Primary Renal Tumors Research Articles

Right side splenorenal fusion with marked extramedullary hematopoiesis, a case report

Developmental abnormalities of the spleen are common, much less common is splenic fusion abnormality. It may present as a renal mass sometimes with symptoms of hypersplenism (anemia) or as a renal mass only, mimicking primary or secondary renal neoplasms on imaging studies. Its documented that occurred on the right side which is significant that provides evidence for the possible migration of spleen cells in embryogenesis as an explanation for some other splenic fusion anomalies.We report a case of splenorenal fusion in a 5-year old girl with only right functional kidney who initially presented with a large renal mass which mimicked a primary renal neoplasm with no history of splenic trauma or splenectomy in past medical history. Also, the child didn't present with symptoms of hypersplenism. The child underwent right nephrectomy for a renal mass that was subsequently confirmed as right splenorenal fusion pathologically.

Case: Secondary polycythemia due to pazopanib in patients with metastatic renal cell carcinoma.

Clear-cell renal cell carcinoma (RCC) is the most common primary malignant renal neoplasm. Up to 30% of patients have metastatic disease at the time of initial diagnosis.1 Small molecule inhibitors of vascular endothelial growth factor receptor tyrosine kinase (VEGFR TKIs) are used as first-line treatment for most patients with incurable RCC. Pazopanib is a TKI inhibiting VEGFR,1-3 as well as plateletderived growth factor receptors (PDGFRs) α and β and stem cell receptor c-kit. The most common side effects of pazopanib are diarrhea, hypertension, changes in hair colour, anorexia, nausea, and vomiting. Severe hepatic toxicity is the adverse effect of greatest concern,but is uncommon. Myelosuppressive effects are also noted, such as anemia, thrombocytopenia, and leukopenia, and are presumably mediated through c-kit inhibition. Erythrocytosis is a wellrecognized paraneoplastic syndrome associated with RCC; however, erythrocytosis due to pazopanib therapy has only recently been described. We report two cases and review of the literature related to this phenomenon.

Cromófobo Renal Gigante

O carcinoma de células renais cromófobo é uma entidade histológica rara de carcinoma de células renais. Descreve-se um caso invulgar, de apresentação clínica invulgar, num homem de 50 anos, assintomático. Trata-se de uma massa renal de grandes dimensões (224 x 180 mm) à direita, sem lesões secundárias associadas.O doente não apresentava sintomas, como dor lombar ou abdominal, ou hematúria, referindo apenas discreto aumento do volume abdominal.O achado foi ecográfico em exames de rotina. O diagnóstico de presunção em imagem de tomografia computorizada foi de tumor renal primário. Realizou-se nefrectomia radical que decorreu sem intercorrências assim como o pós-operatório. O resultado histológico foi de carcinoma de células renais, variante cromófoba.Apesar das dimensões da lesão, existem casos, incluindo o atual, que têm evolução favorável e onde a indicação para a nefrectomia radical é o tratamento de eleição.

Outcomes After Cryoablation Versus Partial Nephrectomy for Sporadic Renal Tumors in a Solitary Kidney: A Propensity Score Analysis

BackgroundWhile partial nephrectomy (PN) is considered the standard approach for a tumor in a solitary kidney, percutaneous cryoablation (PCA) is emerging as an alternative nephron-sparing option. ObjectiveTo compare outcomes between PCA and PN for tumors in a solitary kidney. Design, setting, and participantsPatients who underwent PCA or PN between 2005 and 2015 for a single primary renal tumor in a solitary kidney were identified using Mayo Clinic Registries. Exclusion criteria were inherited tumor syndromes and salvage procedures. InterventionPCA and PN. Outcome measurements and statistical analysisTo achieve balance in baseline characteristics, we used inverse probability of treatment weighting (IPTW) based on propensity to receive treatment. The risk of having a post-treatment complication and percent drop in estimated glomerular filtration rate (eGFR), as well as the risks of local/ipsilateral recurrence, distant metastasis, and cancer-specific mortality, were compared between groups using logistic, linear, and Fine-and-Gray competing risk regression models. Results and limitationsThe cohort included 118 patients (PCA: 54; PN: 64) with a median follow-up of 47 mo (interquartile range 18, 74). In unadjusted analyses, PCA was associated with a lower risk of complications (15% vs 31%; odds ratio [OR]=0.38; 95% confidence interval [CI] 0.15, 0.96; p=0.04). However, upon accounting for baseline differences with IPTW adjustment, there was no longer a significant difference in the risk of complications (28% vs 29%; OR=0.95; 95% CI 0.53, 1.69; p=0.9). There were no significant differences between PCA and PN in percentage drop in eGFR at discharge (mean: 11% vs 16%; β=–5%; 95% CI –13, 3; p=0.2) or at 3 mo (12% vs 9%; β=3%; 95% CI –3, 10; p=0.3). Likewise, no significant differences were noted in local recurrence (HR=0.87; 95% CI 0.38, 1.98; p=0.7), distant metastases (HR=0.60; 95% CI 0.30, 1.20; p=0.2), or cancer-specific mortality (HR=1.13; 95% CI 0.32, 3.98; p=0.8). Limitations include the sample size, given the relative rarity of renal masses in solitary kidneys. ConclusionsOur study found no significant difference in complications, renal function outcomes, and oncologic outcomes between PN and PCA for patients with a tumor in a solitary kidney. Validation in a larger multi-institutional analysis may be warranted. Patient summaryPartial nephrectomy (surgery) and percutaneous cryoablation are both options for treating a kidney tumor while preserving the normal portion of the kidney. In patients with a tumor in their only kidney, we found no difference in the risk of complications, kidney function outcomes, or cancer control outcomes between these two approaches.

