Utility of Chemical Shift Imaging and Diffusion-weighted Images/Apparent Diffusion Coefficient Maps as a Tool for Evaluation of Solid Renal Tumors.

OBJECTIVES: To study the utility of chemical shift imaging (CSI) and diffusion-weighted images (DWI)/apparent diffusion coefficient (ADC) maps for the evaluation of solid renal tumors. METHODS: Magnetic resonance imaging (MRI) has an equivalent application as computerized tomography (CT) in the characterization of renal masses. It offers a radiation-free imaging technique and has a better soft tissue contrast than CT. Also, MRI is favored in patients with chronic kidney disease. MRI is useful when findings on CT are equivocal. The role of DWI in characterizing solid renal lesions as malignant is encouraging, and DWI can be particularly useful when gadolinium is contraindicated. CSI is useful in differentiating angiomyolipoma (AML) from clear cell (cc) renal cell carcinoma (RCC). We did a cross-sectional study on 24 patients with solid renal masses. MRI of the upper abdomen (from the dome of the diaphragm to the iliac crest) will be done on an MRI machine in our department (1.5T, ACHIEVA, Phillips medical system) using the torso coil. RESULT: There was no significant association seen in terms of ADC values and histological subtypes (χ2 = 11.222, p = 0.082). In our study, 50% (one out of two) of AML showed a signal drop, whereas 40% of cases (6 out of 15) of ccRCC and 66% (two out of three) of papillary RCC showed a signal drop. CONCLUSION: In this article, we concluded CSI, although a useful tool to look for microscopic fat, can't be used as a reliable marker to rule in cc-carcinoma as both AML and papillary cell carcinoma have microscopic fat. Further, no histological classification can be done on the basis of DWI/ADC images.

Detection of two synchronous histologically different renal cell carcinoma subtypes in the same kidney: a case report and review of the literature.

INTRODUCTION: Renal cell carcinoma (RCC) is the dominant primary renal malignant neoplasm, encompassing a significant portion of renal tumors. The presence of synchronous yet histologically distinct ipsilateral RCCs, however, is an exceptionally uncommon phenomenon that is rather under-described in the literature regarding etiology, diagnosis, management, and later outcomes during follow-up. CASE PRESENTATION: We aim to present the 9th case of a combination chromophobe RCC (ChRCC) and clear cell RCC (ccRCC) in literature, according to our knowledge, for a 69-year-old North African, Caucasian female patient who, after complaining of loin pain and hematuria, was found to have two right renal masses with preoperative computed tomography (CT) and underwent right radical nephrectomy. Pathological examination later revealed the two renal masses to be of different histologic subtypes. CONCLUSION: The coexistence of dissimilar RCC subtypes can contribute to diverse prognostic implications. Further research should focus on enhancing the complex, yet highly crucial, preoperative detection and pathological examination to differentiate multiple renal lesions. Planning optimal operative techniques (radical or partial nephrectomy), selecting suitable adjuvant regimens, and reporting long-term follow-up outcomes of patients in whom synchronous yet different RCC subtypes were detected are of utmost importance.

Predicting the presence of adherent perinephric fat using MRI radiomics combined with machine learning.

OBJECTIVES: Adherent perinephric fat (APF) poses significant challenges to surgical procedures. This study aimed to evaluate the usefulness of machine learning algorithms combined with MRI-based radiomics features for predicting the presence of APF. MATERIALS AND METHODS: Patients with renal cell carcinoma who underwent surgery between April 2019 and February 2022 at Chonnam National University Hwasun Hospital were retrospectively screened, and 119 patients included. Twenty-one and seventeen patients were set aside for the internal and external test sets, respectively. Pre-operative T1-weighted MRI acquired at 60 s following a contrast injection (T1w-60) were collected. For each T1w-60 data, two regions of interest (ROIs) were manually drawn: the perinephric fat tissue and an aorta segment on the same level as the targeted kidney. Preprocessing steps included resizing voxels, N4 Bias Correction filtering, and aorta-based normalization. For each patient, 851 radiomics features were extracted from the ROI of perinephric fat tissue. Gender and BMI were added as clinical factors. Least Absolute Shrinkage and Selection Operator was adopted for feature selection. We trained and evaluated five models using a 4-fold cross validation. The final model was chosen based on the highest mean AUC across four folds. The performance of the final model was evaluated on the internal and external test sets. RESULTS: A total of 15 features were selected in the final set. The final model achieved the accuracy, sensitivity, specificity, and AUC of 81% (95% confidence interval, 61.9-95.2%), 72.7% (42.9-100%), 90% (66.7-100%), and 0.855 (0.615-1.0), respectively on the internal test set, and 88.2% (70.6-100%), 100% (100-100%), 80% (50%-100%), 0.971 (0.871-1.0), respectively on the external test set. CONCLUSIONS: Our study demonstrated the feasibility of machine learning algorithms trained with MRI-based radiomics features for APF prediction. Further studies with a multi-center approach are necessary to validate our findings.

