Transrectal high-intensity focused ultrasound (HIFU) treatment of localized prostate cancer: review of technical incidents and morbidity after 5 years of use.

The objective of this study was to report on technical incidents and early and late complications occurring in high-intensity focused ultrasound (HIFU) treatment of patients with localized prostate cancer. We performed a retrospective review of patients who were treated by Ablatherm at our centre. We recorded all technical incidents, treatment discontinuations and early (<1 month) and late complications. A total of 74 HIFU procedures were performed in 65 patients (55 first-line HIFU treatments and 10 cases of salvage therapy after radiotherapy) over a 5-year period. Median follow-up was 41 months (10-64 months). All the procedures were well tolerated and no intra- or peri-operative deaths occurred. Six technical incidents in the overall population (8.1%) led to discontinuation of the procedure. The early complication rate in patients undergoing first-line HIFU was 36.4%: urinary retention (20%), dysuria (5.4%), urinary infection (3.6%), haematuria (3.6%) and urethral stenosis (3.6%). The late complication rate was 12.7%: urethral stenosis (9%) and dysuria (3.6%). There were no cases of rectourethral fistula. The long-term urinary incontinence rate was 20% and the de novo erectile dysfunction rate was 77.1%. Nine complications (16.4%) required surgical management. The overall complication rate was 49%. Ablatherm is a reliable technique with a relatively high complication rate. However, most complications were minor and required surgical management in a few cases only. Our results confirm that all patients who are offered HIFU treatment should be properly informed of the risks, in particular with regard to continence and sexual function.

[Primary upper urinary tract tumors and subsequent location in the bladder]. / Tumeur urothéliale primitive du haut appareil urinaire et seconde localisation ultérieure intravésicale.

The urothelium is the epithelium that lines the upper and lower urinary tract. Over 95% of urothelial carcinomas are derived from urothelium. They can be located in the lower tract (bladder, urethra) or upper tract (pyelocaliceal cavities, ureter). Urothelial carcinomas are the fourth most common tumours after prostate (or breast) cancer, lung cancer and colorectal cancer. On one hand, bladder tumours account for 90-95% of urothelial carcinomas. It is the most common malignancy of the urinary tract and the second most common malignancy of the urogenital tract after prostate cancer. It accounts for 5-10% of all cancers diagnosed each year in Europe. On the other hand, upper urinary tract urothelial cell carcinomas (UUT-UCC) are scarce and account for only 5-10% of urothelial carcinomas. Recurrence in the bladder after primary UUT-UCC occurs in 15-50% of UUT-UCC. Differences in treatment modalities of the primary UUT-UCC do not play a key role in the subsequent appearance of a bladder recurrence. However, others factors have been described such as stage and location in the upper tract of the primary tumour or upper tract tumour multifocality. Previous history of bladder tumour is also associated with the risk that another tumour arises in the bladder subsequently. However, it becomes difficult to distinguish between natural history of bladder tumour and evolution of UUT-UCC in these cases. In most cases, bladder cancer occurs in the first two years after UUT-UCC management. Surveillance protocol is based on cystoscopy and on urinary cytology during at least every three months for two years. Current surveillance regimen have a low level of evidence considering the paucity of UUT-UCC.

[Is the recommended treatment for erectile dysfunction effective for men over age 65?]. / Le schéma thérapeutique habituel de la dysfonction érectile est-il adapté après 65 ans ?

OBJECTIVES: To evaluate the recommended erectile dysfunction treatment algorithm for men over age 65. PATIENTS AND METHODS: Between 2004 and 2006, 334 men were treated for ED at our institution, of whom 64 were greater than 65 years old (19.2%). Medical history, ED treatments and patients' satisfaction were reported. The first line therapy was PDE 5 inhibitors except after radical prostatectomy, followed by intracavernous injections (ICI). When conservative treatments failed, penile prosthesis was proposed. Mean follow up was 23.7 months. RESULTS: Mean age was 69.2 years (65-81). Aetiology of ED was organic in 85.9% (39.1% after radical pelvic surgery) and partially drug induced in 45.8%. With PDE 5 inhibitors, the mean success rate was 26.5 and 7.1% after radical pelvic surgery. Because of cost, 30.8 % of satisfied patients stopped PDE 5 inhibitors. Mean ICI success rate was 60.4% but 34.5% of satisfied men interrupted them. Finally, 14% of patients were successfully treated by PDE 5 inhibitors and 29.7% by ICI. Penile prosthesis was implanted in 12 patients (18.7%) with a mean success rate of 83.3%. No successful ED treatment was found in a third of patients. CONCLUSION: PDE 5 inhibitors after 65 were found to be less successful as envisaged. This study points out the probable inadequacy between the patients' expectations and the therapeutic options, including socioeconomic terms.