A Prospective, Phase 1 Dose-Escalation Trial of Stereotactic Ablative Radiation Therapy As an Alternative to Cytoreductive Nephrectomy for Primary Renal Tumors in the Setting of Metastatic Renal Cell Carcinoma

A Prospective, Phase 1 Dose-Escalation Trial of Stereotactic Ablative Radiation Therapy As an Alternative to Cytoreductive Nephrectomy for Primary Renal Tumors in the Setting of Metastatic Renal Cell Carcinoma

Abstract 491: Elucidating de novo PATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma

Abstract Palindromic AT-Rich Repeat (PATRR) - mediated translocations entail exchange across chromosomes at sites enriched in palindromic repeats of the nucleotides adenine (A) and thymine (T). Their precise embryologic origin and associated pathobiology with clear cell renal cell carcinoma (ccRCC) remain incompletely described. In the present study we document an individual with familial non-VHL ccRCC (7 primary renal tumors) who harbors a germline de novo PATRR mediated balanced translocation involving chromosomes 3 and 8 [t(3;8)] validated by spectral karyotyping (SKY). Using translocation specific PCR and DNA sequencing we determined the chromosome 3 breakpoint to be located in an AT-rich palindromic sequence in the third intron of the FHIT gene (chr3p14.2) and the chromosome 8 breakpoint in the first intron of the TRC8 gene (chr8q24.1). Genotyping analysis, using a high density custom exomechip array by Illumina, revealed a loss of the entire aberrant chromosome 8 carrying the 3p segment [der(8)] in all renal tumors tested. We also determined that the [46, XY, t(3;8), (p14.2, q24.1)] translocation was paternally derived by performing a genotypic assessment of the regions that differ between the parental alleles and then establishing which haplotypes are associated with the translocation. The somatic mutational landscape was assessed by Whole Exome sequencing of the renal tumors and the proband’s germline DNA. No germline or somatic deleterious mutations were detected in VHL gene suggesting that the ccRCC phenotype is not associated with Von Hippel-Lindau disease. Furthermore, we measured the transcriptomic profiles of the renal tumors and matched normal tissues employing barcoded probe hybridization technology (NanoString) and RNASeq to fully characterize differential gene expression and define gene ontology networks that are dysregulated. Most significantly, no difference in expression of the VHL gene was detected between tumors and normal counterparts. Aberrant regulation was detected in members of WNT signaling pathway, TGF-beta and MAPK pathways, in addition to NOTCH signaling pathway genes and members of the VEGF family. In summary, in this study we employed advanced genomic and transcriptomic techniques, to delineate the embryologic origin and deleterious biological consequences of the PATRR-mediated t(3;8) balanced translocation associated with clear cell renal cell carcinoma. Citation Format: Marilena Melas, Kevin J. McDonnell, Christopher K. Edlund, Sarah J. Tash, Duveen Y. Sturgeon, Chenxu Qu, Charalampos Lazaris, Peter J. Gruber, Thomas W. Glover, Beverly S. Emanuel, Stephen B. Gruber. Elucidating de novo PATRR-mediated t(3;8) balanced translocation and clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2017-491

Early primary renal tumor response predicts clinical outcome in patients with primary unresectable renal cell carcinoma with synchronous distant metastasis receiving molecularly targeted therapies.

