Microcystic stromal tumour of testis.

Within the group of gonadal sex cord-stromal tumours, microcystic stromal tumour (MCST) is a rare entity. In the literature, most case series and reviews discussed MCST arising in the ovary, only one case-report concerned a testicular MCST. We present a Caucasian man in his late 30s, who presented with an MCST in his right testis. The tumour was encapsulated and composed of vaguely lobulated cellular nodules and cystic spaces with bland spindle cells and hyalinised fibrous stroma. By immunohistochemistry, the tumour cells expressed cluster designation 10, androgen receptor, steroidogenic factor-1 and nuclear beta-catenine, and there was focal nuclear expression of cyclin D1. Molecular diagnostics confirmed the presence of an exon 3 mutation (c.98C>T) in the CTNNB1 gene. These features are similar to MSCT described in the ovary. Clinical follow-up (more than 1 year) was uneventful.Although the clinical and radiological presentation was that of a possible malignant testicular lesion, this entity is benign.

Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells.

Carbonic anhydrase-IXG250/MN (CA9) is a renal cell carcinoma (RCC)-associated antigen ubiquitously expressed in the clear-cell subtype of RCC. Two CA9-derived peptides have been identified defining a cytotoxic T-lymphocyte epitope and human leukocyte antigen (HLA)-DR epitope, able to induce T-cell responses in vitro. A phase I clinical trial was performed with CA9-peptide-loaded dendritic cells (DCs) in patients with progressive, cytokine-refractory metastatic RCC to assess the safety, toxicity, and induction of CA9-specific immunity. Patients with objective progressive metastatic RCC received 5 vaccinations of mature DCs pulsed with the CA9-derived peptides and keyhole limpet hemocyanine (KLH). Peripheral blood was collected at regular intervals, delayed-type hypersensitivity (DTH) was tested at baseline and after the last vaccination, and skin biopsies of positive DTH sites were collected for immunomonitoring purposes. Patients were also monitored for clinical responses. No significant toxicity was observed. All patients developed humoral responses against KLH, and demonstrated DTH conversion. Evaluation of biopsy material suggested an increased influx of T-helper cells. In none of the immunomonitoring assays was evidence for the induction of CA9-peptide-specific immunity observed. No clinical responses were observed. The vaccination of DCs pulsed with KLH and 2 CA9-derived peptides was well tolerated. The lack of induction of CA9-peptide-specific immune responses indicates that this particular vaccine regimen is poor in inducing CA9-peptide-specific immune responses.

The role of adjuvant therapy in non-metastatic RCC.

Renal cell carcinoma (RCC) presents as localized disease in 54% of the cases. For these patients, surgery is the primary curative treatment. Unfortunately, up to 65% of all patients show recurrent disease. For metastatic RCC non-specific immunotherapy is currently the treatment of choice. Nevertheless, several new modalities, e.g. WX-G250, oncophage and anti-angiogenic compounds like sunitinib and sorafenib are being explored with favorable results. Still, their place in the primary treatment of advanced RCC has yet to be determined. Because of the high percentage of recurrent disease, there is a need to identify these patients with conventional and molecular risk factors. Furthermore, adjuvant therapy to reduce risk of recurrence of RCC following nephrectomy is of clinical relevance. A review of recent literature was performed on the topics prognostic models, risk factors and adjuvant treatment for non-metastasized RCC. Combining classical risk factors for progression of RCC has shown to be effective for stratifying patients into risk groups. The UCLA integrated staging system (UISS) is the currently the only validated prognostic model. Whether molecular markers are able to better identify high-risk patients is still under investigation. Adjuvant therapy has been explored in the treatment for RCC and the use of non-specific cytokine regimens has so far not shown to be effective in the adjuvant setting. More specific therapies, e.g. WX-G250, oncophage and anti-angiogenic drugs are clinically active in patients with advanced RCC. Large randomized clinical trials with these drugs are currently ongoing to evaluate their effect in patients with localized RCC.

Validation of an integrated staging system toward improved prognostication of patients with localized renal cell carcinoma in an international population.

PURPOSE: Outcome prediction for patients with renal cell carcinoma is based on a combination of factors. In this study a previously published clinical outcome algorithm based on 1997 T stage, Fuhrman grade and performance score is validated using an international database. MATERIALS AND METHODS: A total of 1,060 patients from Nijmegen, the Netherlands (NN), MD Anderson (MDA) and University of California, Los Angeles (UCLA) who had localized renal cell carcinoma were evaluated for outcome prediction using a clinical outcome algorithm previously shown to stratify patients into low, intermediate and high risk groups. Validation was performed by comparing the 3 risk groups separately within the 3 centers as well as by comparing hazard ratios and concordance indices among the 3 centers. RESULTS: Estimated disease specific survival rates at 5 years for the low risk groups were 94% (NN), 92% (MDA) and 93% (UCLA). The 5-year disease specific survival rates for the intermediate risk groups were 65% (NN), 73% (MDA) and 78% (UCLA), while the rates for the high risk groups were 40% (NN), 30% (MDA) and 48% (UCLA). The concordance indices for each of the databases were 79% (NN), 86% (MDA) and 84% (UCLA). CONCLUSIONS: A clinical algorithm that uses only 3 prognostic variables (1997 T stage, Fuhrman grade and performance status) to stratify patients with localized renal cell carcinoma into 3 risk groups has been shown to be applicable to external databases. This algorithm may be useful for patient counseling, surveillance and identification of high risk patients for enrollment in clinical trials.

