Search

Background/aim: Several cases of concurrent reduction of expression of polycystin 1 (PKD1) and Tuberous Sclerosis Complex 2 (TSC2) that are contiguous in chromosome 16p13 have been previously reported. This study newly addresses the concurrent reduction of expression of PKD1, TSC2 and NTHL1, which is adjacent to TSC2 and is a tumor suppressor gene., Materials and Methods: We investigated the mRNA expression levels of PKD1, TSC2, PKD2, TSC1 and NTHL1 in blood and renal cell carcinoma (RCC) tissues in a proband with autosomal dominant polycystic kidney disease (ADPKD), tuberous sclerosis complex (TSC) and multiple pathologically diverse RCCs, including clear cell, papillary and chromophobe types. Additionally, we investigated germline variants in blood using whole exome sequencing (WES) in the proband and her four siblings., Results: mRNA expression levels of PKD1, TSC2 and NTHL1 were reduced in the proband's blood and RCCs, compared with control groups. WES identified one novel variant with amino acid changes in the PKD1 exon in the three subjects with ADPKD, including the proband. Moreover, two variants in the TSC2 intron specific to the proband were also identified., Conclusion: In this study, we report a novel pathogenic variant in the PKD1 exon which likely led to ADPKD, and two variants in the TSC2 intron, which might have led to reduction in the expression of both TSC2 and NTHL1, consequently leading to TSC and multiple pathologically diverse RCCs., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The current study was conducted to clarify the frequency of systemic circulating tumor cells (CTCs) appearing after surgery for renal cell carcinoma and to evaluate the differences in postoperative CTCs between different surgical procedures., Methods: This prospective, cohort study included 60 consecutive patients who underwent laparoscopic radical nephrectomy (RN) (n = 22), laparoscopic partial nephrectomy (PN) (n = 19), open RN (n = 8), or open PN (n = 11). In this study CTCs were measured by the FISHMAN-R system, and CTCs drawn from a peripheral artery were collected just before and immediately after surgery. The number of pre- and postoperative CTCs and the perioperative changes in CTCs were measured for each surgical method., Results: Six patients were excluded from the current analyses. Preoperative CTCs did not differ significantly by surgical approach (laparoscopic RN: 3.4 ± 4.2; laparoscopic PN: 3.4 ± 4.1; open RN: 7.7 ± 6.8; open PN: 6.0 ± 7.6; P = 0.19). Open RN resulted in a significantly greater number of postoperative CTCs (laparoscopic RN: 4.8 ± 3.7; laparoscopic PN: 7.9 ± 9.1; open RN: 22.5 ± 26.3; open PN: 6.4 ± 6.3; P < 0.001) and perioperative changes in CTCs (laparoscopic RN: 1.3 ± 5.3; laparoscopic PN: 4.5 ± 9.6; open RN: 14.7 ± 25.0; open PN: 0.4 ± 6.3; P < 0.001). No significant differences in these were observed among the three groups except in the open RN group. In the multivariate analysis, the surgical approach was significantly correlated with the number of postoperative CTCs (P = 0.016) and the perioperative change in CTCs (P = 0.01)., Conclusions: This proof-of-concept study indicated that after surgery, more cancer cells can be expelled into the bloodstream, especially after open RN. Sufficient and careful follow-up assessment for the emergence of distant metastases is needed for patients undergoing open RN.

Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.

The patient was a 47 year-old female who had autosomal dominant polycystic kidney disease (ADPKD) with bilateral small renal cell carcinoma (RCC). We performed bilateral partial nephrectomy and radiofrequency ablation to the residual tumor. Pathological diagnosis was clear cell carcinoma,Fuhrman grade 3. Sunitinib therapy was started nine months after the operation because multiple liver metastases occurred. Twenty-six months after the operation,she died from rapid progression of liver metastasis.

Background: Liposarcoma is one of the most common soft tissue sarcomas found in adults. It has a predilection for retroperitoneal space. Renal cell carcinoma is the most common tumor of the kidney., Case Presentation: Concurrent retroperitoneal liposarcoma and renal cell carcinoma were found in a 34-year-old Japanese man. The renal tumor was first detected by ultrasonography, it was confirmed by computed tomography, which also identified a presumptive retroperitoneal liposarcoma, and the tumors were further assessed with magnetic resonance imaging. The patient was treated by surgical resection of retroperitoneal liposarcoma and left nephrectomy and has been disease-free for 10 years., Conclusions: The concomitant occurrence of a renal tumor and a primary primary liposarcoma is rare. The major factors promoting a good prognosis in this case were the favorable histology and the small size of the tumors.

