Endothelin axis expression is markedly different in the two main subtypes of renal cell carcinoma

BACKGROUND. The endothelin axis has been implicated in cancer growth, angiogenesis, and metastasis, but to the authors' knowledge the expression of endothelin genes has not been defined in renal cell carcinoma (RCC). METHODS. Tissue specimens were harvested from both normal and tumor-affected regions at the time of radical nephrectomy from 35 patients with RCC (22 with clear cell RCC [ccRCC] and 13 with papillary RCC [PRCC]). Real-time reverse transcriptase-polymerase chain reaction analysis determined the expression profile of the preproendothelins (PPET-1, PPET-2, and PPET-3), the endothelin receptors (ETA and ETB), and the endothelin-converting enzymes (ECE-1 and ECE-2). RESULTS. PPET-1 was found to be up-regulated in ccRCC tumor specimens and down-regulated in PRCC tumor specimens. ETA was significantly down-regulated in PRCC tumor specimens. ECE-1 was expressed in all tissue specimens at comparable levels, with moderate but significant elevation in normal tissue specimens associated with PRCC. Of the other genes, PPET-2 and ETB were expressed in all tissue specimens and no differences were observed between tumor subtypes or tumor-affected and normal tissue specimens, whereas PPET-3 and ECE-2 were present in all tissue specimens but were barely detectable. CONCLUSIONS. The endothelin axis was expressed differently in the two main subtypes of RCC and appeared to match macroscopic features commonly observed in these tumors (i.e., high expression of PPET-I in hypervascular ccRCC contrasted against low PPET-1 and ETA expression in hypovascular PRCC). The presence of ECE-1 mRNA in these tissue specimens suggested that active endothelin ligands were present, indicating endothelin axis activity was elevated in ccRCC compared with normal kidney, but impaired in PRCC. The current study provided further evidence that it is not appropriate to consider ccRCC and PRCC indiscriminately in regard to treatment. (C) 2004 American Cancer Society.

Expression of apoptotic regulatory molecules in renal cell carcinoma: Elevated expression of Fas ligand

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO- 1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.

High-Risk Merkel Cell Carcinoma of the Skin Treated With Synchronous Carboplatin/Etoposide and Radiation: A Trans-Tasman Radiation Oncology Group Study-TROG 96:07

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. Patients and Methods: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m(2) days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43-86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). Results: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. Conclusion: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation. (C) 2003 by American Society of Clinical Oncology.

Merkel-cell carcinoma of the skin

Merkel-cell carcinoma (MCC) is a rare form of skin cancer of neuroendocrine origin that has been described as the most aggressive cutaneous malignancy. The cell of origin is thought to be the Merkel cell or skin-pressure receptor. It has the propensity for dermal-lymphatic invasion, and nodal and haematogenous spread. Factors that have been implicated in its cause include exposure to sunlight and immunosuppression. The tumour has many similarities to small-cell carcinoma of the lung, with intrinsic sensitivity to ionising radiation and chemotherapy, and an aggressive metastatic potential. The best treatment outcomes can be achieved with early diagnosis and the integration of surgery, radiation, and chemotherapy. The treatment challenges for the clinician are often enormous because many of the patients are elderly and because lesions occur in difficult sites such as the head and neck region and the lower leg.

Canine intra-nasal squamous cell carcinoma treated with chemotherapy prior to surgical resection

A 12-year-old male castrated Samoyed dog was presented with left-sided epistaxis and sneezing. Diagnostic procedures included haematology and biochemistry testing, thoracic radiography, fine needle aspiration of regional lymph nodes, CT, rhinoscopy, incisional biopsy and histopathology. Squamous cell carcinoma of the rostral nasal cavity was diagnosed, with no evidence of metastatic disease. External beam radiation was not an accessible treatment option. Complete surgical resection of the tumour would have required a larger, more disfiguring resection of nasal planum and maxilla than the owner was prepared to accept and may have been associated with an unacceptable morbidity. As an alternative, the extent of disease was reduced using a combination of carboplatin, doxorubicin and piroxicam chemotherapy. This allowed a less extensive nasal planum removal to be performed to remove residual disease with clean margins. The patient achieved a 14 month disease free interval from the time of surgery to the time of local recurrence. Survival time from diagnosis to eventual euthanasia for progressive local disease was 18 months.