Multiple Renal Cell Carcinoma Research Articles

Pakartotinė inkstų navikų krioabliacija ir radijo dažnio abliacija esant vieninteliam inkstui: dviejų klinikinių atvejų aprašymas

Įžanga Perkutaninė inkstų navikų krioabliacija ir radijo dažnio abliacija yra minimaliai invazyvūs gydymo metodai, leidžiantys mak­simaliai išsaugoti inkstų funkciją. Jie vis dažniau naudojami pacientams, sergantiems sunkiomis gretutinėmis ligomis, esant daugybiniams inkstų navikams, pacientams, turintiems tik vieną inkstą ir (ar) turintiems didelį genetinį polinkį susiformuoti dauginiams inkstų navikams, ypač tais atvejais, kai labai svarbu išsaugoti inkstų funkciją. Straipsnyje siekta įvertinti šių mini­maliai invazyvių gydymo metodųnaudą (efektyvumą ir saugumą) pacientams, turintiems vienintelį inkstą. Klinikiniai atvejai Aprašome ir aptariame du klinikinius atvejus pacientų, kuriems buvo diagnozuoti maži inkstųnavikai (<4 cm) vieninteliame likusiame inkste ir kurie buvo pakartotinai gydyti krioabliacijos bei radijo dažnio abliacijos metodais Nacionaliniame vėžio institute. Kontrolinė kompiuterinė tomografija buvo atlikta kitą dieną po procedūros, po 3, 6 ir 12 mėnesių po procedūros ir toliau kas 6 mėnesius, kartu buvo atliekamas fizinis ištyrimas, šlapimo tyrimas ir nustatoma kreatinino koncentracija se­rume. Abu pacientai inkstų navikų krioabliaciją ir radijo dažnio abliaciją toleravo gerai, pooperacinių komplikacijų, ryškesnių inkstų funkcijos pokyčių nebuvo. Serumo kreatinino koncentracija mažai skyrėsi nuo priešoperacinių verčių. Abiem ligoniams pasiekta visiška / radikali naviko abliacija po vienos gydymo procedūros. Išvada Nors neįmanoma daryti tikslių galutinių išvadų apie navikų vieninteliame inkste gydymo minimaliai invaziniais metodais veiksmingumą ir saugumą tik iš dviejų sėkmingų atvejų, tačiau jie parodo, jog inkstų navikų krioabliacija ir radijo dažnio abli­acija leidžia minimaliai invazyviu būdu gydyti inkstų navikus ir siekti gerų onkologinių rezultatų.

Over-expression of DNA-PKcs in renal cell carcinoma regulates mTORC2 activation, HIF-2α expression and cell proliferation.

Here, we demonstrated that DNA-PKcs is over-expressed in multiple human renal cell carcinoma (RCC) tissues and in primary/established human RCCs. Pharmacological or genetic inhibition of DNA-PKcs suppressed proliferation of RCC cells. DNA-PKcs was in the complex of mTOR and SIN1, mediating mTORC2 activation and HIF-2α expression in RCC cells. Inhibiting or silencing DNA-PKcs suppressed AKT Ser-473 phosphorylation and HIF-2α expression. In vivo, DNA-PKcs knockdown or oral administration of the DNA-PKcs inhibitor NU-7441 inhibited AKT Ser-473 phosphorylation, HIF-2α expression and 786-0 RCC xenograft growth in nude mice. We showed that miRNA-101 level was decreased in RCC tissues/cells, which could be responsible for DNA-PKcs overexpression and DNA-PKcs mediated oncogenic actions in RCC cells. We show that DNA-PKcs over-expression regulates mTORC2-AKT activation, HIF-2α expression and RCC cell proliferation.

Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.

Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10−7). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.

AB243. Deep sequencing reveals intensive interindividual and intraindividual heterogeneity in TCR-beta repertoire across multiple renal cell carcinoma subtypes