The aim of the present study was to investigate the prognostic factors for patients with primary unresectable renal cell carcinoma (RCC) with synchronous distant metastasis receiving molecularly targeted therapies. A total of 26 patients with primary unresectable RCC with synchronous distant metastasis underwent molecularly targeted therapies at the Kurume University Hospital (Kurume, Japan) between March 2008 and March 2016. Early primary renal tumor response was evaluated at 8-12 weeks after the introduction of molecularly targeted therapy and a 10% decrease in the diameter of primary renal tumor was used as the cut-off value. The median overall survival from the initiation of first-line molecularly targeted therapy was 18.3 months. Univariate analyses for various factors identified early primary renal tumor response (P=0.0004) and best response to first-line treatment (P=0.0002) as prognostic variables. Multivariate analyses also identified early primary renal tumor response (P=0.0099) and best response to first-line treatment (P=0.0054) as independent prognostic factors. A comparison of clinical characteristics between the group with ≥10% shrinkage and the group with disease progression or <10% shrinkage revealed that the number of metastatic sites and pretreatment monocyte-to-lymphocyte ratio tended to be predictive factors for primary renal tumor response. These results suggest that early primary renal tumor shrinkage is highly variable for patients with primary unresectable RCC with synchronous distant metastasis receiving molecularly targeted therapies.

Initial computed tomography imaging details during first-line systemic therapy is of significant prognostic value in patients with naïve, unresectable metastatic renal cell carcinoma.

PurposeWe aimed to determine the prognostic significance of computed tomography imaging parameters of unresectable primary renal tumor lesions, obtained at baseline and at first follow-up, on overall survival in naïve, unresectable metastatic renal cell carcinoma patients during first-line systemic therapy.Materials and methodsClinicopathological parameters of 56 patients treated between 2007 and 2015, including imaging parameters (such as the longest tumor diameter, necrotic area diameter, and attenuation in primary renal tumor lesions on baseline vs. follow-up computed tomography), were retrospectively reviewed to derive predictive factors of overall survival. The best overall response was measured according to the RECIST v1.1.ResultsThe median treatment period was 206.3 days and the median follow-up was 14.6 months. Forty-four (78.6%) patients progressed after a median 4.6 months of progression-free survival, and 6 (10.7%) patients survived with a median overall survival of 12.5 months. Multivariate analysis showed that the baseline tumor diameter (hazard ratio [HR] 0.903) and mean attenuation (HR 0.936), change of tumor diameter (HR 0.714) and necrosis diameter (HR 0.861), change in the percentage of tumor diameter (HR 1.483) and of necrosis diameter (HR 1.028) between baseline and follow-up computed tomography images; treatment duration (HR 0.986) and baseline serum hemoglobin (HR 1.790) and albumin level (HR 0.060) were significant factors for overall survival (p<0.05).ConclusionThe study showed that baseline and first follow-up computed tomography findings of primary renal lesions during first-line systemic therapy are useful and significant predictors of OS in patients with naïve unresectable mRCC.

Understanding the effects of a calorie restriction mimetic on renal cancer progression and CD8 T cell immunity

Abstract Metastatic renal cell carcinoma (RCC) exhibits high mortality rates and chemotherapeutic resistance. Immune-based therapies, including high-dose IL-2 and anti-PD1, are efficacious in ~20% of patients; however, both are associated with substantial toxicity. This highlights the need for additional research aimed at improving response rates while also limiting toxicity. Previous findings by other groups have demonstrated that nutrient deprivation prior to chemotherapy reduces treatment toxicity and may improve therapeutic efficacy in cancer patients. Recent murine research shows that diets containing calorie restriction mimetics (CRMs) can recapitulate these beneficial effects by enhancing anti-cancer immunity. Here, we examined the impact of the alpha-glucosidase inhibitor acarbose, a potential CRM, on renal tumor burden and immune profiles. BALB/c mice were fed an acarbose-containing diet or macronutrient-matched control diet for 4 weeks prior to challenge with syngeneic Renca renal carcinoma cells. Although no significant differences were observed in primary renal tumor outgrowth or spontaneous lung metastases (both, p&amp;lt;0.05), acarbose-fed mice exhibited severe weight loss following intra-renal tumor challenge (p=0.02). Tumor-bearing mice fed an acarbose diet displayed increased percentages of total splenic (p=0.03) and intra-tumoral (p=0.04) CD8 T cells versus controls. Future experiments will evaluate the effects of the acarbose CRM on immunotherapeutic efficacy and ensuing immune responses. Our findings demonstrate that further research is required to understand how specific CRMs impact tumor outgrowth and anti-cancer immunity.