["I'd like to have a high-dose chemotherapy with stem cell transplantation!"]. / "Eine Hochdosischemotherapie mit Stammzelltransplantation, bitte!"

Patients with factitious disorders can imitate complex diseases and cause multiple investigations and therapies. The presented patient showed the typical signs and behaviour of this psychiatric disorder. Confrontation may not be helpful in severe cases, whereas a supportive approach might help to avoid further useless and dangerous procedures.

Immunotherapy of patients with hormone-refractory prostate carcinoma pre-treated with interferon-gamma and vaccinated with autologous PSA-peptide loaded dendritic cells--a pilot study.

PURPOSE: We conducted a pilot trial to assess the feasibility and tolerability of a prime/boost vaccine strategy using interferon-gamma (IFN-gamma) and autologous dendritic cells (DCs) pulsed with HLA-A2-specific prostate-specific antigen (PSA) peptides (PSA-1 [141-150]; PSA-2 [146-156]; PSA-3 [154-163]) for the treatment of 12 patients with hormone refractory prostate carcinoma. PATIENTS AND METHODS: All patients were vaccinated four times with intracutaneously injected PSA-peptide loaded DCs after subcutaneous administration of IFN-gamma 2 hr before DC administration (50 microg/m(2) body surface). Objectives were safety, clinical benefit, clinical and biochemical response, quality of life, and immunological parameters. RESULTS: The vaccination was well tolerated without any vaccination-associated adverse events. One partial and one mixed responder were identified, four patients showed stable diseases. Two patients had a decrease and four a slow-down velocity slope in the PSA serum level. All responders showed a positive DTH-response, but only two a slight increase in PSA-peptide specific T-lymphocytes. CONCLUSION: The immunotherapy with IFN-gamma and PSA-peptide loaded DCs was feasible and well tolerated. The observed responses imply a potential antitumor activity.

An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma.

BACKGROUND: The number of effective cytotoxic agents for the treatment of patients with metastatic adult type soft tissue sarcoma (STS) is limited, when patients have failed anthracyline-based chemotherapy. The aim of this trial was to evaluate the efficacy of gemcitabine in this setting. METHODS: Between August 2001 and March 2003 19 patients were eligible to enter. Gemcitabine was administered as a 30-minutes infusion at a dosage of 1 g/m2 on day 1, 8 and 15 every 4 weeks. All patients had progressive disease during (n = 12) or shortly after an anthracycline-based regimen (n = 3). RESULTS: Four of 19 patients did not start study treatment because of fulminant progression. Fifteen patients with a median age 47 years (32-72) were assessable. All patients had received at least one prior treatment regimen (range, 1-6) for metastatic disease containing anthracyclines (n = 15) and ifosfamide (n = 11). To date, a total of 72+ cycles have been applied (median; 3, 1-28+). Seven patients (47%) had progressive disease after completion of two cycles at the first response assessment. One patient (6%) attained a partial remission, and 7 patients (47%) achieved disease stabilisations. One patient is still on treatment after more than 2.5 years. The calculated progression-free rate at 3 and 6 months was 46.7% (CI(95%), 21.4-71.9) and 13.3% (CI(95%), (0-30.5). 95% of the cycles have been applied without any dose modification or treatment delay. CONCLUSIONS: Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.

Direction of the recognition specificity of cytotoxic T cells toward tumor cells by transduced, chimeric T-cell receptor genes.

