Malte Böhm

Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer

Normal lung epithelium and 52 lung carcinomas obtained at surgical resection were examined by immunofluorescence for their expression levels and patterns of the calcium-dependent intercellular adhesion molecule E-cadherin. In dysplastic lung tissue and in well-differentiated squamous cell and adenocarcinomas, expression of E-cadherin was confined to the lateral cell border, similar to the expression level and pattern of normal lung tissue. The E-cadherin level was reduced and expression pattern was spotty or diffuse in moderately and poorly differentiated squamous cell and in small cell carcinomas of the lung. Most metastases resected also had a reduced level and an altered pattern of E-cadherin expression. In contrast, no such correlation was found in adenocarcinomas of the lung. This indicates that different cellular mechanisms are responsible in the progression of squamous cell carcinomas and adenocarcinomas of the lung.

Pathobiology and prognosis of chromophobe renal cell carcinoma

OBJECTIVES To analyze pathobiology and prognosis of chromophobe renal cell carcinoma (CRCC). PATIENTS AND METHODS We studied 124 patients with CRCC who underwent nephrectomy from 1989 to 2006 at two institutions. Clinicopathological characteristics and survival were compared with 1,693 consecutive patients with clear-cell RCC. RESULTS Compared with clear cell RCC, patients with CRCC presented with less advanced tumors, but had a higher prevalence of concomitant sarcomatoid features (15% vs. 6%, P < 0.001). Metastatic CRCC showed a high incidence of sarcomatoid features (50%) and a predilection for liver metastases. The 5-year DSS rate for all patients with CRCC was 78% compared with 60% for patients with clear-cell RCC (P = 0.008). When adjusted for metastatic status, this survival difference disappeared. Nonmetastatic RCCs had similar prognosis (P = 0.157), whereas survival of metastatic CRCC was inferior to that of patients with metastatic clear-cell tumors (median: 6 vs. 19 months, P = 0.0095). In multivariate analysis, ECOG PS, symptomatic presentation, T stage, N stage, M stage, nuclear grade, and presence of sarcomatoid features, but not histological sub-type, were independent prognostic factors of DSS. Ten patients received immunotherapy, none of whom were responders. CONCLUSIONS Compared with clear-cell RCC, patients with CRCC present with less advanced tumors, which lead to better survival rates on the whole. However, adjustment for metastatic status negates this difference. Patients with metastatic CRCC show a high prevalence of sarcomatoid features, predilection for liver metastases, no response to immunotherapy, and exhibit poor prognosis.

Clinicopathological features and prognosis of synchronous bilateral renal cell carcinoma: an international multicentre experience.

An interesting group of papers in this section is headed by two papers on synchronous bilateral renal tumours, one from an international group of authors and one from Germany. The large series of patients are examined carefully by both groups, and the findings should be useful for all who are interested in this area.

Deletion analysis at the DEL-27, APC and MTS1 loci in bladder cancer: LOH at the DEL-27 locus on 5p13-12 is a prognostic marker of tumor progression

Inactivation of relevant tumor‐suppressor genes by allelic or homozygous deletion is a characteristic event in tumor cells. Here, the prognostic value of allelic deletions on 5p13‐12 at the putative del‐27 tumor‐suppressor locus and in the APC tumor‐suppressor gene on 5q21, as well as homozygous deletions of the MTS1 (p16INK4, CDKN 2) tumor‐suppressor gene on 9p21 was assessed in 87 bladder cancers using microdissection and PCR‐based assays. Tumor‐specific LOH was detected in 10 of 38 (26%, del‐27), and 15 of 30 (50%, APC) informative specimens. Homozygous deletion of the MTS1 gene was detected in 33% of 84 tumors investigated. These deletion frequencies implicate the 3 tumor‐suppressor regions in the genesis of transitional‐cell carcinoma. In contrast to deletions of the APC or MTS1 genes, LOH at the del‐27 locus correlated with tumor progression. This suggests that loss of the putative tumor‐suppressor gene DEL‐27 is involved in an aggressive behavior of the tumor cells and appears to be a prognostic marker for the clinical outcome of patients with transitional‐cell carcinoma. Int. J. Cancer 74:291‐295, 1997.

Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer

A critical region of loss of heterozygosity on human chromosome 13q14 harbors the tumor suppressor gene DICE1 (DDX26). To elucidate the reduced DICE1 expression in tumor cells, the putative promoter sequence upstream of the DICE1 gene was analysed. This sequence shows a high GC content and is rich in CpG sites and binding sites of transcriptional factors. Promoter activity was identified within three overlapping fragments of the 800 bp sequence upstream of the DICE1 gene. A 13 bp deletion polymorphism detected in the DICE1 promoter region showed a decreased activity compared with the undeleted variant. However, this 13 bp deletion was seen in male control samples and patients with prostate cancer or benign prostatic hyperplasia at similar rates. A reduced DICE1 expression was observed in prostate cancer cell lines DU145 and LNCaP. This downregulation is associated with hypermethylation of the DICE1 promoter. Treatment of both prostate cancer cell lines with 5-azacytidine leads to upregulation of DICE1 expression. Hypermethylation of CpG sites of the DICE1 promoter was observed in four of eight analysed prostate cancers. This study suggests that transcriptional repression of DICE1 is caused by hypermethylation of the DICE1 promoter region in prostate cancer cells.

The effect of gender and age on kidney cancer survival: Younger age is an independent prognostic factor in women with renal cell carcinoma

OBJECTIVE Gender-specific differences in incidence of renal cell carcinoma (RCC) and its outcome have previously been reported. We used age as a surrogate to test whether this might be hormone-related in a large international RCC cohort. METHODS AND MATERIALS This study included patients treated by nephrectomy at 10 international academic centers. Clinicopathologic features were assessed using chi-square and the Student t-tests. Kaplan-Meier survival estimates and Cox proportional hazards models addressed the effect of gender and age on disease-specific survival. RESULTS Of the 5,654 patients, 3,777 (67%) were men and 1,877 (33%) were women. Generally, women presented at lower T stages (P<0.001), had fewer metastases (P<0.001), and had lower-grade tumors (P<0.001). Women more frequently had clear-cell (87% vs. 82%) and less frequently had papillary RCC (7% vs. 12%) than men (P<0.001). Women had a 19% reduced risk of death from RCC than men (hazard ratio 0.81, 95% confidence interval 0.73-0.90, P<0.001). The survival advantage for women was present to the greatest degree in the age group<42 years (P = 0.0136) and in women aged 42 to 58 years (P<0.001), but was not apparent in patients aged 59 years and older (P = 0.248). Age was an independent predictor of disease-specific survival in women (hazard ratio 1.011, 95% confidence interval 1.004-1.019, P = 0.004), but not in men. CONCLUSIONS As a group, women present with less advanced tumors, leading to a 19% reduced risk of RCC-specific death compared with men. This survival difference is present only in patients aged<59 years. Because this gender-based survival difference is not related to pathologic features, the role of hormonal effects on the development and progression of RCC needs to be investigated.

Evaluation of peri-operative peripheral and renal venous levels of pro- and anti-angiogenic factors and their relevance in patients with renal cell carcinoma

To evaluate peri‐operative peripheral and renal venous plasma levels of vascular endothelial growth factor (VEGF), platelet‐derived growth factor type BB (PDGF‐BB), transforming growth factor (TGF)‐β1, endostatin, and thrombospondin‐1 (TSP‐1) in relation to pathological variables and prognosis, as pro‐ and anti‐angiogenic factors are important for tumour growth and treatment of patients with renal cell carcinoma (RCC).

