Michael Siebels

Diagnosis of urothelial carcinoma of the bladder using fluorescence endoscopy

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of superficial bladder cancer are now well established, significant challenges remain, which influences patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity, and increase quality of life and survival. Fluorescence endoscopy, often referred to as ‘photodynamic diagnosis’ (PDD), with intravesical application of photosensitizing agents, has been developed to enhance the early detection of bladder cancer. There is growing evidence that PDD using 5‐aminolaevulinic acid (ALA), hexyl‐ALA ester or hypericin enhances the detection of bladder cancer, particularly of high‐grade flat lesions. Furthermore, transurethral resection of bladder tumour under fluorescence guidance reduces the risk of recurrent tumours. However, the impact on the progression of disease remains unclear and must be investigated in prospective randomized trials.

QUANTIFICATION OF 5-AMINOLEVULINIC ACID INDUCED FLUORESCENCE IMPROVES THE SPECIFICITY OF BLADDER CANCER DETECTION

PURPOSE 5-Aminolevulinic acid induced fluorescence endoscopy has outstanding sensitivity for detecting early stage bladder cancer. Nevertheless, a third of the lesions that show specific fluorescence are histologically benign. We decreased the false-positive rate of 5-aminolevulinic acid induced fluorescence endoscopy by incorporating protoporphyrin IX fluorescence quantification into the standard cystoscopy procedure. MATERIALS AND METHODS In 25 cases (53 biopsies) of a history of or suspicion for bladder cancer 5-aminolevulinic acid induced fluorescence endoscopy and fluorescence image quantification were performed. For fluorescence image quantification images obtained with a target integrating color charge-coupled device camera were digitized and stored in a personal computer. Red-to-blue ratios were calculated from fluorescence positive lesions and results were correlated with hematoxylin and eosin histology. RESULTS Malignant fluorescence positive lesions showed significantly stronger fluorescence intensity than fluorescing lesions with benign histology. A threshold was established that decreased the false-positive rate by 30% without affecting sensitivity. CONCLUSIONS Fluorescence image quantification is a new endoscopic method for objectively selecting multicolor fluorescence bladder lesion images for biopsy. It has the potential of eliminating human error by different surgeons with variable experience in fluorescence endoscopy.

Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma

Study Type – Therapy (case series)

Large de novo renal cell carcinoma in a 10-year-old transplanted kidney: successful organ-preserving therapy.

BACKGROUND A recent review of the Cincinnati Transplant Tumor Registry recorded 24 de novo renal cell carcinomas developing in renal allografts. However, late development of these tumors after transplantation is very rare. Only four reports exist regarding conservative surgery on kidney transplant tumors. METHODS This is a report on a case of a large 6-cm de novo renal cell carcinoma in a 10-year-old transplanted kidney. Optimal therapy by transplant nephrectomy or tumor enucleation was discussed. RESULTS Partial resections or enucleations of renal cell carcinoma are still less than ideal in carcinomas larger than 3 cm considering the higher risk of local recurrence. But the recipient in this case had done so well and had had such a high quality of life after transplantation that partial nephrectomy as therapy of choice was selected. Now the patient is 2 years tumor free. CONCLUSION The case report demonstrates that in certain select cases of large tumors, organ-preserving surgery could be an alternative approach in combining complete tumor removal with preservation of graft function.

Immunotherapy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma has a poor prognosis. Conventional therapies such as chemotherapy, radiation or hormonal treatment have hardly any effect on the progression of this disease. As renal cell carcinoma seems to be an immunogenic tumor, several immunotherapeutic approaches with different response rates have been developed since the early 1990s. We present an overview of various immunotherapeutic approaches such as cytokine-based regimes, with and without different cytotoxic chemotherapy, of metastatic renal cell carcinoma. In addition, local therapies (e.g. inhalation of interleukin-2) are reviewed.

Cell-based vaccines for renal cell carcinoma: genetically-engineered tumor cells and monocyte-derived dendritic cells

Initial vaccine developments for renal cell carcinoma (RCC) have concentrated on cell-based approaches in which tumor cells themselves provide mixtures of unknown tumor-associated antigens as immunizing agents. Antigens derived from autologous tumors can direct responses to molecular composites characteristic of individual tumors, whereas antigens derived from allogeneic tumor cells must be commonly shared by RCC. Three types of cell-based vaccine for RCC have been investigated: isolated tumor cell suspensions, gene modified tumor cells and dendritic cells (DCs) expressing RCC-associated antigens. Approaches using genetic modification of autologous RCC have included ex vivo modification of tumor cells or modification of tumors in vivo. We have used gene-modification of allogeneic tumor cell lines to create generic RCC vaccines. More recently, emphasis has shifted to the use of DCs as cell-based vaccines for RCC. DCs have moved to a position of central interest because of their excellent stimulatory capacity, combined with their ability to process and present antigens to both naive CD4 and CD8 cells. The long impasse in identifying molecular targets for specific immunotherapy of RCC is now rapidly being overcome through the use of tools and information emerging from human genome research. Identification of candidate molecules expressed by RCC using cDNA arrays, combined with protein arrays and identification of peptides presented by MHC molecules, allow specific vaccines to be tailored to the antigenic profile of individual tumors, providing the basis for development of patient-specific vaccines.