Cellular transformation does not necessarily require the expression of proteins with neoantigenic properties, and for this reason, immunosurveillance does not register all tumor cells. They frequently express potentially immunogenic components, but are able to escape elimination by immune mechanisms. One explanation for this escape is poor antigen presentation by the tumor cells, resulting in little or no measurable antitumor immunity in immunocompetent hosts. T cells remain naive or even become anergic to the tumor cells. Reasons for the deficient antigen presentation by the tumor cells include the reduced or absent expression of major histocompatibility complex (MHC) molecules and the absence of tumor antigens in the groove of class I or class II MHC molecules as a consequence of defective protein processing. Other reasons are the absence or inadequate levels of expression of adhesion molecules, the absence or inadequate levels of costimulatory molecules or the expression of lymphocyte suppressive cytokines like transforming growth factor (TGF-ß) or interleukin 10 (IL-10) by tumor cells (1-5).

Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vitro growth of human head and neck cancer cells and cause rapid tumor regression in vivo.

Overexpression of the ErbB2 and epidermal growth factor receptor (EGFR) tyrosine kinases is frequently observed in squamous cell carcinomas of the head and neck, and has been correlated with shorter overall survival. By immunoblot analysis, we have found EGFR and ErbB2 expression in 6 out of 6 established head and neck cancer cell lines. Elevated EGFR protein levels were noted in 3 and elevated ErbB2 levels in 5 of them. Significant expression of EGFR and ErbB2 was also detected in 17 of 47 and 26 of 45 primary tumor samples. Due to their enhanced expression on the tumor cell surface, these receptors can be regarded as suitable targets for directed cancer therapy. We have analyzed the antitumoral activity of recombinant single-chain antibody toxins specific for ErbB2 and EGFR against head and neck cancer cells in vitro and in vivo. The recombinant toxins consist of the variable domains of the heavy and light chains of monoclonal antibodies (MAbs) genetically fused to a truncated Pseudomonas exotoxin A (ETA). At low concentrations, the ErbB2-specific single-chain antibody (scFv) toxin scFv(FRP5)-ETA and the EGFR-specific toxins scFv(225)-ETA and scFv(14E1)-ETA inhibited the in vitro growth of established head and neck cancer cell lines and primary tumor cells. In a nude mouse tumor model, intratumoral injection of the antibody toxins resulted in the rapid regression of subcutaneously growing CAL 27 tumor xenografts, with scFv(FRP5)-ETA and scFv(14E1)-ETA treatment being most effective and leading to the cure of up to 50% of the animals. Our results suggest that EGFR and ErbB2-specific antibody toxins may become valuable therapeutic reagents for the treatment of squamous cell carcinomas of the head and neck.

Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by hyperproliferation of the erythroid, myeloid, and megakaryocytic lineages. Although it has been shown that progenitor cells of patients with PV are hypersensitive to several growth factors, the molecular pathogenesis of this disease remains unknown. To investigate the molecular defects underlying PV, we used subtractive hybridization to isolate complementary DNAs (cDNAs) differentially expressed in patients with PV versus normal controls. We isolated a novel gene, subsequently named PRV-1, which is highly expressed in granulocytes from patients with PV (n = 19), but not detectable in normal control granulocytes (n = 21). Moreover, PRV-1 is not expressed in mononuclear cells from patients with chronic myelogenous leukemia (n = 4) or acute myelogenous leukemia (n = 5) or in granulocytes from patients with essential thrombocythemia (n = 4) or secondary erythrocytosis (n = 4). Northern blot analysis showed that PRV-1 is highly expressed in normal human bone marrow and to a much lesser degree in fetal liver. It is not expressed in a variety of other tissues tested. Although PRV-1 is not expressed in resting granulocytes from normal controls, stimulation of these cells with granulocyte colony-stimulating factor induces PRV-1 expression. The PRV-1 cDNA encodes an open reading frame of 437 amino acids, which contains a signal peptide at the N-terminus and a hydrophobic segment at the C-terminus. In addition, PRV-1 contains 2 cysteine-rich domains homologous to those found in the uPAR/Ly6/CD59/snake toxin-receptor superfamily. We therefore propose that PRV-1 represents a novel hematopoietic receptor. (Blood. 2000;95:2569-2576)

A novel animal model for the evaluation of the efficacy of drugs directed against the ErbB2 receptor on metastasis formation.