BackgroundTumor immunogenicity has been proved to have an essential role in tumor development and metastasis. Cancer cell recognition of T cells can be potentially utilized in tumor prognosis and immunotherapy. However, the understanding of immune responses and T cell receptor (TCR) repertoires in many types of tumor is yet to be complete. Our aim was to explore the TCR beta-chain (TCRb) heterogeneity across renal cell carcinoma (RCC) patients, as well as the TCRb heterogeneity between tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs).MethodsTumor and blood samples of thirty-nine treatment-naïve RCC patients, and blood samples of two renal neoplasm patients and ten healthy volunteers were obtained. Genomic DNA was extracted from the frozen tumor tissues and the isolated PBMCs. To prepare the TCRb library, primers were designed to amplify the CDR3 region of the TCRb gene for the followed high-throughput sequencing. The sequencing data was analyzed by an in-house immune repertoire analyzing pipeline, including Shannon diversity, clonotype abundance, pair-wise overlap and distance, and other analyses.ResultsTCRb repertoires in the RCC tumor tissues have lower diversity compared to the RCC PBMC samples while the TCRb repertoires in the non-carcinoma PBMC samples possess the highest diversity among them. The abundance of highly expressed clonotypes (HECs) in the RCC tumor samples is higher than the HECs in the RCC PBMC samples, whereas the abundance of HECs in the non-carcinoma PBMC samples was the lowest. The pair-wise distance data generated by comparing the overlap of any two included samples suggest that TCRb repertoires in RCC do not produce distinguishable pattern across pathologically classified subtypes. The comparison of two cladograms generated from the pair-wise distances with or without the HECs suggests that HEC was a major contributor to the intraindividual difference in TCRb repertoires between TILs and PBMCs.ConclusionsIntensive interindividual and intraindividual heterogeneity in TCRb repertoire across multiple RCC subtypes can be observed in the aspect of diversity, abundance of HECs, and pair-wise distance; the intraindividual heterogeneity in RCC is mainly contributed by HECs.

Fluorescent and chromogenic in situ hybridization of CEN17q as a potent useful diagnostic marker for Birt-Hogg-Dubé syndrome–associated chromophobe renal cell carcinomas

Birt-Hogg-Dubé syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82, and Ksp-cadherin similar to their sporadic counterparts. Highly reliable markers for BHD-associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs, and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm. All chromophobe RCCs and HOCTs were disomic except for 1 chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic (P = .0008). The state of chromosomes 2 and 6 were also statistically different (P = .0074 and P = .0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that fluorescent and chromogenic in situ hybridization of the centromeric region of chromosome 17 long arm should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing.

Pattern of recurrence after partial and total nephrectomy in non-metastatic renal cell carcinoma (RCC) of low, intermediate and high risk: Implications for follow-up.

601 Background: Guidelines recommend risk-adapted follow-up (FUP) after (partial) nephrectomy in non-metastatic RCC. VEGF-targeted therapy does not cure multiple metastatic RCC. FUP should therefore focus on local recurrences or single-/-oligometastases that may potentially be cured by local therapy. The rate of potentially curable recurrences per risk group is unknown and their pattern and management were analyzed in this study. Methods: From an IRB approved database non-metastatic RCC patients who underwent (partial) nephrectomy from 2004 to 2011 with a minimum FUP of ≥4 years and regular cross-sectional imaging were identified. Risk stratification was assigned to Leibovich- (clear-cell ) or UICC-stage- (non-clear cell) risk groups . Local recurrence, solitary and oligometastases defined as < 3 lesions at a single site were considered potentially curable by local therapy modalities. Recurrences were recorded as was the time to detection of recurrence (TDR) and their management. Results: From 230 patients identified, 191 (clear-cell) and 39 (non-clear cell) were assigned to the Leibovich- or UICC-risk groups respectively. Together, 69 developed recurrences (30 %), of whom 29 (42 %) were potentially curable. Of low-risk patients (32.6 %), only 9 (12 %) had recurrences of which 5 (55.6 %) were potentially curable. In high-risk (19.1 %), of 26 (59.1%) recurrences, the majority were multiple and rapid at a median TDR of 8.4 months (IQR 13.7) with only 6 (23.1 %) potentially curable at a median TDR of 17.6 (IQR 53.8) months. Of 24 recurrences (33.8 %) in intermediate risk, 12 (50 %) potentially curable lesions were detected after a median TDR of 26 (IQR 36.2) months. Together, of 29 potentially curable lesions 15 (51.7 %) were not treated because of comorbidity, poor performance or prognosis and irresectability. Conclusions: High-risk patients predominantly develop multiple metastases early during FUP. A benefit of FUP might derive from identifying potentially curable lesions which develop with latency especially in intermediate and high risk. With only 48 % of potentially curable lesions treated locally the impact of FUP on OS remains controversial.