Tumor antigens and markers in renal cell carcinoma.

Tumor markers are mainly used to diagnose specific malignancies. The methods commonly involve immunohistochemistry and cytogenetics, including FISH and RT-PCR. In RCC, the investigated tumor markers (summarized in Table 1) show additional prognostic value over classical prognostic factors such as stage and grade. These markers can be used for better patient selection, a more accurate individualization of treatment, and improved follow-up. Nevertheless, their definitive value must be reconfirmed in larger patient cohorts. Ultimately, these factors should be shown to be of value in a prospective well-controlled trial. One of the most promising new techniques involves gene expression profiling of solid tumors. This cDNA microarray technique applied in RCC has improved understanding of the molecular mechanism of the underlying tumor genesis and its correlation to the clinical course. Tumor antigens that are specific for RCC (eg, G250) and that induce a specific immune response can be used for vaccine treatment modalities. With the use of dendritic cells, antigen presentation can be improved. Several phase I studies are currently underway. More research is needed to obtain better antigens and markers in RCC to improve insight into the molecular mechanism of the development of RCC, to improve the selection of patients for treatment, and to increase its effectiveness.

Immunotherapy for renal cell carcinoma.

Renal cell carcinoma (RCC) is the most prevalent malignancy within the kidney and the incidence is rising. Due to improved radiological evaluation over 50% of the renal cancers are found incidentally. Despite the fact that these incidentalomas are often confined to the kidney, around 50% of all patients diagnosed with kidney cancer will develop systemic disease. Metastatic RCC has a poor prognosis. Traditional treatment modalities like chemo- and radiotherapy show overall response percentages of 2-6%. In view of the observed spontaneous remissions of advanced renal cancer, immune mechanisms have been suggested to play a role in the natural disease course of RCC. At present, several non-specific cytokine regimens are used in the treatment of mRCC, e.g. interleukin-2 and interferon-alpha, in combination or as monotherapy or in combination with substances like 13-cis-retinoic acid and/or 5-fluorouracil. Collective data of trials evaluating cytokine-based therapies for mRCC show an overall response rate of approximately 15%, with 5% of the patients showing complete responses. More importantly, cytokine treatment clearly translates into a significant survival benefit in a subset of patients. Nevertheless, the toxicity profile of these cytokine regimens is significant. With the enhanced knowledge of tumor-immunology, the identification of immunogenic tumor proteins, and antibodies recognizing tumor-associated antigens, new treatment strategies with increased specificity and fewer side effects are of interest. Here we review the different immunotherapeutical modalities currently used as well as new approaches for the treatment of advanced RCC.

Vaccination of patients with metastatic renal cell carcinoma with autologous dendritic cells pulsed with autologous tumor antigens in combination with interleukin-2: a phase 1 study.

Dendritic cells (DC) have been recognized as the most potent antigen presenting cells (APC) of the immune system. We performed a phase 1 study in twelve patients with metastatic renal cell carcinoma (RCC) using autologous immature DC loaded with autologous tumorlysate (TuLy) as a vaccine based on our earlier in vitro observations that such DC can activate tumor-specific cytotoxic T-lymphocytes. The treatment was combined with low-dose interleukin (IL)-2, as this has shown benefit in DC-based therapies. Patients received three intradermal vaccinations at two weekly intervals, and, after each vaccination, IL-2 was administered for 5 consecutive days. In six patients, keyhole-limpet hemocyanin (KLH) was added to the DC culture for immunologic monitoring purposes. In general, DC phenotype was CD14(low), CD86(high), CD40(high), CD80(low), and CD83(low). We noticed that the number of CD14+ cultured DC increased during treatment. Nevertheless, ovalbumin uptake remained high, underlining that these cells were still functional immature DC. The vaccine was able to elicit cellular anti-KLH responses, emphasizing the ability of the injected DC to mount an immunologic response. However, proliferative responses against TuLy were not detected, and humoral responses against TuLy or KLH were absent. Objective clinical responses were not observed, but extended stable disease was noted. The absence of cellular, humoral, or clinical antitumor responses suggests that the vaccination strategy with immature DC has little benefit for patients with advanced RCC. Nevertheless, this study shows the feasibility of a completely autologous DC and tissue culture methodology for the generation of TuLy pulsed DC.