Masatoshi Muramoto

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

BACKGROUND Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. OBJECTIVES We aimed to investigate the prognosis of Japanese patients and their prognostic factors. DESIGN, SETTING, AND PARTICIPANTS The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. MEASUREMENTS The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. RESULTS AND LIMITATIONS The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. CONCLUSIONS The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.

Clinical outcome of high-intensity focused ultrasound for treating benign prostatic hyperplasia: Preliminary report

OBJECTIVES To preliminarily summarize the clinical outcomes of the transrectal high-intensity focused ultrasound procedure using the prototype Sonablate (HIFU1) and the new Sonablate-200 (HIFU2) for treating symptomatic benign prostatic hyperplasia. METHODS We treated 35 and 22 patients with HIFU1 and HIFU2, respectively. Preoperative and postoperative evaluations were made using the International Prostate Symptom Score (IPSS), quality of life (QOL) data, and the results of uroflowmetry and transrectal ultrasound, and any complications were noted. RESULTS IPSS and QOL scores showed significant improvement after using both HIFU1 and HIFU2 at 3, 6, and 12 months, postoperatively (P < 0.0001 to < 0.01; Wilcoxon signed-ranks test). Maximum flow rate (8.9 to 15.5 mL/s, P < 0.001) and prostatic volume (32.2 to 22.8 mL, P < 0.01) were significantly improved at 12 months postoperatively in patients who underwent HIFU2 treatment but not in patients who underwent HIFU1. Two hematospermia and one gross hematuria in patients treated with HIFU1 and one epididymitis in a patient treated with HIFU2 were seen but no severe complications were noted. CONCLUSIONS Focused ultrasound is an effective new technology by which tissue can be destroyed at a site distant from the source of energy without damaging surrounding tissue. The clinical efficacy of HIFU2 was superior to that of the prototype HIFU1.

Clinical significance of p53, mdm2, and bcl-2 proteins in renal cell carcinoma.

OBJECTIVES To improve our understanding of the clinical relevance of p53, mdm2, and bcl-2 protein overexpression in renal cell carcinoma, we retrospectively investigated the immunohistochemical expression of p53, murine double minute 2 (mdm2), and bcl-2 and the relationship of this expression to clinicopathologic characteristics. p53 regulates the transcription of downstream effectors such as the oncoprotein mdm2, and bcl-2 has been shown to inhibit apoptosis triggered by wild-type p53. METHODS The expression of p53, mdm2, and bcl-2 protein was studied by immunohistochemical methods in paraffin-embedded nephrectomy specimens from 112 patients whose clinicopathologic data confirmed renal cell carcinoma. RESULTS The expression of the p53 and bcl-2 protein was recognized in 15 (13.4%) and 52 (42.0%) cases, respectively; the expression of the mdm2 protein, however, was seen in only 2 cases (1.8%). No correlation was noted between these three proteins and any clinicopathologic parameters, except p53 expression and Stage T1-2/T3-4 (P = 0.0208). However, in multivariate analysis, stage (hazard ratio 3.586; P = 0.0002), expression of p53 (hazard ratio 6.090; P = 0.0126) and of mdm2 (hazard ratio 22.016; P = 0.0156), and coexpression of p53/mdm2 (hazard ratio 6.146; P = 0.0005) demonstrated a statistically significant effect on prognosis by proportional hazards regression tests. CONCLUSIONS Our results indicate that stage, p53 expression, mdm2 expression, and coexpression of p53/mdm2 are useful to predict the clinical outcome in patients with renal cell carcinoma.

Parathyroid Hormone-Related Protein Is an Independent Prognostic Factor for Renal Cell Carcinoma

Parathyroid hormone‐related protein (PTHrP) has been shown to be the principal cause of humoral hypercalcemia associated with renal cell carcinoma (RCC). Recent studies have demonstrated that the amino‐terminal region of PTHrP has growth factor‐like activities, suggesting it may play a role in the development of RCC. In this study, expression of the carboxy‐terminal region of PTHrP was assessed immunohistochemically and its significance in predicting the prognosis of RCC was studied.

Antitumor effect of bcl-2 antisense phosphorothioate oligodeoxynucleotides on human renal-cell carcinoma cells in vitro and in mice.

