Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3.

The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel-Lindau disease (VHL) associated with germline VHL mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (SDHA-D) encoding succinate dehydrogenase. A subset of individuals with SDHB and SDHD germline DNA mutations and variants develop RCC. RCC has never been described as a component of SDHC-associated PGL3. The European-American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline SDHC mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking SDHC and VHL. The proband with unilateral CBT had a germline SDHC c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the SDHC locus. Both ccRCC and pRCC did not have a somatic SDHC mutation but showed LOH for intragenic and flanking markers of the SDHC locus. LOH was also present for the VHL locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the SDHC gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.

Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker?

BACKGROUND AND AIMS: Thymidylate synthase (TS) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (5-FU). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas. METHODS: TS expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies. RESULTS: The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours. CONCLUSION: Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis.

Pre-clinical evaluation of the activity of irinotecan as a basis for regional chemotherapy.

BACKGROUND: Irinotecan alone and in combination with 5-fluorouracil (5-FU) displays potent activity in advanced colorectal cancer. The aim of this study was to estimate the potential efficacy of irinotecan for hepatic arterial infusion (HAI) chemotherapy. MATERIALS AND METHODS: We investigated the anti-proliferative effects of irinotecan alone and in combination with 5-FU in HT29 and NMG64/84 colon and COLO-357, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines and in fresh tumors from patients with primary colon cancer (n=2) and colorectal liver metastases (n=11) in vitro, using the MTT growth assay and the human tumor colony-forming assay (HTCA), mimicking conditions which are achievable during HAI. RESULTS: Irinotecan displayed concentration- and time-dependent cytotoxic effects in all tested cell lines. Treatment of cell lines with irinotecan followed by 5-FU did not result in synergistic anti-proliferative effects. In the HTCA, the sensitivity of each cell line varied depending on the incubation times (30, 90, 180 and 1440 min). Independent of the individual sensitivity, the IC50 concentration and time products were lowest when incubating with irinotecan for 30 min for all cell lines. The IC50 of irinotecan in HT29, NMG64/84, COLO-357, MIA PaCa-2 and PANC-1 cells at 30 min were 200, 160, 100, 400 and 150 microg/ml, respectively, in the HTCA. All isolated tumor samples displayed concentration-dependent inhibition of colony formation after exposure to irinotecan for 30 min. The IC50 of irinotecan of 5 of the 11 liver metastases was <100 microg/ml. CONCLUSION: Irinotecan seems to be suitable for HAI therapy phase II studies. Due to the observation that several liver metastases had IC50 values that may be clinically achievable by HAI, patients with such tumors may benefit in the future from HAI using irinotecan.