Jehonathan H. Pinthus

Photodynamic therapy with Pd-Bacteriopheophorbide (TOOKAD): successful in vivo treatment of human prostatic small cell carcinoma xenografts.

Small cell carcinoma of the prostate (SCCP), although relatively rare, is the most aggressive variant of prostate cancer, currently with no successful treatment. It was therefore tempting to evaluate the response of this violent malignancy and its bone lesions to Pd‐Bacteriopheophorbide (TOOKAD)‐based photodynamic therapy (PDT), already proven by us to efficiently eradicate other aggressive non‐epithelial solid tumors. TOOKAD is a novel bacteriochlorophyll‐derived, second‐generation photosensitizer recently, developed by us for the treatment of bulky tumors. This photosensitizer is endowed with strong light absorbance (ϵ0 ∼ 105 mol−1 cm−1) in the near infrared region (λ=763nm), allowing deep tissue penetration. The TOOKAD‐PDT protocol targets the tumor vasculature leading to inflammation, hypoxia, necrosis and tumor eradication. The sensitizer clears rapidly from the circulation within a few hours and does not accumulate in tissues, which is compatible with the treatment of localized tumor and isolated metastases. Briefly, male CD1‐nude mice were grafted with the human SCCP (WISH‐PC2) in 3 relevant anatomic locations: subcutaneous (representing tumor mass), intraosseous (representing bone metastases) and orthotopically within the murine prostate microenvironment. The PDT protocol consisted of i.v. administration of TOOKAD (4 mg/kg), followed by immediate illumination (650–800 nm) from a xenon light source or a diode laser emitting at 770 nm. Controls included untreated animals or animals treated with light or TOOKAD alone. Tumor volume, human plasma chromogranin A levels, animal well being and survival were used as end points. In addition, histopathology and immunohistochemistry were used to define the tumor response. Subcutaneous tumors exhibited complete healing within 28–40 days, reaching an overall long‐term cure rate of 69%, followed for 90 days after PDT. Intratibial WISH‐PC2 lesions responded with complete tumor elimination in 50% of the treated mice at 70–90 days after PDT as documented histologically. The response of the orthotopic model was also analyzed histologically with similar results. The study with this model suggests that TOOKAD‐based PDT can reach large tumors and is a feasible, efficient and well‐tolerated approach for minimally invasive treatment of local and disseminated SCCP.

The role of indirect radionuclide cystography during the acute phase of pyelonephritis in young women

Authors from Israel have investigated the use of dynamic renal scans in young female patients with acute pyelonephritis, combined with indirect radionuclide cystography. They found that using these techniques may avoid up to half of the delayed voiding cysto‐urethrograms, preventing the related inconvenience and cost.

Lack of MHC expression and retention of ultrastructural characteristics by xenograft transmissible venereal tumor cells in SCID mice

Canine transmissible venereal tumor (CTVT) is primarily a tumor of adult dogs with a high incidence of spontaneous regression. We recently reported a xenograft model of CTVT (XTVT) in NOD/SCID mice. XTVT cells retain cytological and histological features of CTVT as well as characteristic rearranged LINE/c-MYC junction [Am. J. Vet. Res. 62 (2001) 907]. In this paper, we demonstrate that XTVT cells maintain ultrastructural characteristics of CTVT and do not express MHC classes I and II molecules.

