 patients were identified as pathological stage II and underwent 2 cycles of cisplatin-based chemotherapy. Antegrade ejaculation was preserved in all patients. Mean follow-up is currently 66.0 months. Over this period no recurrence occurred in 24 pathological stage II patients, while 6 pulmonary recurrences and 1 tumour marker recurrence were observed in pathological stage i patients (5.3%); In additional 1 patiant (0.7%) contralateral retroperitoneal recurrence occurred because of false negative histological report of lymphadenectomy specimen resulting in lack of adjuvant treatment. In orchiectomy specimen of all but one patient with recurrence either vessel invasion, more than 90 % embryonal carcinoma or both features were l~resert. All patients were salvaged by cisplatin-based chemotherapy and additional surgery :n 2 patients). All other patients have remained free of relapse; no patient died of Lttmour progression.
CONCLUSIONS: In stage I seminoma two cycles of carboplatin monotherapy were found highly effective from an oncologic standpoint and associated with only minimal morbidity.
CONCLUSIONS: Open and L-RPLND depend on an experienced urolog!st and pathologist; the diagnostic accuracy of L-RPLND was as good as that of the open procedure published in literature, while the morbidity is significantly lower. Tumour control was not compromised by the laparoscopic approach.
MATERIAL & METHODS: From February 1990 until August 2004, 162 patients received two adjuvant cycles of single-agent carboplatin (400mg/m2 bodysurface, day 1 and day 22) two weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once weekly until the nadir occurred after the second treatment cycle.
0i~
~NEYiUM~USS! BASiC~ES~CHD~6No$is~NDTRFATMENT
679
680
RAPID IDENTIFICATION OF RENAL CELL CARCINOMAS BY MULTICOLOUR F I S H
H E M A T O G E N O U S VERSUS LYMPHATIC DISSEMINATION: THE ROLE OF THE VASCULAR E N D O T H E L I A L G R O W T H FACTOR (VEGF) FAMILY IN THE METASTATIC PROCESS OF CLEAR CELL RENAL CELL CARCINOMA
Junker K. ~, Sanjmyatav J J, Hindermama W.z, Ilse B. 1, Hartmann A. 3 , Schubert J.] aKlinikum der Friedrich-Schiller-Universit/it, Dept. of Urology, Jena, Germany, 2Kliniknm der Friedrich-Schiller-Universit~it, Institute of Pathology, Jena, Germany, SUniversity of Regensburg, Institute of Pathology, Regensburg, Germany
Seiler D., Leppert J., Lam J., Yu H., Seligson D., Dong J., Horvath S., Pantuck A., Fi~lin R., Belldegmn A. University of California Los Angeles, Urology, Santa Monica, United States
INTRODUCTION & OBJECTIVES: An accurate differentiation of renal cell carcinoma (RCC) on the basis of histopathological features alone is some times difficult, especially on biopsies. Earlier genetic studies have shown that each RCC subtype is characterized by a specific genetic pattern. FISH on interphase nuclei has been shown to be an efficient method for detecting genetical alterations in tumour cells. The aim of the study was to develop a rapid FISH test set for differentiation of RCC based on known genetic alterations and to verify the suitability of this test for practical
INTRODUCTION & OBJECTIVES: The Vascular Endothelial Growth Factor qVEGF) superfamily includes distinct pathways to signal either angiogenesis or lymphangiogenesis. The relative expressionof these pathwaysis thought to determine a mmour's ability to spread via hematogenousor lymphatic pathways. We compared the protein expressionof the VEGF family with the pattern of spread of clear cell renal cell carcinoma (RCC).
MATERIAL & METHODS: We composed 2 multi-colour FISH test sets using 6 eentromere specific and 2 region specific DNA probes. The test set 1 contains the centromere probes of chromosomes 1, 2, 6 and 9 labelled by 4 different fluorescence dyes. For the test set 2 we have chosen 3p25 and 3p21 regions as well as centromere probes of chromosomes 7 and 17. Interphase nuclei of tumour specimens and normal renal samples were prepared from 50 pm frozen tissue sections and fixed on the slides. Both sets were hybridized simultaneously on the same slide side by side.
MATERIAL & METHODS: A tissue microarray was constructed from paraffin-embedded clear cell (N=340) RCC specimens from patients treated with nephrectomy. inununohistochemistrywas perfomaedwith monnclonalantibodies directed againstVEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3. The percentage of tumour cells expressing each marker was scored in 3 locations and averaged. Expression of the receptors was also scored in tumour associated endothelium. The Kruskal-Wallis test was used to compare the expressionof each marker with the TNM staging system. Spearmanco~xelation coefficients (sp) were determined for each marker and clinical variable. Logistic regression was used to determine the ability of a marker to predict the presence of lymphatic or hematogenous metastases.
RESULTS: 25 RCC of different histological types (clear cell, papillary, chromophobe RCC, oncocytoma) were evaluated by this method and the results were compared with CGH findings and pathological reports. Analysing normal renal samples cut-offs were defined for each DNA probe. The genetic alterations of mmour samples detected by this test correlated with the CGH results. 22 Analyzed tumours could be identified correctly analysing 50-100 cells. In 3 samples, no alterations were detected by FISH and CGH. In three cases, the histopathological diagnosis was corrected after FISH analysis. Furthermore, biopsies from 3 patients with renal mmour were accurately classified as clear cell and papillary RCC, respectively.
RESULTS: Markers found to be over expressedin patients with metastatic disease included: VEGF-A (sp-0.12, p=0.03), VEGFR-1 (sp=0.18, p=0.0009), VEGFR-2 (sp=0.15, p=0.008) and endothelial expressionof VEGFR-1 (sp=0.13, p=0.02). Hematngenousspread correlated with over expression of VEGFR-I (sp=0.14, p=0.009), VEGFR-2 (sp 0.15, p=0.0053) and VEGFR-1 expression in tumour endothelium (sp 0.14, p 0.008). VEGFR-1 (p=0.006) and VEGFR-2 (p=0.02) were significant predictors of distant metastases by logistic regression. Lower expression of VEGFR-3 within the tumour endothelium correlated with lymphatic spread in all patients with clear cell RCC (sp:-0.21, p=0.00019) and in patients with no evidence of distant metastasis (sp--0.17, p=0.026). In logistic regression, VEGFR-3 expressionwas a significantpredictor of lymph node positive disease (p=0.00028).
CONCLUSIONS: The results of this study demonstrate that the performed test set allows the identification of most frequent RCC types in one hybridization step. Therefore, FISH represents a highly effective method for rapid detection and classification of RCC. In the futm-e, this new technique could represent an additional or an alternative method to the classical histo-pathological evaluation in cases with uncertain diagnosis or in cases of small sample size like biopsies.
CONCLUSIONS: Increased expression of the angiogenesissignalling pathway (VEGF-A, VEGFR-1 and VEGFR-2) is associated with hematogenous spread of clear cell RCC. Decreased expressionof the lymphangiogenesisreceptor (VEGFR-3) in tumour endothelium is related to the spread of tumour to the lymphatic system.The expressionof the VEGF family of ligands and receptors offers a molecular explanation for the pattern of spread of clear cell RCC.
use.
European Urology Supplements 4 (2005) No. 3, pp. 172