Sorafenib after combination therapy with gemcitabine plus doxorubicine in patients with sarcomatoid renal cell Carcinoma: a prospective evaluation

BackgroundSarcomatoid renal cell cancer (RCC) is a distinct histological variant of RCC that is associated with rapid progression and a poor prognosis. The optimal treatment for patients with sarcomatoid RCC remains to be defined. Gemcitabine plus doxorubicine (GD) has shown some efficacy, however durability of response is limited. We carried out a prospective, open-label study to investigate the efficacy and safety of sorafenib in patients after GD failure in sarcomatoid RCC.MethodsFifteen patients with pure sarcomatoid RCC and objective progressive disease were treated with GD (gemcitabine 1500 mg/m2, doxorubicine 50 mg/m2 administered by weekly intravenous infusion) until progression of disease. Subsequently 9 patients were switched to sorafenib (400 mg twice daily). Tumor response was measured by physical examination and computerized tomography scans and evaluated according to Response Evaluation Criteria in Solid Tumors criteria.ResultsMedian time to progression (TTP) under GD was 6.6 months (range 0.8 - 8 months). During GD treatment there were no remissions and 6 patients died from progressive disease. Median TTP for the 9 patients switched to sorafenib was 10.9 months (range 0.6 - 25.5 months). During sorafenib therapy one patient had a partial remission lasting for 3 months and 4 patients experienced stable disease with a duration of 3 to 9 months. Four patients immediately progressed on sorafenib treatment but had a slower dynamic of tumor progression than under GD. Dosing in both treatment phases was generally well tolerated with manageable toxicities and no requirement for dose reduction.ConclusionsChemotherapy with GD was ineffective in our patients with pure sarcomatoid RCC. Subsequent anti-angiogenic treatment using the multi-tyrosine kinase inhibitor sorafenib resulted in additional progression-free survival in 5 of 9 patients. Further evaluation of targeted anti-angiogenic agents for the treatment of sarcomatoid RCC is warranted.

Autofluorescence and 5-aminolevulinic acid induced fluorescence diagnosis of penile carcinoma – new techniques to monitor Nd:YAG laser therapy

Abstract. Nd:YAG laser coagulation is possible for superficial tumors of the penis. The value of photodynamic diagnosis (PDD) and autofluorescence imaging (AF) in detecting malignant lesions on the penis was evaluated. Twelve patients with biopsy-confirmed squamous cell cancer (SCC) of the penis were examined with PDD and AF. For the PDD and AF the penis was illuminated with the blue excitation light from a xenon arch lamp. Biopsies were taken from suspicious lesions detected by PDD or AF and then treated with Nd:YAG laser coagulation. Neoplastic lesions presented with a positive red fluorescence under PDD or a diminished appearance under AF. The HPV-analysis was positive in eight of the 12 lesions. Fluorescence diagnosis is used for the detection of neoplastic lesions. It assists the urologist in detecting neoplastic and preneoplastic lesions, ensuring a more reliable destruction of all tumor material in penile sparing surgery.

Use of hydro-jet cutting for laparoscopic partial nephrectomy in a porcine model

OBJECTIVES To evaluate whether a laparoscopic hydro-jet device can provide a safe and effective partial nephrectomy. Partial nephrectomy is still one of the most challenging operations in urologic laparoscopy. The control of hemorrhage is very difficult to achieve with laparoscopic techniques. In open surgery, hydro-jet resection is used to cut the renal parenchyma selectively, avoiding damage to the vascular structures or collecting system.Methods. Laparoscopic wedge, as well as pole, resections of the kidney were performed in 5 pigs under general anesthesia. After exposure of the kidney, the renal capsule was incised using electrocautery. The hydro-jet was then used to dissect the renal parenchyma. In pole resections, the collecting system and central vessels were divided using an Endo-GIA. Hemostasis was achieved by electrocoagulation or clips. The dissection time and intraoperative complications were evaluated.Results. The operations were performed successfully in all animals without temporary ischemia. The hydro-jet generator allowed precise and effective tissue dissection without significant hemorrhage. The parenchymal vessels were selectively coagulated. The collecting system and central vessels remained intact and could be divided after application of the Endo-GIA. The mean dissection time was 42 +/- 6 minutes for the wedge resections and 54 +/- 8 minutes for the pole resections. CONCLUSIONS These experimental results demonstrate the suitability of hydro-jet dissection for safe laparoscopic partial nephrectomy without temporary ischemia and with reduction of the operative trauma to the kidney. On the basis of our own experiences with other techniques, including electrocautery and laser technology for partial nephrectomy, we conclude that laparoscopic hydro-jet resection represents an interesting alternative to other techniques.

Complete remission achieved with angiogenic therapy in metastatic renal cell carcinoma including surgical intervention.

BACKGROUND Former systemic therapy for metastatic renal cell cancer (mRCC) based on immunomodulation could achieve complete remissions (CR) in only some patients. Angiogenic therapy with sunitinib, sorafenib, and temsirolimus changed the paradigm of treating mRCC based on a doubled progression-free survival (PFS) and 10% to 30% of patients achieving partial remission (PR). Unfortunately, CR is rarely seen. Within our patients we could achieve some CR, which we are presenting in this study. PATIENTS AND METHODS We assessed 194 consecutive patients of an institutional database that were treated for mRCC with either sorafenib or sunitinib between 05/2006 and 12/2007. Restaging with repeated high-resolution computed tomography (CT) of thorax and abdomen was performed in an 8 to 10 weeks interval. Five patients who achieved CR in repeated CT under therapy are included in this analysis. RESULTS Of the patients in whom we achieved CR, two were female and three were male. Median age was 63.2 years (range 52-70). All patients had clear cell histology. In three of the five patients, CR was achieved by surgery after partial remission, and in two patients it was achieved by sole medical therapy. All patients remained in CR until now with a median duration of CR of 24 months (range 24-29 months). One patient still is on therapy, while four patients do not receive any systemic treatment. CONCLUSIONS We proof long-term confirmed CR in mRCC achieved by anti-angiogenic therapy alone or in combination with surgery. Combining surgery and anti-angiogenic therapy based on sorafenib and sunitinib could render patients free of disease even after repeated cycles of systemic treatment.