Development and validation of a clinical and ultrasound features-based nomogram for preoperative differentiation of renal urothelial carcinoma and central renal cell carcinoma.

PURPOSE: This study aimed to develop and validate an ultrasound (US)-based nomogram for the preoperative differentiation of renal urothelial carcinoma (rUC) from central renal cell carcinoma (c-RCC). METHODS: Clinical data and US images of 655 patients with 655 histologically confirmed malignant renal tumors (521 c-RCCs and 134 rUCs) were collected and divided into training (n = 455) and validation (n = 200) cohorts according to examination dates. Conventional US and contrast-enhanced US (CEUS) tumor features were analyzed to determine those that could discriminate rUC from c-RCC. Least absolute shrinkage and selection operator regression was applied to screen clinical and US features for the differentiation of rUC from c-RCC. Using multivariate logistic regression analysis, a diagnostic model of rUC was constructed and visualized as a nomogram. The diagnostic model's performance was assessed in the training and validation cohorts by calculating the area under the receiver operating characteristic curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness of the US-based nomogram. RESULTS: Seven features of both clinical features and ultrasound imaging were selected to build the diagnostic model. The nomogram achieved favorable discrimination in the training (AUC = 0.996, 95% CI: 0.993-0.999) and validation (AUC = 0.995, 95% CI: 0.974, 1.000) cohorts, and good calibration (Brier scores: 0.019 and 0.016, respectively). DCA demonstrated the clinical usefulness of the US-based nomogram. CONCLUSION: A noninvasive clinical and US-based nomogram combining conventional US and CEUS features possesses good predictive value for differentiating rUC from c-RCC.

Ablative Radioembolization (SIRT) of a Large Inoperable Renal Cell Carcinoma Invading the Liver That Resulted in Hematuria Control and Complete Necrosis by mRECIST Criteria.

ABSTRACT: We report the successful application of radioembolization (SIRT) in a 77-year-old man with end-stage renal disease on hemodialysis and repeated episodes of macroscopic hematuria due to a large renal cell carcinoma of the right kidney extending to liver segment VI. A compassionate SIRT therapy was performed with resin microspheres through the upper pole renal artery and the feeding segmental artery of liver segment VI. Hematuria was resolved after treatment, and 4 months later, a follow-up CT scan revealed tumor size reduction and complete tumor necrosis (Response Evaluation Criteria in Solid Tumors criteria). Ablative SIRT therapy could be a safe and efficient option in a large inoperable RCC.

Percutaneous Microwave Ablation Versus Robot-Assisted Partial Nephrectomy for Stage I Renal Cell Carcinoma: A Propensity-Matched Cohort Study Focusing Upon Long-Term Follow-Up of Oncologic Outcomes.