The ErbB2 receptor tyrosine kinase is often overexpressed in human malignancies and causally involved in transformation. High levels of ErbB2 in tumor cells correlate with an unfavorable prognosis. This makes the ErbB2 receptor an interesting target for tumor therapy, and several strategies have been designed to direct drugs to ErbB2-expressing cells. We established a novel cellular model that allows preclinical evaluation of ErbB2-directed drugs in immunocompetent animals. Renal carcinoma (Renca) cells are an established tumor cell line that originated in Balb/c mice. Upon intravenous transplantation, these cells form pulmonary metastases in Balb/c mice. The transforming genetic lesions in these cells are not fully characterized, but do not seem to involve alterations in ErbB2 gene expression. We transfected Renca cells with the gene encoding the human ErbB2 receptor to provide a target structure for specific drugs and with the bacterial lacZ gene to provide a sensitive means of detection of the tumor cells in the transplanted animals. These genetically modified cells form lung metastasis and can be easily visualized on the surface of lung tissue by staining with an X-gal solution. This allows a quantitative analysis of the number of ErbB2-expressing pulmonary metastasis. We previously used these Renca cells to evaluate the efficacy of an ErbB2-specific tumor toxin on pulmonary metastases in an adjuvant and a palliative treatment setting. In both cases, we achieved a dramatic reduction of disseminated lung lesions. Here we show that even at an advanced stage of metastasis formation, the ErbB2-specific toxin is able to efficiently reduce the number of pulmonary tumors.

Proliferation and survival of mammary carcinoma cells are influenced by culture conditions used for ex vivo expansion of CD34(+) blood progenitor cells.

Malignant cell contamination in autologous transplants is a potential origin of tumor relapse. Ex vivo expansion of CD34(+) blood progenitor cells (BPC) has been proposed as a tool to eliminate tumor cells from autografts. To characterize the influence of culture conditions on survival, growth, and clonogenicity of malignant cells, we isolated primary mammary carcinoma cells from pleural effusions and ascites of patients with metastatic breast cancer and cultured them in the presence of stem cell factor (SCF), interleukin-1beta (IL-1beta), IL-3, IL-6, and erythropoietin (EPO), ie, conditions previously shown to allow efficient ex vivo expansion of CD34(+) BPC. In the presence of serum, tumor cells proliferated during a 7-day culture period and no significant growth-modulatory effect was attributable to the presence of hematopoietic growth factors. When transforming growth factor-beta1 (TGF-beta1) was added to these cultures, proliferation of breast cancer cells was reduced. Expansion of clonogenic tumor cells was seen in the presence of SCF + IL-1beta + IL-3 + IL-6 + EPO, but was suppressed by TGF-beta1. Cocultures of tumor cells in direct cellular contact with hematopoietic cells showed that tumor cell growth could be stimulated by ex vivo expanded hematopoietic cells at high cell densities (5 x 10(5)/mL). In contrast, culture under serum-free conditions resulted in death of greater than 90% of breast cancer cells within 7 days and a further decrease in tumor cell numbers thereafter. In the serum-free cultures, hematopoietic cytokines and cellular contact with CD34(+) BPC could not protect the tumor cells from death. Therefore, ex vivo expansion of CD34(+) BPC in serum-free medium provides an environment for efficient purging of contaminating mammary carcinoma cells. These results have clinical significance for future protocols in autologous progenitor cell transplantation in cancer patients.

Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells.