Loss of Heterozygosity on Chromosome 5p13-12 Predicts Adverse Prognosis in Advanced Bladder Cancer Independent of Tumor Stage and Grade

PURPOSE The individual prognosis in patients with bladder cancer is only partially predicted by tumor stage and grade. Various molecular markers have been shown to correlate with disease progression and prognosis but few add some predictive capacity beyond that offered by standard clinical and pathological parameters. MATERIALS AND METHODS A total of 191 urothelial carcinomas from 157 patients were analyzed. Paired normal and tumor cells were microdissected by manual and microbeam-microdissection of membrane mounted native tissue, and analyzed for loss of heterozygosity (LOH) at a critical region of LOH on chromosome 5p13-12 that is involved in bladder cancer progression. LOH data were correlated with progression-free and tumor specific survival by multivariate analysis. RESULTS Informativity of the assay was 60.7%. Log rank analysis of 100 evaluable patients showed a progression-free survival benefit without LOH at 5p13-12 of more than 3 years (p <0.01). Mean followup was 36 months. Multivariate analysis revealed that this benefit was not predicted by tumor stage and grade alone in advanced disease (stages T3/4 and/or N+/M+, stages III/IV). CONCLUSIONS LOH at the critical region on chromosome 5p13-12 is a molecular marker of adverse prognosis in advanced bladder carcinoma independent of tumor stage and grade.

Pretreatment with interleukin-2 modulates peri-operative immuno-dysfunction in patients with renal cell carcinoma.

OBJECTIVE Complex peri-operative immuno-dysfunction occurs in patients with renal cell carcinoma undergoing nephrectomy. Here, the effect of pretreatment with interleukin-2 (IL-2) is addressed. METHODS Of 63 patients who underwent tumor nephrectomy, 26 patients received 4 doses of 10 Mio IE/m(2) IL-2 b.d. s.c. (i.e. a total of 40 Mio IE/m(2)) a week before operation, 37 did not. Parameters of cellular and humoral immunity (differential blood count, T-cell markers CD2, CD3, CD4, and CD8, B-cell markers CD19 and CD20, monocyte markers CD13 and CD14, NK (natural killer)-cell marker CD16, activation markers CD25, CD26, CD69, and HLA-DR, and cytokines IL-1-receptor antagonist (IL-1RA), IL-2, soluble IL-2-receptor (sIL-2R), IL-6, IL-10, and TGFbeta) were measured in venous blood. Blood was drawn before IL-2, 1 day before and immediately after the operation, and on the 1st, 3rd, 5th, and 10th postoperative day. RESULTS All patients showed postoperatively elevated leukocyte and granulocyte counts, and elevated serum levels of cytokines IL-6 and IL-10. T-cell and activation markers were decreased. However, all these alterations were less accentuated in patients who had been pretreated with IL-2. Monocyte counts and IL-2 and TGFbeta levels were decreased, but IL-1RA and sIL-2R levels were elevated in pretreated patients. IL-2 related toxicity was WHO grades I-II in all patients, grade III in one patient. The anesthetic regimen had no measurable effect. IL-6 concentrations were higher in renal venous than in venous pool blood, indicating IL-6 production in the tumor in vivo. CONCLUSIONS Pretreatment with IL-2 modulates peri-operative immuno-dysfunction in patients undergoing tumor nephrectomy. This affects in particular T-cell-mediated immunity and levels of cytokines IL-10 and IL-6. The IL-2 administration scheme used here was followed by distinct counter-regulation including monocytes, IL-2, sIL-2R, IL-1RA and TGFbeta.

Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas

We have previously observed loss of heterozygosity (LOH) at a single locus (del‐27) on human chromosome 5p13‐12 to correlate with bladder tumor progression. In this study, we examined 33 bladder tumors for their pattern of allelic loss on chromosome 5p using 7 microsatellite markers. In 14 of 15 bladder tumors with LOH at locus del‐27, allelic loss was confined to chromosomal region 5p13‐12. This region included the microsatellite marker D5S2025 that showed LOH in 5 of 11 (45%) informative cases with LOH at del‐27. This suggests that D5S2025 and del‐27 are located within a single critical region of LOH on 5p13‐12 harboring a tumor suppressor gene involved in bladder tumor progression. Recurrent LOH at other loci was observed at microsatellite markers located at 5p15. However, these losses appeared to be independent of LOH at 5p13‐12 and occurred predominantly in poorly differentiated (G3) and advanced (T3‐T4) tumors. Int. J. Cancer (Pred. Oncol.) 89:194–197, 2000.