PURPOSE: To retrospectively compare long-term oncologic outcomes of percutaneous computed tomography-guided microwave ablation (MWA) and robot-assisted partial nephrectomy (RAPN) for the treatment of stage 1 (T1a and T1b) renal cell carcinoma (RCC) patients. MATERIALS AND METHODS: Institutional database research identified all T1 RCC patients who underwent either MWA or RAPN. Models were adjusted with propensity score matching. Kaplan-Meier log-rank test analyses and Cox proportional hazard regression models were used to compare the oncologic outcomes. Patient and tumor characteristics, technical success as well as oncologic outcomes were evaluated and compared between the 2 groups. RESULTS: After propensity score matching, a total of 71 patients underwent percutaneous MWA (mean age 70 ± 10 years) and 71 underwent RAPN (mean age 60 ± 9 years). At 8-year follow-up, the estimated survival rates for MWA cohort were 98% (95% confidence interval [CI] 95-100%) for overall survival, 97% (95% CI 93-100%) for recurrence-free survival, and 97% (95% CI 93-100%) for metastasis-free survival. The matched cohort that underwent RAPN exhibited survival rates of 100% (95% CI 100-100%) for overall survival, 98% (95% CI 94-100%) for recurrence-free survival, and 98% (95% CI 94-100%) for metastasis-free survival. After performing log-rank testing, these rates were not significantly different (p values of 0.44, 0.67, and 0.67, respectively). CONCLUSION: The results of the present study suggest that both MWA and RAPN are equally effective in terms of oncologic outcome for the treatment of T1 RCC.

FDG PET/CT in the Diagnosis and After Sunitinib Follow-up of Synchronous Base of Tongue and Thyroid Metastases From Renal Cell Carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) is a leading cause of mortality among genitourinary malignancies with limited therapeutic options. The hematogenous route, lymphatic spread, and direct invasion have been documented in RCC. Usually, metastases are regional lymph nodes, lungs, bone, liver, adrenal glands, contralateral kidney, and brain. Metastases to the rare sites such as skin, breast, head and neck were documented in the literature. In the present case, we describe the synchronous metastases to the base of the tongue and thyroid gland in RCC and the response to sunitinib therapy on 18F-FDG PET/CT.

The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations.

Purpose To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions. Materials and Methods From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation. Results A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%. Conclusion FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%. Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney © RSNA, 2024.

Radiogenomic analysis based on lipid metabolism-related subset for non-invasive prediction for prognosis of renal clear cell carcinoma.

PURPOSE: Multiple lipid metabolism pathways alterations are associated with clear cell renal cell carcinoma (ccRCC) development and aggressiveness. In this study, we aim to develop a novel radiogenomics signature based on lipid metabolism-related genes (LMRGs) that may accurately predict ccRCC patients' survival. MATERIALS AND METHODS: First, 327 ccRCC were used to screen survival-related LMRGs and construct a gene signature based on The Cancer Genome Atlas (TCGA) database. Then, 182 ccRCC were analyzed to establish radiogenomics signature linking LMRGs signature to radiomic features in The Cancer Imaging Archive (TCIA) database included enhanced CT images and transcriptome sequencing data. Lastly, we validated the prognostic power of the identified radiogenomics signature using these patients of TCIA and the Third Xiangya Hospital. RESULTS: We identified the LMRGs signature, consisting of 13 genes, which could efficiently discriminate between low-risk and high-risk patients and serve as an independent and reliable predictor of overall survival (OS). Radiogenomics signature, comprised of 9 radiomic features, was created and could accurately predict the expression level of LMRGs signature (low- or high-risk) for patients. The predictive performance of this radiogenomics signature was demonstrated through AUC values of 0.75 and 0.74 for the training and validation sets (at a ratio of 7:3), respectively. Radiogenomics signature was proven to be an independent risk factor for OS by multivariable analysis (HR = 4.98, 95 % CI:1.72-14.43, P = 0.003). CONCLUSIONS: The LMRGs radiogenomics signature could serve as a novel prognostic predictor.

Percutaneous Image-Guided Cryoablation of Endophytic Renal Cell Carcinoma.