AB205. Deep sequencing reveals intensive interindividual and intraindividual heterogeneity in TCR-beta repertoire across multiple renal cell carcinoma subtypes

ObjectiveTumor immunogenicity has been proved to have an essential role in tumor development and metastasis. Cancer cell recognition of T cells can be potentially utilized in tumor prognosis and immunotherapy. However, the understanding of immune responses and T cell receptor (TCR) repertoires in many types of tumor is yet to be complete. Our aim was to explore the TCR beta-chain (TCRb) heterogeneity across renal cell carcinoma (RCC) patients, as well as the TCRb heterogeneity between tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs).MethodsTumor and blood samples of thirty-nine treatment-naïve RCC patients, and blood samples of two renal neoplasm patients and ten healthy volunteers were obtained. Genomic DNA was extracted from the frozen tumor tissues and the isolated PBMCs. To prepare the TCRb library, primers were designed to amplify the CDR3 region of the TCRb gene for the followed high-throughput sequencing. The sequencing data was analyzed by an in-house immune repertoire analyzing pipeline, including Shannon diversity, clonotype abundance, pair-wise overlap and distance, and other analyses.ResultsTCRb repertoires in the RCC tumor tissues have lower diversity compared to the RCC PBMC samples while the TCRb repertoires in the non-carcinoma PBMC samples possess the highest diversity among them. The abundance of highly expressed clonotypes (HECs) in the RCC tumor samples is higher than the HECs in the RCC PBMC samples, whereas the abundance of HECs in the non-carcinoma PBMC samples was the lowest. The pair-wise distance data generated by comparing the overlap of any two included samples suggest that TCRb repertoires in RCC do not produce distinguishable pattern across pathologically classified subtypes. The comparison of two cladograms generated from the pair-wise distances with or without the HECs suggests that HEC was a major contributor to the intraindividual difference in TCRb repertoires between TILs and PBMCs.ConclusionsIntensive interindividual and intraindividual heterogeneity in TCRb repertoire across multiple RCC subtypes can be observed in the aspect of diversity, abundance of HECs, and pair-wise distance; the intraindividual heterogeneity in RCC is mainly contributed by HECs.

Percutaneous Cryoablation for Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. Nephron sparing resection (partial nephrectomy) has been the “gold standard” for the treatment of resectable disease. With the widespread use of cross sectional imaging techniques, more cases of renal cell cancers are detected at an early stage, i.e. stage 1A or 1B. This has provided an impetus for expanding the nephron sparing options and especially, percutaneous ablative techniques. Percutaneous ablation for RCC is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection or when there is a need to preserve renal function due to comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. During the last few years, percutaneous cryoablation has been gaining acceptance as a curative treatment option for small renal cancers. Clinical studies to date indicate that cryoablation is a safe and effective therapeutic method with acceptable short and long term outcomes and with a low risk, in the appropriate setting. In addition it seems to offer some advantages over radio frequency ablation (RFA) and other thermal ablation techniques for renal masses.

Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome.

Birt–Hogg–Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell carcinomas (RCC). Diagnostic markers that distinguish between FLCN-related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non-metastatic B (GPNMB) between FLCN-related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT-PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN-related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN-related RCCs was 23-fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work-up for BHD.

Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN-associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp-cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA-IX. All clear cell RCCs were positively stained for CA-IX and negative for CK7. These data confirmed that mutant FLCN-associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp-cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri-nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA-IX, Ksp-cadherin, CD82 and CK7.

Case of Successful Radiofrequency Ablation of Multiple Bilateral Renal Cell Carcinomas in von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome that manifests as a variety of benign and malignant tumors in various organs. Notably, renal cell carcinoma (RCC) in patients with VHL disease tends to be multifocal and bilateral, and tends to recur or new tumors develop after removal. Radiofrequency ablation (RFA) has recently been introduced as a minimally invasive treatment for small hereditary RCCs with a low complication rate and a minimal decrease in renal function. We present a case of successful RFA of multiple bilateral RCCs in a 24-year-old female with VHL. Computed tomography (CT) of the abdomen revealed multiple bilateral RCCs. The patient received sequential RFA for the bilateral RCCs, resulting in a complete response. At the time of writing, there was no sign of recurrence or renal failure. In conclusion, percutaneous RFA is a promising treatment for VHL patients who cannot undergo surgery, with excellent treatment outcomes and minimal change in renal function. (Korean J Med 2014;87:603-608)

Comparison of Contrast-Enhanced Ultrasound Scan (CEUS) and MRI in the follow-up of cryoablation for small renal tumors. Experience on 25 cases