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., (Copyright 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Sarcomatoid renal cell carcinoma (SRCC) is associated with an aggressive course, high incidence of bone metastasis, and an extremely poor prognosis. There are a few case reports concerning the effectiveness of chemotherapy on metastasis in SRCC. To our knowledge, however, there are no reports describing its effectiveness on bone metastasis. We report a 22-year-old woman with an 8-cm x 7-cm left renal mass. Left nephrectomy was done. The pathological diagnosis was SRCC, INF-beta, pT3aN2. Although, she received continuous infusion of interferon alpha-2a (INFalpha-2a) and interleukin-2 (IL-2) as adjuvant therapy, liver metastasis appeared 2 months later. Resection of the liver metastasis was done. After resection of the metastasis, multiple bone metastases appeared, in both humeri, the left chest wall, the left fourth rib, and the left iliac bone. The patient was treated with gemcitabine, 1000 mg/m(2) (days 1, 8), docetaxel 80 mg/m(2) (day 1), and carboplatin 300 mg/m(2) (day 1). A computed tomography (CT) scan after the first cycle revealed that the multiple osteolytic bone tumors had significantly decreased in size. Her ability of daily life (ADL) improved and this continued for almost 2 months. A second course of chemotherapy, with gemcitabine and IL-2 was given, but it was ineffective, and the patient died approximately 16 months after the initial diagnosis of SRCC. Combination chemotherapy with gemcitabine, docetaxel, and carboplatin was effective for the bone metastasis of SRCC.

Background: The present study provides data from clinical experience with gamma-knife radiosurgery (GK) in patients with brain metastasis from renal cell carcinoma (RCC) and shows the value of this less invasive treatment modality., Methods: Forty-two patients received GK. Twenty of the 42 cases had multiple brain metastases. Extracranial metastases were observed in the lung (38 cases), bone (12 cases), liver (9 cases), lymph node (5 cases) and skin (6 cases)., Results: Neurological symptoms seen in 40 patients were rapidly improved after GK in 32 patients (80%). Magnetic resonance imaging (MRI) evaluation after GK in 32 patients showed the disappearance of brain tumor in 9 patients (28%). Complete response was obtained by GK in tumors up to 30 mm in diameter. Repeated GK for newly developed lesions was conducted in 11 patients. Extracranial tumor resection was conducted in 7 cases (lung: 3, skin: 2, liver: 1, adrenal: 1). Chemo-radiotherapy or immunotherapy was effective in 8 cases (lung: 5, liver: 2, bone: 1). The actual one-, two- and three-year survival rates were 44.9%, 16.8%, and 11.2%, respectively. The median survival time was 12.5 months. In univariate analysis, the patients with successfully treated extracranial metastases had significantly better prognosis. In multivariate analysis, the patients with Karnofsky performance scale (KPS) > or = 80%, who were treated by GK more than once and obtained complete response (CR) or partial response (PR) by GK, had significantly better prognosis., Conclusion: Gamma-knife radiosurgery for RCC is an effective non-invasive modality of treatment. It offers a high local control rate and an improved quality of life and survival rate.

Alteration of sialyltransferase expression has been implicated in carcinogenesis. Out of sialyltransferases cloned to date, we focused on ST3Gal IV expression in human renal cell carcinoma (RCC). Levels of ST3Gal IV mRNA were examined in human RCC in comparison with non-tumor kidney. ST3Gal IV cDNA obtained by polymerase chain reaction from cDNA library of human RCC cell line ACHN was identical to STZ in nucleotide sequence. Northern blot analysis was performed for 24 non-tumor kidney and 25 primary RCC tissues, and 5 metastases. ST3Gal IV mRNA level was decreased in 16 cases of 22 primary RCC tissues compared to 21 non-tumor kidney tissues. The mRNA level was low in 4 and equivocal in one, of 5 metastases. The 6 cases that possessed almost the same levels of ST3Gal IV mRNA in primary tumor tissues as those in non-tumor kidneys showed favorable prognoses, as assessed by Kaplan-Meier curve. These results indicate that down-regulation of ST3Gal IV mRNA may be one of the factors associated with the malignant progression of human RCC.