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies

Renal cell carcinoma (RCC) affects > 60,000 people in the United States annually, and ~ 30% of RCC patients have multiple metastases at the time of diagnosis. Metastatic RCC (mRCC) is incurable, with a median survival time of only 18 months. Immune-based interventions (e.g., interferon (IFN) and interleukin (IL)-2) induce durable responses in a fraction of mRCC patients, and multikinase inhibitors (e.g., sunitinib or sorafenib) or anti-VEGF receptor monoclonal antibodies (mAb) are largely palliative, as complete remissions are rare. Such shortcomings in current therapies for mRCC patients provide the rationale for the development of novel treatment protocols. A key component in the preclinical testing of new therapies for mRCC is a suitable animal model. Beneficial features that recapitulate the human condition include a primary renal tumor, renal tumor metastases, and an intact immune system to investigate any therapy-driven immune effector responses and the formation of tumor-induced immunosuppressive factors. This report describes an orthotopic mRCC mouse model that has all of these features. We describe an intrarenal implantation technique using the mouse renal adenocarcinoma cell line Renca, followed by the assessment of tumor growth in the kidney (primary site) and lungs (metastatic site).

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies.

Renal cell carcinoma (RCC) affects > 60,000 people in the United States annually, and ~ 30% of RCC patients have multiple metastases at the time of diagnosis. Metastatic RCC (mRCC) is incurable, with a median survival time of only 18 months. Immune-based interventions (e.g., interferon (IFN) and interleukin (IL)-2) induce durable responses in a fraction of mRCC patients, and multikinase inhibitors (e.g., sunitinib or sorafenib) or anti-VEGF receptor monoclonal antibodies (mAb) are largely palliative, as complete remissions are rare. Such shortcomings in current therapies for mRCC patients provide the rationale for the development of novel treatment protocols. A key component in the preclinical testing of new therapies for mRCC is a suitable animal model. Beneficial features that recapitulate the human condition include a primary renal tumor, renal tumor metastases, and an intact immune system to investigate any therapy-driven immune effector responses and the formation of tumor-induced immunosuppressive factors. This report describes an orthotopic mRCC mouse model that has all of these features. We describe an intrarenal implantation technique using the mouse renal adenocarcinoma cell line Renca, followed by the assessment of tumor growth in the kidney (primary site) and lungs (metastatic site).

Fate of newly developed pulmonary embolism after surgery for renal cell carcinoma with vena cava thrombus.

Pulmonary embolism with viable tumor cells developed after surgery for renal cell carcinoma may metastasize to lung. We investigated the incidence and fate of newly developed pulmonary embolism after surgery for renal cell carcinoma with vena cava thrombus. Among 4549 renal cell carcinoma patients treated with curative surgery at our institute from 1998 to 2015, 81 non-metastatic renal cell carcinoma patients with vena cava thrombus were included. The clinical course of pulmonary embolism and its impact on oncological outcomes were assessed. Postoperatively, pulmonary embolism developed in 13 patients (16.0%), who had higher level of vena cava thrombus (p=0.004), more frequent liver mobilization (p=0.005), and higher amount of intraoperative transfusion (p=0.024) than patients without pulmonary embolism. The rate of lung metastasis was similar between patients with and without pulmonary embolism (30.8 vs. 35.3%, p=1.000). In the multivariate analysis, the significant risk factors for disease recurrence were non-clear cell histology (p=0.014) and larger primary renal tumor size (p=0.032). Non-clear cell histology (p=0.003) was the only significant risk factor for cancer-specific survival. Pulmonary embolism was not associated with both recurrence-free and cancer-specific survival. Pulmonary embolism after surgery for renal cell carcinoma with vena cava thrombus was not associated with worse oncological outcomes and can be closely followed up with anticoagulation therapy.