Percutaneous ablation in the kidney is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection. Its increasing use has been largely prompted by the rising incidental detection of renal cell carcinomas with cross-sectional imaging and the need to preserve renal function in patients with comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. To date, clinical studies indicate that cryoablation is an effective therapy with acceptable short- to intermediate-term outcomes and with a low risk in the appropriate setting. This article focuses on the efficiency of contrast enhanced ultrasound scan (CEUS) as compared to contrast enhanced magnetic resonance imaging (MRI) during the follow-up after cryoablation of small renal tumors. In our Department, percutaneous or laparoscopic assisted cryoablation is offered in the treatment of small renal masses. Between January 2009 and January 2013, 25 patients (pts) were treated with laparoscopic assisted cryoablation or percutaneous cryoablation for renal tumors <3.5 cm in pts unfit for surgery. All pts had severe comorbidities (ASA score 3). Transperitoneal laparoscopic approach was performed in 11 pts, extraperitoneal approach in 3 pts, percutaneous technique was performed in 11 patients. "Tru-cut biopsy" of the renal mass was always performed before cryoablation. The SeedNet system (Galil Medical, Arden Hills, MN) was used in 12/25 pts; the Precise system (Galil Medical, Arden Hills, MN) was used in 13/25 pts. In all cases, IceRod needles were used. Real-time ultrasound guidance was used to localize the tumour and to monitor the progression of "iceball". A double "freeze-thaw cycle" was used. All pts had MRI and CEUS before cryoablation and the follow-up consisted in CEUS/MRI every 3 months during the first year and every 6 months thereafter. The mean age of the 25 pts was 67.7 years (range 56-79); 5 pts were females and 20 were males. The mean tumor size was 2.8 cm (range 1.5-3.5). No patient required conversion to open procedure. 19 tumors were located at the lower pole, 4 were interpolar and 2 tumors were located at the upper pole. There were no intraoperative complications. The mean hospital stay was 4 days (range 1-7). Two pts required a blood transfusion; there was no statistically significant difference between preoperative and postoperative serum creatinine levels. The biopsy showed RCC in all cases. In 24/25 patients both CEUS and MRI showed no enhancement. In 1/25 pts, during the follow-up, CEUS and MRI showed a well visible recurrence at the perfusion study. It was histologically confirmed. The final results of CEUS and MRI were concordant in all pts. CEUS is effective during the follow-up of renal tumor cryoablation. It could be an alternative technique to standard CT and MRI, with some advantages: low cost, short time consuming procedure, no radiation exposure, reduced amount of contrast agent (1-2 mL) and rare adverse reactions.

A Case of Multiple Metastatic Renal Cell Carcinoma Detected by a Tumor of the Upper Gingiva, and a Review of the Literature

Oral metastasis of renal cell carcinoma is rare. We report a case of renal cell carcinoma with multiple metastases that initially presented as a tumor of the upper gingiva. The patient was a 66-year-old man who visited our department because of a swelling of the upper anterior gingiva. Biopsy was performed, and gingival metastasis from renal cell carcinoma was strongly suspected on histopathological examination. Computed tomography (CT) demonstrated a large mass of the right kidney and multiple metastases of the lungs. Renal cell carcinoma with metastases to the lungs and upper gingiva was diagnosed. Resection of the gingival tumor was performed because of its rapid growth and difficulties in eating. Nephrectomy was performed at the same time. The patient then underwent administration of sunitinib. Finally, he died of pulmonary metastasis at 7 months after the surgery. However, surgical resection of gingival metastasis and dentures for the resected part are useful for improving patients' quality of life. We reviewed the literature on oral-region metastasis of renal cell carcinoma, and found 29 cases reported in Japan.

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with ‘capsulomas’ without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt-Hogg-Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small-sized capsular angiomyolipomas known as 'capsulomas' in a 39-year-old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and 'capsulomas' developing in a patient without genetic features, having potential for novel genetic variation.

Cryoablation versus Radiofrequency Ablation for Renal Tumor Ablation: Time to Reassess?

