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B. A. median MS: 56 vs . 35 months. A. B. C. median MS: 144 vs . 58 months. (N=40). (N=40). (N=37). (N=37).

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Introduction

B

A

median MS: 56 vs. 35 months

A

B

C

median MS: 144 vs. 58 months

(N=40)

(N=40)

(N=37)

(N=37)

Fig. 1: CA9 staining was present in 93,3 % of all metastases from ccRCC patients. Representative punches show A low CA9 expression and B high CA9 expression. C In normal lung tissue no CA9 staining was observed.

Materials and Methods

Patients

Table 1: Patients clinical characteristics by CA9 expression in lung metastases of ccRCC

  • study cohort consisted of 82 ccRCC Patients (51 ♂ and 31 ♀)

  • all underwent radical or partial nephrectomy and have developed lung metastases, which were resected by laser-based surgery from 1999 to 2004 in Coswig (Germany), Center for Pneumology and Thoracic surgery

  • median age at pulmonary surgery was 63 (41 - 77) years

  • at lung metastases surgery, lymph nodes were resected and reviewed on microscopic slides for tumor affection

  • 48/82 patients died of RCC, 4 patients did not die by a cancer-specific death

  • median survival after metastases surgery was 25 (2 – 60) months for the 48 patients who died of RCC-related cause and 41 (2 - 95) months for all patients

  • median overall survival after nephrectomy was 45 (5 - 376) months and 69 (5 - 376) months, respectively

  • median progression-free survival (PFS) was 19 (1 – 176) months and 65 (0 – 351) months, respectively

  • median follow-up after pulmonary surgery was 40 (2 – 95) months, after nephrectomy 71 (5 – 376) months

  • primary tumors were classified according to the 2002 TNM staging and the UICC criteria of 19974

Fig. 3: Kaplan-Meier estimates according to CA9 expression for A overall survival (OS) and B metastases survival (MS) for patients with metastatic ccRCC.

CA9

low

high

characteristics

overall

p value

Patients824042

Gender

male5123280.395

female311714

Age (year)

at time of nephrectomy0.101

mean596158

median606259

range40-7540-7542-70

at time of metastases surgery0.622

mean636463

median636563

range41-7741-7749-77

T stage primary tumor0.394

T1+T2401921

T3+T4331914

Node metastases at primary tumor0.451

no522527

yes853

Metastasis at time of nephrectomy0.243

No522428

Yes23149

Grading primary tumor0.059

1+2472027

319136

Staging primary tumor0.278

I+II301416

III19911

IV25159

No. lung metastases0.888

mean8.288.4

median333

range1-641-491-64

Grading lung metastases0.398

1+2572631

3251411

Node metastases at pulmonary surgery0.054

No582434

Yes23158

Relapse after first pulmonary surgery

No1697

Yes663135

Deaths

No301119

Yes522923

B

A

Tissue microarray construction

  • lung metastases were obtained from Center for Pneumology and Thoracic Surgery, Coswig Germany and embedded in paraffin

  • 548 metastases of 82 patients were evaluated by a skilled pathologist (MM)after hematoxylin-eosin staining

  • two punches from every lung metastases and one punch from morphologically normal appearing lung tissue were taken from selected morphologically representative regions of each tissue block

  • punches were precisely arrayed on a recipient block using a manual tissue array instrumentas described by Kononen et al. (Kononen et al., 1998)

Immunohistochemistry

  • sections (4 µm) from each tissue array block were transferred to silanized slides (Dako)

  • evaluation of histology and grade after Thoenes criteria was assessed on hematoxylin and eosin stained tissue array sections by a pathologist (MM) blinded to clinicopathological variables

  • all lung metastases were of the clear cell subtype of RCC

  • immunohistochemical staining of tissue sections for CA9 was done using a peroxidase technique with antigen retrieval using heat treatment in citrate buffer pH 6.0

  • CA9 antibody M75 (kindly provided by Dr. Oosterwijk)was used in a dilution of 1:200

  • evaluation of positively stained tumor cells was based on scale of 0 to 100 percent and staining intensity on a 4 point scale of 0 to 3 (3 = strongest staining)

  • CA9 score was calculated by product of positively stained tumor cells and staining intensity (low <300, high = 300)