BACKGROUND AND PURPOSE Programmed cell death is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the bcl-2 oncogene. Antisense oligodeoxynucleotides (ODNs) targeted to specific oncogenes have been used with some therapeutic success in animal models of leukemia and melanoma cells and human Hodgkins lymphoma. We evaluated the effects of antisense ODNs targeted to the bcl-2 oncogene on the proliferation of human renal-cell carcinoma (RCC) cells in vitro and on the growth of human RCC xenografts in BALBc nude (nu/nu) mice. MATERIALS AND METHODS Expression bcl-2 mRNA in five RCC cell lines (ACHN, Caki-1, RCZ, RCW, and OS-RC-2) was analyzed by reverse transcriptase-polymerase chain reaction. The effects of phosphorothioated ODNs containing human bcl-2 sense and bcl-2 antisense sequences that were transfected with Lipofectin on the proliferation and viability of cultures of established human RCC cell lines were determined by MTS assay. The expression of Bcl-2 protein in ACHN tumor cells following antisense bcl-2 (AS2) ODN treatment was evaluated by Western blot analysis, and the extent of apoptosis in these cells was determined by fluorescence-activated cell sorter (FACS) analysis. The antitumor activity in ACHN xenografts in nu/nu mice was monitored by measuring differences in tumor weight in treated and control mice. RESULTS Expression of bcl-2 mRNA was detected in all five RCC lines. Treatment with antisense bcl-2 ODNs inhibited the growth of all tested RCC cells and decreased Bcl-2 protein expression in ACHN cells. The AS2 antisense ODN complementary to the coding region of bcl-2 mRNA showed a superior antiproliferative effect compared with AS1 ODN complementary to the translation initiation region. Inhibition by antisense bcl-2 ODNs of ACHN cells was dose dependent. The FACS analysis revealed that growth inhibition was associated with the induction of programmed cell death. In vivo, AS2 ODN antitumor activity was noted in locally injected groups. CONCLUSIONS Treatment of human RCC with antisense ODNs targeted to bcl-2 inhibits growth and is associated with the induction of programmed cell death. These results suggest therapeutic use of antisense bcl2 in the treatment of RCC.

Reclassification of the current tumor, node, metastasis staging in pT3 renal cell carcinoma

Objectives:  Although the tumor, node, metastasis (TNM) staging classification of renal cell carcinoma (RCC) was last modified in 2002, pT3 staging has continued to be debated. It has been suggested that direct adrenal gland involvement and pT3b with pT3a should be reclassified. This study accordingly explores reclassification of the current 2002 TNM staging in pT3 RCCs.

Metastasis to the penis from cecum carcinoma

Progression of cecal carcinoma occurs either by direct invasion or by metastasis through the hematogenous or lymphatic route. The most commonly involved organs are the liver and lymph nodes. However, metastasis to the penis is rare, with only 300 cases reported to date. The most common primary site of tumors that metastasize to the penis is the pelvic organs, and penile metastasis from tumors of the cecum or colon is particularly rare. This is the third reported case of penile metastasis from a cecal carcinoma. A 67-year-old Japanese man with clinical T3N1M0 cecal carcinoma underwent ileocecal resection. Histopathological examination of the resected specimen showed a well-differentiated adenocarcinoma of the cecum. The pathological stage was T3N1M0 stage IIIB (Dukes C). The patient remained well until 12 months after surgery, when he presented with increasing pain in the penis and inguinal region. Multiple palpable nodules were present on the dorsum of the penile shaft. The body of the penis was elastic hard , but there was no true priapism. Pathological examination of specimens obtained by excisional biopsy of the penile nodules and high inguinal orchiectomy showed a welldifferentiated adenocarcinoma compatible with metastasis from the cecal carcinoma. A computed tomography (CT) scan revealed no other distant metastases. Because pain was poorly controlled by nonsteroidal anti-inflammatory drugs and morphine, total penectomy and vesicostomy were carried out 15 months after ileocecal resection. Histopathological examination of the specimens showed multiple nodules in the corpus carvernosum penis, consisting of moderately to welldifferentiated adenocarcinoma compatible with metastases from the carcinoma of the cecum. Penectomy decreased pain and improved the patient’s quality of life. Two weeks after penectomy, a CT examination revealed multiple lung metastases, mediastinal lymph-node metastasis, and left adrenal metastasis. The patient received nine courses of combination chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate (FOLFOX4 regimen), followed by four courses of a combination of irinotecan, 5-fluorouracil, and levofolinate (FOLFIRI regimen). He survived for 26 months after the diagnosis of penile metastasis. Although the penis has an abundant blood supply, penile metastasis is extremely rare. Penile metastasis from cecal carcinoma was previously reported by Perez-Mesa et al. and Perdomo et al.; to our knowledge this is the third reported case in the English-language literature. The metastatic route to the penis from cecal carcinoma is unknown. If the primary lesion is an intrapelvic tumor, such as rectal cancer or prostate cancer, tumor cells may obstruct the intrapelvic venous plexus and the proximal portion of the lymph ducts, causing tumor cells to flow in a retrograde manner into the dorsal veins of the penis and the lymph ducts. Such flow can lead to retrograde venous or lymphatic transplantation. However, cecal carcinomas are anatomically less likely to cause retrograde metastasis or direct lymphatic spread. Histopathological examination in our own patient revealed no tumor emboli in blood or lymphatic vessels. The outcomes of patients with penile metastasis have been very poor (Table 1). All three patients had metastases to organs besides the penis. Since penile metastasis is only one sign of systemic disease, systemic chemotherapy is necessary to improve survival. Penectomy should be carried out only to improve patients’ quality of life, including pain control. This treatment option should be carefully explained to the patient before surgery.