Primitive Neuroectodermal Tumors of the Kidney

Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) rarely occurs as a primary renal tumor. The disease affects young adults and children and has an aggressive course. The clinical presentation and imaging of these tumors are nonspecific, and they often present at an advanced stage. We present the clinical features, imaging, diagnosis, and treatment of 7 cases of renal PNET (4 men, 3 women; median age, 32 years). Common presenting symptoms were flank or abdominal pain and a mass in the abdomen. On imaging, a large heterogenous infiltrating renal mass with areas of calcification, hemorrhage, and necrosis and tumor thrombus can give a clue to the diagnosis of renal PNET. Immunohistochemistry and molecular studies are essential to confirm the diagnosis. The prognosis of renal ES/PNET is generally poor. Radical nephrectomy combined with chemotherapy and radiotherapy is the standard treatment for renal PNET. An early and accurate diagnosis is crucial for the proper management of these aggressive tumors.

A case of Wilms tumor with right ventricular extension of tumor thrombus

Primary renal tumors comprise 6% of all childhood cancers. Wilms tumor is the most common primary renal tumor in pediatric age group and the peak age of diagnosis is 3-4 years. In 10% of cases tumor extension into hepatic vein and inferior vena cava can be seen. But tumor extension into whole inferior vena cava, right atrium and right ventricle is only seen in less than 1% of patients. A 2-year-old girl was admitted to the hospital because of abdominal distension that was noticed by the parents two weeks ago. Imaging studies revealed that she had a mass at the right renal lodge which was favoring to Wilms tumor and on thorax tomography tumor thrombus was seen in the whole inferior vena cava, right atrium and right ventricle. Neoadjuvant chemotherapy was given for 7 weeks. On the 8th week of diagnosis, under cardiopulmonary bypass, surgical operation by pediatric and cardiovascular surgery teams for primary renal tumor and for cavo-atrial tumor thrombus was performed. Pathological examination of the mass was reported as stage 3 diffuse anaplastic Wilms tumor. The patient completed 24 weeks of chemotherapy protocol and she is being followed for 15 months without any morbidity. We present our case to emphasize the importance of multidisciplinary approach in Wilms tumor with cardiac extension.

Primary Renal Neuroendocrine Tumour Presenting as an Enormous Cystic Lesion.

Primary Renal Neuroendocrine Tumour Presenting as an Enormous Cystic Lesion.

Changing the Stage, Grade and Histological Subtypes of Renal Cell Carcinomas during 10 Years Period.

Renal cell carcinomas (RCCs) account 80-85% of all primary renal neoplasms and originate from the renal cortex. The patients who underwent radical or partial nephrectomy for renal tumour in our unit between January 2005 and 2015 were evaluated retrospectively. The patients were divided into two groups; group 1 includes patients who were treated between January 2005 and December 2009, group 2 those from January 2010 to 2015. There were 103 patients in group 1. The patients were between 21 and 89 years with mean age of 61.46 year. Renal cell carcinomas account 83.4% of the patients, benign renal tumours were 8.7% and transitional cell carcinomas were 7.7% of the patients in group 1. A total of 32.5% RCCs were classified as pT1a, 24.4% as pT1b, 15.1% as pT2a, 11.6% as pT2b, 15.1% as pT3a and 1.1% as pT4. There were 202 patients in group 2 and the patients were between 27 and 81 years with mean age of 58.5 year. Renal cell carcinomas comprised the main bulk of the tumours with 182 nephrectomy specimens. According to the pathological classification of RCCs, 51 specimens were found as pT1a, 54 were pT1b, 13 were pT2a, 14 were pT2b, 48 were pT3a and 2 were pT4. Although, the incidence of small renal masses has been increasing with widespread use of imaging techniques and recent advancements, the proportion of high grade and advanced stage renal tumours increased during the study period.

Renal neoplasia in horses - a retrospective study.

Being confronted with a case series of renal neoplasia in several horses which was in striking divergence to literature data, we recognized the need of a retrospective study to assess the presence of renal neoplasms in horses. Anamnestic animal data, necropsy findings and results of histological and immunohistochemical examinations from 2010 through 2015 were collected and evaluated regarding renal neoplasia. Data from postmortem examinations of 1069 horses revealed 20 horses with renal tumors constituting a prevalence of 1.87 %. Primary renal neoplasms built the majority of cases (n=15; 75 % of total renal neoplasms) and comprised nine renal carcinomas, four renal adenomas, one renal neuroendocrine tumor and a single nephroblastoma. Among the five secondary renal neoplasms lymphosarcoma was most common (3/5). Remaining metastatic tumors comprised one melanoma and one hemangiosarcoma. No breed or sex predilections were noticeable. Except for the case of nephroblastoma in a stillborn foal, all horses presenting with renal tumors were more than 10years of age, often older than 20years. Anamnestic data and clinical symptoms were inconclusive and not assigned to renal disease in most cases. Merely one horse with renal carcinoma presented with renal insufficiency and two horses showed signs of shock due to severe bleeding after tumor capsule rupture in renal carcinoma. Renal tumors occur more often than anticipated, especially in older horses. Contradictorily to the literature, primary renal tumors significantly outnumbered secondary neoplasms in this study.