Computerized Tomography Measurement of Visceral Adiposity Predicts Plasma Adiponectin Levels and Metastatic Disease in Patients with Clear Cell Renal Cell Carcinoma

Background: Obesity is a risk factor for renal cell carcinoma (RCC). Plasma levels of adiponectin, a hormone secreted solely by adipocytes, inversely correlate with adverse prognostic factors in RCC. Since the volume of the metabolically active visceral adipose tissue (VAT) better reflects obesity associated morbidity than body mass index (BMI), we measured and correlated it to adiponectin levels and disease characteristics in patients with clear cell RCC (ccRCC). Patients and Methods: Visceral and subcutaneous adipose tissues were measured using preoperative CT scans in 25 ccRCC patients who had no previous history of other cancers, diabetes or impaired renal function. Tissue at fat density was separated into subcutaneous and visceral components and the pixels were summed across 3 transverse slices (upper aspect of the L2 vertebral body, the umbilicus and the anterior superior iliac spine) to create a surrogate score of percentage of VAT (visceral fat area/visceral plus subcutaneous fat area). This score was correlated to preoperative fasting plasma adiponectin levels, tumor size, grade, presence of metastasis and BMI by univariate and multivariate linear regression analysis. Results: BMI correlated strongly with total but not visceral fat. Percentage of VAT correlated inversely with plasma adiponectin levels (p < 0.05) and directly with the presence of metastasis (p < 0.05) but not with grade. BMI did not predict either. Conclusion: Visceral obesity is associated with lower levels of plasma adiponectin and also appears to be associated with metastatic disease in ccRCC. CT measurements of percentage of VAT may help in preoperative prognostication of ccRCC patients.

Uncovering the Metabolic Complications of Androgen Deprivation Therapy in Patients with Prostate Cancer—Where Do We Take it Next?

DURING the last decade observational data have within 6 months of initiation, ADT produces sigprompted concern that treatment of the patient with prostate cancer with androgen deprivation therapy (ADT) might cause or accelerate cardiovascular disease. In support, various studies associated ADT with a high prevalence of the metabolic syndrome, a constellation of risk factors associated with insulin resistance, diabetes and cardiovascular disease. A randomized, controlled trial of ADT against placebo with prespecified cardiovascular and metabolic end points would be the most definitive means to ascertain a causal role of ADT in cardiovascular disease and its risk factors because randomization negates the influence of confounders. Nevertheless, such a randomized trial would be considered unethical and impractical, given the widespread acceptance of ADT when indicated clinically. Accordingly, our current understanding of the association between ADT and the development of cardiovascular risk factors and disease is mainly based on accumulating evidence from observational studies and analysis of administrative data sets. In this issue of The Journal 2 studies provide additional evidence to suspect a deleterious role of ADT in the development of diabetes and the metabolic syndrome. Tsai et al (page 1956) explored the role of primary ADT in the development of diabetes using a retrospective cohort of 12,191 patients with localized prostate cancer who were followed for a median of 4.9 years. ADT was associated with a 1.61-fold increased risk of diabetes (95% CI 1.38e1.88), a higher risk than the 1.36 to 1.44-fold reported in previous publications. Importantly, the calculated number needed to harm was 29, indicating 1 additional diabetes event among 29 recipients of ADT vs nonADT. The association between ADT and the development of the metabolic syndrome has long been suspected based on retrospective analysis. The observational study by Morote et al (page 1963) is unique as the authors prospectively assessed the longitudinal changes in the prevalence of the metabolic syndrome and its components. Evidently

The RADICAL-PC trial.

178 Background: Cardiovascular disease (CVD) occurs frequently in men with prostate cancer (PC), but the reasons are unclear. Specifically, the role of androgen deprivation therapy (ADT) in promoting CVD remains uncertain. There is a lack of evidence to inform preventive strategies against CVD in this high risk group. It is unknown if the evidence to support CVD preventive strategies in the general population can be validly extrapolated to men with PC. Methods: RADICAL-PC combines two prospective studies, one of which is embedded in the other. The Role of Androgen Deprivation Therapy in Cardiovascular Disease – A Longitudinal Prostate Cancer Study (RADICAL PC1) is a prospective cohort study of men within one year of their first diagnosis of PC, or who are within one month of commencing ADT for the first time. Its goal is to identify factors associated with the development of CVD among men with PC, with a particular focus on ADT. The Randomized Intervention for Cardiovascular and Lifestyle Risk Factors in ...