Kazuo Oba

Two putative tumor suppressor genes on chromosome arm 8p may play different roles in prostate cancer

Although loss of heterozygosity (LOH) on the short arm of chromosome 8 has been frequently observed in human prostate cancer, the relationship between LOH and clinical background is poorly understood. Fluorescence in situ hybridization (FISH) was employed to evaluate the chromosomal deletion on 8p in 42 prostate cancers using a centromeric probe for chromosome 8, in combination with 4 cosmid probes spanning 8p12 to 8p22. Deletions for at least one locus on the 8p were observed in 29 (69.0%) tumors. The most frequently deleted regions were 8p22 (54.8%) and 8p21.3 (52.4%), in almost the same frequency. The second most frequently deleted region was 8p21.1-p21.2 (38.1%). Deletions of 8p22 and 8p21.3 significantly correlated with tumor grade (P=0.0034, Fishers exact probability test). A significantly higher frequency of the deletion on 8p21.1-p21.2 was observed in advanced prostate cancer (beyond capsular penetration or positive nodal metastases) than in localized prostate cancer (P=0.0033). In particular, deletion of 8p21.1-p21.2 was more frequently observed in the cases with lymph node metastases than without them (P=0.0029). No clinicopathological parameters had significant relation to deletions on 8p12. These results suggest that deletions on 8p22-p21.3 play an important role in tumor differentiation, while an 8p21.1-p21.2 deletion plays a role in the progression of prostate cancer.

The allelic loss of chromosome 3p25 with c-myc gain is related to the development of clear-cell renal cell carcinoma.

To explore the role of allelic losses at 3p25 and genetic alterations of chromosome 8, we investigated the relationships between genetic alterations in these chromosomal regions and clinicopathologic findings (such as tumor size and grade), by employing fluorescence in situ hybridization (FISH). Fifty Japanese clear‐cell renal cell carcinomas (RCCs) were examined by dual‐color FISH using cosmid DNA probes for 3p25.1–25.3 combined with probes for chromosome 3 centromere, 8p12, 8p21.1, 8p21.3, 8p22 and 8q24.12–24.13 (c‐myc), and chromosome 8 centromere. Deletion at 3p25.1–25.3 was detected in 38 patients (76%), while 8p12 deletion, 8p21.1 deletion, 8p21.3 deletion, 8p22 deletion and c‐myc gain were detected in 23 (46%), 25 (50%), 25 (50%), 25 (50%), and 20 patients (40%), respectively. There was a significant correlation between 8p21.1 deletion, 8p21.3 deletion and 8p21.1 deletion with c‐myc gain and tumor grade (p = 0.04, 0.04 and 0.02, respectively). Deletions at 8p21.1 and 8p21.3 with 3p deletion were significantly related to tumor grade; the statistical significance was identical to that of sole 8p deletion with tumor grade. The deletion at 3p25.1–25.3 with c‐myc gain showed a significant correlation with tumor size, indicating an association with tumor progression. Our results suggest that the allelic loss of chromosome 3p25 with c‐myc gain is related to the development of clear‐cell RCC.

Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence.

To investigate whether nonrandom aberrations of chromosomal numbers could predict tumor recurrence in patients with bladder cancer, archival urine cytology specimens (Giemsa-stained) from patients previously treated for transitional cell carcinoma of the urinary bladder were studied retrospectively by fluorescence in situ hybridization. A total of 48 patients (pTis, 6; pTa, 2: pT1, 32; and pT2-4, 8) were consecutively enrolled in this study, and numerical aberrations of chromosomes 9 and 17 were investigated. Cytology was diagnosed as negative for malignancy in 18 patients and positive in 30 patients. Twenty-seven of the 48 patients (56%) had one or more chromosomal aberrations. The frequency of numerical aberrations of chromosome 17 was correlated with increasing stage and grade, whereas loss of copies of chromosome 9 (monosomy) was frequently observed at a lower stage and grade. Chromosomal aberrations were detected in 9 (50%) of 18 patients with negative or equivocal cytology (class I, II, or III) by the Papanicolaou classification. Of eight patients with negative or equivocal cytology who developed tumor recurrence, four (50%) showed monosomy 9 and one (14%) showed a numerical aberration of chromosome 17. All six patients who showed monosomy of chromosome 9 developed tumor recurrence within 12 months, whereas four of the nine patients who did not show monosomy of this chromosome developed recurrence within 12 months (P<0.05, Fisher test). These results suggest that monosomy of chromosome 9 might be a prognostic marker for early tumor recurrence in patients with negative or equivocal cytology specimens.

Transitional cell carcinoma of the renal pelvis with vena caval tumor thrombus.

We report a case of transitional cell carcinoma of the renal pelvis with vena caval tumor thrombus. To our knowledge only 14 cases of transitional cell carcinoma of the renal pelvis protruding into the vena cava have been reported. The literature regarding these cases is reviewed, and the differential diagnosis of this tumor from renal cell carcinoma is discussed.

Clinical significance of allelic loss of chromosome region 5q22.3 q23.2 in nonpapillary renal cell carcinoma

To analyze the clinical significance of copy number gain and loss at chromosome region 5q21∼q23, 105 nonpapillary renal cell carcinomas (RCC) were examined by interphase cytogenetic analysis using the dual-color fluorescence in situ hybridization (FISH) technique. DNA probes for D5S23 (5p15.2), cCI5-243 (5q21.2∼q21.3), and cCI5-215 (5q22.3∼q23.2) were used, and the signals for cCI5-243 and cCI5-215 were compared with those for D5S23 as the numerical control. Aneusomy (three or more copies) of chromosome 5 was found in 22 tumors (21.0%). Aneusomy was significantly correlated with loss at 5q21∼q23, while disomy with gain at 5q21∼q23 (P 7 cm, P<0.05). Both loss at cCI5-215 and aneusomy of chromosome 5 were significantly related to poor disease-specific survival (P<0.05). In conclusion, alterations of chromosome 5 (including allelic loss of 5q22.3∼q23.2) could be a useful genetic marker for predicting the patient prognosis of RCC.

Oral etoposide following combination chemotherapy and radiation therapy in a patient with advanced adult neuroblastoma led to long survival

Abstract Although neuroblastoma is a common tumor of early childhood, it is rare in adults. In spite of the poor prognosis of advanced neuroblastoma in adults, there is still no effective treatment for this condition in adults. Here we report that oral etoposide salvage chemotherapy was able to prolong the survival of an adult patient with advanced neuroblastoma. A 26-year-old man had advanced neuroblastoma that was resistant to combination intravenous chemotherapy and radiation therapy. He was then treated with oral etoposide, at a dose of 50 mg daily for 5 days in a 21-day course. Toxicity was very mild and he was followed as an outpatient while he received 76 courses of this oral etoposide salvage chemotherapy. Seventy months after diagnosis, this patient is still alive and has no new distant metastases.