PURPOSE: Endophytic renal cancer treatment is a challenge. Due to difficulties in endophytic tumor visualization during surgical extirpation, image-guided percutaneous cryoablation (PCA) is an attractive alternative. The minimally invasive nature of PCA makes it favorable for comorbid patients as well as patients in which surgery is contraindicated. Oncological outcomes and complications after PCA of endophytic biopsy-proven renal cell carcinoma (RCC) were reviewed in this study. MATERIALS AND METHODS: Patients were included after a multidisciplinary team conference from January 2015 to November 2021. Inclusion criteria were endophytic biopsy-proven T1 RCC treated with PCA with one year of follow-up. Complications were reported according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) classification system and the Clavien-Dindo classification (CDC) system. Major complications were defined as a grade ≥ 3 according to the CDC. RESULTS: Fifty-six patients were included with a total of 56 endophytic tumors treated during 61 PCA sessions. The median RENAL nephrometry score was 9 (IQR 2), and the mean tumor size was 25.7 mm (SD ± 8.9 mm). Mean hospitalization time was 0.39 (SD ± 1.1) days. At a mean follow-up of 996 days (SD ± 559), 86% of tumors were recurrence free after one PCA. No patients progressed to metastatic disease. According to the CIRSE classification, 10.7% (n = 6) had grade 3 complications, and 5.4% (n = 3) had CDC major complications. CONCLUSION: This study demonstrates that PCA of endophytic biopsy-proven T1 RCC is safe with few major complications and excellent local tumor control rates at almost three-year mean follow-up. LEVEL OF EVIDENCE 3: Retrospective cohort study.

Study of radiomics based on dual-energy CT for nuclear grading and T-staging in renal clear cell carcinoma.

INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cell carcinoma with a high invasive potential. Radiomics has attracted much attention in predicting the preoperative T-staging and nuclear grade of ccRCC. OBJECTIVE: The objective was to evaluate the efficacy of dual-energy computed tomography (DECT) radiomics in predicting ccRCC grade and T-stage while optimizing the models. METHODS: 200 ccRCC patients underwent preoperative DECT scanning and were randomized into training and validation cohorts. Radiomics models based on 70 KeV, 100 KeV, 150 KeV, iodine-based material decomposition images (IMDI), virtual noncontrasted images (VNC), mixed energy images (MEI) and MEI + IMDI were established for grading and T-staging. Receiver operating characteristic analysis and decision curve analysis (DCA) were performed. The area under the curve (AUC) values were compared using Delong test. RESULTS: For grading, the AUC values of these models ranged from 0.64 to 0.97 during training and from 0.54 to 0.72 during validation. In the validation cohort, the performance of MEI + IMDI model was optimal, with an AUC of 0.72, sensitivity of 0.71, and specificity of 0.70. The AUC value for the 70 KeV model was higher than those for the 100 KeV, 150 KeV, and MEI models. For T-staging, these models achieved AUC values of 0.83 to 1.00 in training and 0.59 to 0.82 in validation. The validation cohort demonstrated AUCs of 0.82 and 0.70, sensitivities of 0.71 and 0.71, and specificities of 0.80 and 0.60 for the MEI + IMDI and IMDI models, respectively. In terms of grading and T-staging, the MEI + IMDI model had the highest AUC in validation, with IMDI coming in second. There were statistically significant differences between the MEI + IMDI model and the 70 KeV, 100 KeV, 150 KeV, MEI, and VNC models in terms of grading (P < .05) and staging (P ≤ .001). DCA showed that both MEI + IDMI and IDMI models outperformed other models in predicting grade and stage of ccRCC. CONCLUSIONS: DECT radiomics models were helpful in grading and T-staging of ccRCC. The combined model of MEI + IMDI achieved favorable results.

The Association of Body Composition Parameters Measured by Computed Tomography with Cancer Stage, Prognosis, and Survival in Patients with Renal Cell Carcinoma.

OBJECTIVE: This study aims to investigate the association of preoperative body composition parameters, measured by computed tomography in patients undergoing surgery for renal cell carcinoma, with its stage and to survey the relationship with postoperative hospitalization duration and survival. METHODS: Demographic data, pathology results, cancer stages, and hospitalization duration of 104 patients undergoing surgery at the urology clinic due to renal cell carcinoma between 2019 and 2023 were analyzed retrospectively. On computed tomography scans acquired during diagnosis, visceral adipose tissue, subcutaneous adipose tissue, total adipose tissue, and skeletal muscle area were measured. The ratios of body composition parameters were computed. RESULTS: When the correlation between survival time and body composition in deceased patients was analysed, a moderate but significant correlation was observed between skeletal muscle area value and total adipose tissue / skeletal muscle area ratio (r=0.630, p=0.001; r=0.598, p=0.002). A significant and strong correlation was observed between total adipose tissue value and survival (r=0.704, p<0.001). Subcutaneous adipose tissue / skeletal muscle area was found to be an independent risk factor associated with mortality, and a ratio of 0.98 or less increased the mortality risk approximately 16-fold. CONCLUSION: The relationship between body composition parameters measured by computed tomography, which can be easily evaluated pre-treatment, and mortality, postoperative recovery and length of hospital stay can be evaluated, giving clinicians an idea about the potential difficulties that patients may encounter during the treatment process. For this purpose, the subcutaneous adipose tissue / skeletal muscle area ratio is the most helpful parameter that can be used.