Of the widely available methods for renal tumor ablation, cryoablation was the first to be assessed in the treatment of renal cell carcinoma (RCC) by using open surgical approaches. Open surgical access was necessary because early cryoprobes were too large for percutaneous application. Initial evaluation of percutaneous approaches to renal tumor ablation in humans included a “treat-and-resect” case reported by Zlotta et al (1) in 1997 and the first case with ablation as the sole planned treatment reported by McGovern et al (2) in 1999. With the advent of percutaneous needle applicators, renal tumor ablation moved to interventional radiology suites with ultrasound (US), computed tomography, and, in some cases, magnetic resonance imaging guidance. With percutaneous cryoprobes available shortly thereafter, the next several years saw expansion of the use of percutaneous image-guided radiofrequency (RF) ablation and cryoablation of renal tumors. Most recently, newer modalities such as microwave (MW) ablation and irreversible electroporation (IRE) have been assessed, and even promoted by some, to treat small tumors. The appeal of percutaneous needle applicators for tumor ablation was the avoidance of surgery in selected patients. Indications for renal tumor ablation include advanced age, multiple comorbid conditions, solitary kidneys, familial syndromes, or multiple sporadic RCC. Early experience with small tumors showed a high technical effectiveness rate with a low recurrence rate over short follow-up intervals (3–5). These early successes led to growing enthusiasm for its use in growing numbers of patients, as documented by a Surveillance, Epidemiology, and End Results database trend evaluation comparing the

Multiple metastatic renal cell carcinoma treated with cytoreductive nephrectomy after neoadjuvant Sunitinib therapy: a case report and literature review

Objective To report a multiple metastatic renal cell carcinoma (RCC) case successfully treated with cytoreductive nephrectomy after neoadjuvant Sunitinib,and discuss the efficacy and treatment regime of neoadjuvant targeting therapy.Methods A 51 years man presented with painless gross hematuria for one week and admitted into our hospital in August 2010.Abdominal CT demonstrated a 6.6 cm ×6.3 cm left lower pole renal tumor associated with renal vein tumor thrombus,bulky hilar lymph nodes and extensive local invasion.The patient was also found to have lung and right tibial metastasis.The clinical stage was T3bN1 M1.Percutaneous biopsy confirmed clear cell renal carcinoma.Neoadjuvant Sunitinib 50 mg daily was administered with 4 weeks on,2 weeks off schedule for two cycles.Cytoreductive nephrectomy was preformed 2 weeks after discontinuation of neoadjuvant Sunitinib.Imaging evaluation was performed to assess the primary tumor and metastatic sites.The patient was followed up till present.Results After two cycles of neoadjuvant treatment,CT scan revealed 23％ size reduction of left renal tumor to 5.1 cm ×4.4 cm,renal vein tumor thrombus regression,local perirenal invasion improvement,lung metastasis resolution and static right tibial metastasis.According to RECIST criteria,the objective response was stabilization of disease (SD).Cytoreductive nephrectomy was successfully performed to remove the primary tumor in December 2010.Pathology revealed Fuhrman Ⅱ renal cell carcinoma with major necrosis in primary tumor and thrombus localized in renal vein.During 6 months of post-operative follow-up,there was no local recurrence,lung metastasis had vanished completely and tibial metastasis had not progressed.Local recurrence and other distant metastasis were not demonstrated in 20mon follow-up till now.Disease control of this patient was partial response (PR) by RECIST.Conclusions Neoadjuvant Sunitinib treatment could result in downstaging of primary tumor and facilitate cytoreductive nephrectomy,thus eventually increase patient overall survival. Key words: Metastatic renal cell carcinoma; Neoadjuvant therapy; Sunitinib; Cytoreductive nephrectomy

Distinctive Features of the Differentiated Phenotype and Infiltration of Tumor-Reactive Lymphocytes in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (RCC) is considered an immunogenic tumor, but it has been difficult to identify tumor-infiltrating lymphocytes (TIL) that show in vitro tumor recognition. We compared the characteristics of fresh RCC TIL to peripheral blood lymphocytes (PBL) or melanoma TIL. Our results showed that RCC TIL contained fewer CD27(+) T cells, and fewer naïve and central memory (CM) T cells, but more effector memory (EM) T cells than melanoma TIL or renal PBL. We hypothesized that factors in the RCC microenvironment were skewing TIL phenotype toward EM. One possibility was the expression of CD70 on nearly all human RCCs, but not melanomas. Differentiation of naïve T cells to EM cells only occurred from CD70 costimulation in concert with T-cell receptor (TCR) stimulation (signal one), suggesting that EM TIL responding to CD70 would be enriched for T cells reactive with local antigens, including those associated with RCC. Clonotypic analysis of TCRs in fresh RCCs showed that EM T cells were more clonally expanded than CM or naïve T cells, and the clonal expansion occurred at the tumor site as oligoclonal TCRs were distinct from PBL TCRs from the same patient. In addition, we found that 2 TCRs from the highly represented EM TIL clones, when reexpressed in fresh PBL, recognized an MHC-class II or MHC-class I-restricted antigens shared by multiple RCC lines. Our results suggest that RCC-reactive TIL do exist in situ, but may be difficult to recover and study because of proliferative exhaustion, driven by tumor-expressed CD70.