Carboplatin-based Nanomedicine to Enhance the Anticancer Effect in SK-NEP-1 WilmsꞌTumor Cells.

Wilms tumor (WT) is the most common pediatric malignant primary renal tumor. Carboplatin (CRB), a platinum compound is widely used in the treatment of multiple cancers including ovarian, lung, head and neck, and wilm's tumor. However, lower uptake of CRB in cancer cells and toxicity concerns in healthy cells often limited its clinical outcome. The aim of this study was to investigate the antitumor effect of CRB on SK-NEP-1 wilm's cancer cells. Earlier, CRB was formulated in nanoparticulate formulations and characterized its biophysical parameters. SK-NEP-1 cell growth in vitro was assessed by MTT. Then, apoptosis potential was investigated by TUNEL, Hoechst, and colony formation assay. CRB treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. TUNEL, Hoechst, and colony formation assay demonstrated that CRB was more effective in killing wilm's cancer cell when encapsulated in nanoparticle formulations. Overall, the present study demonstrates that CRB treatment resulted in marked inhibition of cell proliferation and cell apoptosis. These results may pave way for the effective treatment of wilm's tumor in clinical models.

Expression of paired Box-2 gene product in renal tumors as a diagnostic immunomarker

Objective: This study was aimed at evaluating the usefulness of paired box-2 gene (PAX-2) in the diagnosis of renal tumors. Materials and Methods: This study included 60 renal tumors. The newly prepared hematoxylin and eosin stained slides of all cases were evaluated and the diagnoses were confirmed or revised for each tumor according to the 2004 World Health Organization classification of renal tumors. Representative and consecutive sections of each tumor were submitted for anti-PAX-2 antibody immunohistochemistry. The pattern of staining (nuclear or cytoplasmic) was also noted. PAX-2 expression in tumors was correlated with low- and high-nuclear grades (Fuhrman nuclear grades). Results: The 45/60 (75%) cases showed PAX-2 nuclear immunoexpression. The frequency of positivity in renal tumors was seen in 29/34 (85.5%) and 12/15 (80%) cases of clear cell RC, papillary RCC, respectively. The PAX-2 was positive in 20/45 cases for score 1+. The 16/45 cases were categorized into score 2+, and 9/45 cases were categorized into score 3+. Conclusion: PAX-2 is a diagnostically useful marker for primary renal tumors and is inversely proportion to the grades of the renal tumor.

Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma.

To evaluate the safety and feasibility of sorafenib prior to surgery for downsizing tumors in patients with non-metastatic cT1-3 renal tumors together with a characterization of functional intratumoral heterogeneity (ITH). The effects of 4-week sorafenib prior to curative surgery were assessed in a prospective, single-center, randomized, placebo-controlled, double-blinded, pilot trial in patients with T1-3N0M0 renal cell carcinoma (RCC). Patients received sorafenib or placebo for 28days prior to surgery. MRI was performed at baseline and prior to surgery to calculate tumor volume. The clinical responses were further characterized on the molecular level by immunohistochemical stainings for Ki-67, cleaved caspase-3, and CD31. After enrolling 20 patients into the study, 14 patients were randomized, of which 12 patients were available for analysis. While no significant change in tumor volume was seen for placebo (range=-24.2-0.2%) a reduction of 29.0% (range=-4.9-61.1%) was detected for sorafenib (p<0.05). Primary renal tumor diameter changed from 10.6cm (range=6.5-10.8) to 10.7cm (range=6.7-11.1) in the placebo group, and from 5.4cm (range=4.3-7.3) to 4.4cm (range=3.5-6.8) for the sorafenib group, at baseline vs. 28days of treatment. Correlative assessment of proliferation, apoptosis, and microvessel density revealed an enhanced degree of functional ITH in treated patients suggesting adaptive and/or regenerative processes with potential relevance for the development of drug resistance. Sorafenib in standard dosage, given preoperatively for 28days, was clinically active in downsizing tumors in patients with locally confined, non-metastatic RCC together but led to an enhanced functional ITH in the residual tumor tissue.