  • comparison of CA9 expression between the two punches of all metastases showed a concordance of 93.4% for intensity and 62.3% for area

A

B

Statistical analysis

  • analyses were performed with SPSSsoftware

  • outcome of interest was progression-free survival(PFS) from time at nephrectomy to first pulmonary metastases, metastases-free survival(MFS) from time at pulmonary surgery to metastases relapse, metastases survival (MS) from time at pulmonary surgery to death or last follow-up and overall survival (OS) from time at nephrectomy to death or last follow-up

  • statistical software was used to define a cutoff to classify patients according to the CA9 expression

  • Mann-Whitney-U test was used to test association of CA9 expression with clinicopathologic variables

  • Kaplan-Meier method was used to visualize association of CA9 expression with survival

  • log-rank test was used to test difference between stratified survival functions

  • Cox proportional hazard model was used to test the statistical independence and significance of CA9 expression for the prediction of survival based on clinical variables

median MFS: 21 vs. 9 months

median PFS: 53 vs. 21 months

PFS

(N=40)

(N=42)

Fig. 2: Kaplan-Meier estimates according to CA9 expression for A progression-free survival (PFS) and B metastases-free survival (MFS) for patients with metastatic ccRCC

Investigation of CA9 expression in pulmonary metastatic lesions from patients with clear cell renal cell carcinoma

Pierre Tennstedt1, Peter Schneider1, Egbert Oosterwijk2, Axel Rolle4, Susanne Fuessel1, Matthias Meinhardt3, Marc-Oliver Grimm1, Manfred P. Wirth1

1 Department of Urology, Technical University Dresden, Germany; 2 Experimental Urology, Radboud University Nijmegen, Netherlands, 3 Institute of Pathology, Technical University Dresden, Germany, 4 Center for Pneumology and Thoracic Surgery, Fachkrankenhaus Coswig, Germany

Introduction

Results

A

B

  • renal cell carcinoma (RCC) is one of the most aggressive tumors

  • metastases to lung are most frequent with prevalence rates as high as 72% (Weiss et al., 1988)and 76% (Saitoh et al., 1981)in autopsy studies

  • in RCC, expression of prognostic marker carbonic anhydrase 9 (CA9) was found in 95% of the clear cell subtype (ccRCC) (Liao et al., 1997)

  • high expression of CA9 in primary tumors was associated with improved prognosis in ccRCC patients (Bui et al., 2003)

  • controversially, high expression of CA9 was associated with worse prognosis in several other malignancies e.g. cervix, uterine corpus and lung and breast cancer (Loncaster et al., 2001; Giatromannolaki et al., 2001; Chia et al., 2001)

  • aim of this study was to examine the expression of CA9 in pulmonary metastases from ccRCC patients which were treated by laser-based surgery

Fig. 4: Kaplan-Meier estimates for A overall survaval (OS) and B metastases survival (MS) according to low primary tumor grade substratified by CA9 expression.

Conclusion

  • CA9 expression in 93,3% of all pulmonary metastases (Fig. 1)

  • CA9 expression in pulmonary metastases of ccRCC demonstrates its association with survival (Fig. 2 & 3):

     significantlonger overall survival after nephrectomy (OS) and metastasectomy (MS) as well as longer progression-free survival (PFS) and time to metastases relapse (MFS) for patients with high CA9 expression

  • CA9 expression specifically stratified OS and MS for clinical variables (primary pN0, primary low grade, low metastases´ grade; examples in Fig. 4)

     CA9 is an independent predictor of survival, particularly for stratification of survival for patients with favorable clinical parameters

  • investigation of CA9 expression in patients with ccRCC could be an important factor to decide on adjuvant therapy

References

corresponding should be address to:

Dr. rer. nat. Pierre Tennstedt

Technical University Dresden

Department of Urology

Fetscherstraße 74

01307 Dresden

Germany

e-mail: [email protected]

Bui MHT et al. (2004) J. of Urol. 171:2461-2466.

Chia SK et al. (2001) J Clin. Oncol. 19: 3660–8.

Giatromanolaki A et al. (2001) Cancer Res. 61: 7992–8.

Liao S-Y et al. (2001) Cancer Res. 61: 6394–9.

Saitoh H (1981) Cancer 48:1487–91.

Weiss L et al. (1988) J. Cancer Res. Clin. Oncol. 114:605–12.


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