Synchronous Occurrence of Papillary Urothelial Carcinoma, Cystic Clear Cell Carcinoma, Multiple Papillary Renal Cell Carcinomas of Unknown Malignant Potential and Multiple Cortical Cysts in Same Kidney: A Rare Case Report

Synchronous Occurrence of Papillary Urothelial Carcinoma, Cystic Clear Cell Carcinoma, Multiple Papillary Renal Cell Carcinomas of Unknown Malignant Potential and Multiple Cortical Cysts in Same Kidney: A Rare Case Report

Synchronous Occurrence of Papillary Urothelial Carcinoma, Cystic Clear Cell Carcinoma, Multiple Papillary Renal Cell Carcinomas of Unknown Malignant Potential and Multiple Cortical Cysts in Same Kidney: A Rare Case Report

Synchronous Occurrence of Papillary Urothelial Carcinoma, Cystic Clear Cell Carcinoma, Multiple Papillary Renal Cell Carcinomas of Unknown Malignant Potential and Multiple Cortical Cysts in Same Kidney: A Rare Case Report

498P - First-In-Human Phase I Administration of YS110, A Humanized Monoclonal Antibody Directed Against the CD26 Molecule in Cancer Patients

ABSTRACT Background YS110 is a recombinant humanized IgG1 monoclonal antibody that selectively binds with high affinity to the extracellular domain of the CD26 antigen. CD26, a widely distributed 110-kDa transmembrane glycoprotein with intrinsic DPPIV activity and its truncated soluble form (sCD26/DPPIV) also present in serum and fluids, is known to play an important role in tumor biology. CD26 is frequently highly expressed on multiple cancer cell types, especially mesothelioma and renal cell carcinoma (RCC). In addition to its role in proteolysis via the DPPIV activity, CD26 also acts as a receptor involved in T-cell co-stimulation and immune regulation. Preclinical evaluations of YS110 have demonstrated anti-tumor effects in cancer cell lines and xenografts expressing the CD26 antigen without significant side effects in toxicology studies (up to 100 mg/kg as single dose or 30 mg/kg for 5 weekly doses in cynomolgus monkeys). Phase I design and endpoints The ongoing YSCMA-EU-0001 trial is a Phase I/II study of YS110 escalating dose administered intravenously once every 2 weeks for 3 doses (Days 1, 15, 29). Patients must have progressive locally advanced inoperable and/or metastatic histologically confirmed solid tumors, refractory to prior standard therapies, with confirmed CD26+ tumor expression (≥ 20% of the tumor cells by central IHC evaluation). The primary endpoint is to determine the Maximum Tolerated Dose/Recommended Dose of YS110 and the pattern of DLTs. Secondary endpoints are the determination of the PK/PD parameters (i.e. analysis of cytokine release, immunophenotyping, circulating DPPIV activity and sCD26 antigen level). Preliminary antitumor efficacy is evaluated by RECIST1.1 criteria at Day 43. Patients demonstrating objective response or stable disease receive additional treatment cycles. Status of the study As of May 1st 2012, 22 patients (13 mesothelioma, 9 RCC) have been treated with 3 bi-weekly infusions over 29 days at 0.1, 0.4, 1 and 2 mg/kg. Based on PK data for them, the next cohort of 3 patients will be dosed at 2 mg/kg with weekly infusions over 29 days starting in May 2012. Safety, PK/PD, and preliminary efficacy data will be presented. Disclosure T. Podoll: Compensated employment position : President of Y\\'s Therapeutics Compensated Consultant role. I. Miyashita: Compensated Employment role: Director Kissei Pharmaceuticals Co, Ltd. Y. Kaneko: Compensated employment role : managing board of directors Y's AC Stock ownership: Y's AC. C. Morimoto: Compensated Consultant role : Kissei Pharmaceuticals Co, Ltd Stock ownership: Y's Therapeutics Honororia: Kissei Pharmaceuticals Co, Ltd Research funding: Y's Therapeutics. All other authors have declared no conflicts of interest.