Background: The present study examined adrenal metastasis resulting from renal cell carcinoma (RCC), with the aim of assessing the need for routine ipsilateral adrenalectomy during radical nephrectomy., Methods: Ipsilateral and contralateral adrenal metastases were investigated in 256 patients with RCC who had undergone radical nephrectomy from 1977 to 1996 at the Tohoku University School of Medicine., Results: Twelve of the 256 patients (4.7%) had adrenal metastasis. Ten of these 12 patients had progressed to disseminated disease with very poor prognosis. Two patients who had solitary adrenal metastases remained disease-free for 21 and 7 years. Four patients showed metastases to the contralateral adrenal gland. Adrenal metastases in seven of 12 patients were identified by pre- or postoperative computed tomography (CT), and in another five macroscopically during surgery., Conclusions: Adrenalectomy was regarded as a possible curative treatment for patients with solitary adrenal metastasis. However, the incidence of this kind of metastasis was minimal and contralateral adrenal metastases may occur in RCC cases. We therefore believe that adrenalectomy should only be performed if radiographic evidence reveals metastases in the adrenal gland or if gross disease is present at the time of nephrectomy.

We have previously described the SART1 gene, which encodes both the SART1(259) antigen expressed in the cytosol of the majority of squamous cell carcinomas and some adenocarcinomas and the SART1(800) antigen expressed in the nucleus of the majority of proliferating cells. The SART1(259) antigen is recognized by HLA-A24 and A26-restricted cytotoxic T lymphocytes (CTLs). The present study investigated the expression of these two antigens in renal cell carcinomas (RCCs) in order to identify an appropriate molecule for use in specific immunotherapy for RCC patients. These two antigens were detected in all RCC cell lines and cells of the primary cultures of the RCCs tested. Further, they were detectable in cells of the primary cultures of non-tumorous kidney tissues. In contrast to these cultured cells, SART1(259) was detectable in only a few uncultured RCC tissues (5/20, 25%) and was undetectable in non-tumorous kidney tissues. SART1(800) was also scarcely detectable in uncultured RCC tissues (3/20, 15%) and non-tumorous kidney tissues (4/20, 20%). HLA-A2402-restricted and tumor-specific CTL (KE4-CTL) used for the cloning of the SART1 gene showed significant levels of cytotoxicity to both the cells from the RCC cell line and the cells from the primary cultures of RCC tissues, but did not lyse any normal cells, including cells from the primary cultures of non-tumorous kidney tissues. The SART1-derived peptide at positions 690-698 induced HLA-A24 restricted CTLs cytotoxic to RCC cells from peripheral blood mononuclear cells (PBMCs) of RCC patients. Therefore, the SART1 peptide could be an appropriate molecule for use in peptide-based specific immunotherapy for RCC patients.

Background: Pulmonary resection for metastatic renal cell carcinoma were studied to assess the indication of surgical management., Methods: Between January, 1981 and December 1994, 17 consecutive patients (14 men and 3 women) underwent complete pulmonary resection for metastatic renal carcinoma. Median age was 61 years (range, 45 to 73 years). Eleven were appeared lung metastasis after resection of primary tumor. Median time between nephrectomy and pulmonary resection was 32 months (range, 0 to 127 months)., Results: There were no operative deaths. One patient had solitary metastasis, 4 had two, 2 had three, 2 had four, one had seven, one had eight and 6 had more than twenty-two. Segmental resection was performed in 12 patients, lobectomy in 2, lobectomy and segmentectomy in 3 and segmentectomy for total lobes in 3. Four patients had another site operation of renal metastasis, brain tumor resection, chest wall and ribs resection, contra-lateral adrenalectomy and contralateral partial nephrectomy. Median follow-up was 44 months (range, 10 to 129 months). The cause specific survival rate and disease free survival after pulmonary resection was 55 and 48 percent at 5 years and 27 and 14 percent at 10 years, respectively., Conclusion: Pulmonary resection for metastatic renal cell carcinoma was considered effective in some selected slow-growing cases. Multiple and both lungs metastases is not contraindication and the patients under 10 metastatic focuses had good prognosis.

Twenty-nine cases of bone metastases from renal cell carcinoma were examined. Eight had metastatic bone pain as the initial symptom and were diagnosed that the primary lesion was in a kidney. In eight cases bone metastases appeared after treatment of the primary site. Seven had only bone metastases and another 22 cases had multiple metastases in organs such as the lung and lymph node when the bone metastasis was found. Curable surgical treatment was performed in only 2 cases. The survival curve of these patients were: 1 year; 41 per cent, 2 year; 30 per cent and 3 year; 15 per cent. Bone scan used for detection of bone metastases of carcinoma frequently ends with false positive results. CT scan and angiography are available for differential diagnosis of bone metastasis. We examined 6 cases (9 lesions) of bone metastases from renal cell carcinoma (3 pelvic bones, 2 lumbar bones, 2 femurs and 2 humerus). All lesions were hypervascular by angiography and were easily diagnosed as bone metastases. For early detection of bone metastases from renal cell carcinoma, angiography is useful because hypervascularity and tumor stain are easily detected even in such small lesions as 2 cm. Angiography was also useful for chemoembolization.