Receptor-mediated targeted tumor therapy is an important applied consequence of the studies on the genetic causes of cancer. These therapy concepts have to be evaluated in novel animal models that reflect the molecular aberrations found in human tumors. Here we introduce an animal model that allows the evaluation of drugs directed against a surface receptor that is frequently altered in primary human adenocarcinomas. Tumor toxins are polypeptides in which a tumor cell-specific recognition domain and a toxic effector domain have been joined by DNA recombination in vitro. Tumor cell recognition is contributed by a single-chain antibody domain specific for the extracellular domain of the erbB-2 receptor [scFv(FRP5)] and cytotoxicity by the enzymatically active domain of a bacterial exotoxin (exotoxin A from Pseudomonas aeruginosa). The erbB-2 receptor is overexpressed in many primary human cancer cells and is a favorable target for directed tumor therapy. The fusion protein scFv(FRP5)-exotoxin A has previously been shown to be able to efficiently and specifically kill erbB-2 receptor-expressing tumor cells. We have investigated the potential of this tumor toxin to detect and eliminate metastasizing tumor cells upon systemic administration. Murine renal carcinoma cells genetically modified with human erbB-2 receptor and bacterial beta-galactosidase genes form large pulmonary metastases when injected into the tail vein of BALB/c mice. Administration of the tumor toxin over a 10-day time period starting 1 day after tumor cell transplantation totally suppressed the formation of metastases. The treatment of animals 11 days after tumor cell transplantation, allowing the establishment of many pulmonary metastases, led to a drastic reduction in their number and size.

Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins.

Tumor cells have been found in autologous hematopoietic cell transplants used after high-dose chemotherapy. To specifically eliminate contaminating mammary tumor cells during ex vivo expansion of CD34+ hematopoietic progenitor cells, we used recombinant immunotoxins (ITs) directed against cell-surface antigens expressed on mammary carcinoma cells. ITs were expressed from fusion cDNAs combining a single-chain antibody fragment (scFv) directed against the Erb-B2 or epidermal growth factor (EGF) receptors with a truncated Pseudomonas exotoxin A fragment devoid of its cell-binding domain. CD34+ hematopoietic progenitor cells did not express Erb-B2 and EGF receptors as detected by Western blotting. Ex vivo expansion of total hematopoietic cells or of colony-forming cells from CD34+ progenitors in the presence of stem-cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (Epo) was not affected when ITs were added to the cultures. In contrast, MDA-MB 453 and MCF-7 mammary carcinoma cells were depleted in a dose- and time-dependent manner by more than 3 log in coculture with CD34+ cells over a period of 7 days in the presence of 100 to 1,000 ng/mL of anti-Erb-B2 IT. This included elimination of the subpopulations with regrowth potential. Similarly, addition of either anti-Erb-B2 or anti-EGF receptor ITs to primary breast cancer cells isolated from patients with metastatic disease resulted in elimination of cytokeratin-positive cells in seven of seven samples. ITs are highly efficient and convenient to use for the depletion of mammary tumor cells during ex vivo expansion of hematopoietic progenitor-cell autografts.

Therapy of invasive aspergillosis with itraconazole: improvement of therapeutic efficacy by early diagnosis.

We report on the treatment of invasive aspergillosis with the new triazole antimycotic agent itraconazole. All 11 patients suffered from pulmonary invasive aspergillosis. Two patients also had cerebral aspergillosis; in one of these patients the paranasal sinuses were also invaded. Underlying diseases were acute lymphoblastic leukaemia (n = 3), acute myeloid leukaemia (n = 4); one patient underwent allogeneic bone marrow transplantation before he developed aspergillosis; another was transplanted after successful aspergillosis treatment, liver cirrhosis (n = 1), lung infarction after pulmonary embolism (n = 1), chronic bronchitis after pulmonary tuberculosis (n = 1) and AIDS (n = 1). In five cases initial diagnosis was established by means of mycological methods and clinical signs. In six patients invasive pulmonary aspergillosis was initially diagnosed due to the clinical criteria presented in this paper. Secondary mycological confirmation after onset of therapy was achieved in five out of these six patients. All of the patients initially responded to therapy. One female patient experienced a relapse of aspergillosis and died of cerebral involvement and relapsing leukaemia. Two further patients died due to underlying diseases (pulmonary embolism, relapsing leukaemia). Nine patients (82%) were cured of the mycosis, including the patient with cerebral involvement; two underwent surgical resection of residual pulmonary lesions. Itraconazole is a very effective drug for treatment of invasive aspergillosis. Therapeutic efficacy can be optimized by early diagnosis using clinical criteria and prompt start of treatment.