Percutaneous microwave ablation of T1a renal cell carcinomas: A 10-year single-center retrospective review.

INTRODUCTION: Partial nephrectomy is currently the preferred treatment option for T1a renal cell carcinomas (RCC), with nephron-sparing techniques, including microwave ablation, becoming more common in select patients. Primary aims are to document outcomes of microwave ablation for T1a RCCs in an Australian tertiary centre to add to the evidence for its safety and efficacy. METHODS: The prospectively maintained Sir Charles Gairdner Hospital Interventional Radiology database was retrospectively searched for all Renal Microwave ablations completed between June 2012 and February 2022. This database and a combination of hospital programmes including Agfa Impax PACS, Bossnet digital medical record and iSoft Clinical Manager were used to extract the relevant data which was anonymized and entered into an Excel spreadsheet for analysis. RESULTS: Forty-eight patients underwent microwave ablation for 50 tumours. Of these, there were two local and two distant recurrences. A fifth patient had metastases on presentation. Higher local recurrence rates were associated with larger tumour size (P = 0.043). Tumour proximity to the collecting system <4 mm was associated with higher rates of complications (P = 0.020). RENAL scores did not show statistically significant correlation with complications (P = 0.092) or local or distant recurrence. Notably, the study follow-up time was longer than many comparative studies (mean = 2796, ~7.66 years censoring for death and mean = 832 days, ~2.28 years not censoring for death). CONCLUSION: Consistent with the literature, this study further demonstrates that microwave ablation is a safe and efficacious option for treatment of T1a RCC.

Renal cell carcinoma with an "uncoiling" tumor thrombus: intraoperative shift from level III to level IV.

BACKGROUND: The gold standard treatment for renal cell carcinoma (RCC) with tumor thrombus (TT) is complete surgical excision. The surgery is complex and challenging to the surgeon, especially with large tumor thrombus extending into the inferior vena cava (IVC) and right atrium. Traditionally, these difficult cases required the use of cardiopulmonary bypass (CPB) with or without deep hypothermic cardiac arrest, but in recent years, different surgical techniques derived from the field of liver transplantation have been used in efforts to avoid CPB. CASE PRESENTATION: We present a case of RCC with TT level IIIc (extending above major hepatic veins) that "uncoiled" intraoperatively into the right atrium after division of the IVC ligament, transforming into a level IV TT. Despite the new TT extension, the surgery was successfully completed exclusively through an abdominal approach without CPB and while using intraoperative transesophageal echocardiography (TEE) monitoring and a cardiothoracic team standby. CONCLUSIONS: This case highlights the need for a multidisciplinary approach and the utility of intraoperative continous TEE monitoring which helped to visualize the change of the TT venous extension, allowing the surgical teamto modify their surgical approach as needed avoiding a catastrophic event.

Deep learning using contrast-enhanced ultrasound images to predict the nuclear grade of clear cell renal cell carcinoma.

PURPOSE: To assess the effectiveness of a deep learning model using contrastenhanced ultrasound (CEUS) images in distinguishing between low-grade (grade I and II) and high-grade (grade III and IV) clear cell renal cell carcinoma (ccRCC). METHODS: A retrospective study was conducted using CEUS images of 177 Fuhrmangraded ccRCCs (93 low-grade and 84 high-grade) from May 2017 to December 2020. A total of 6412 CEUS images were captured from the videos and normalized for subsequent analysis. A deep learning model using the RepVGG architecture was proposed to differentiate between low-grade and high-grade ccRCC. The model's performance was evaluated based on sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver operating characteristic curve (AUC). Class activation mapping (CAM) was used to visualize the specific areas that contribute to the model's predictions. RESULTS: For discriminating high-grade ccRCC from low-grade, the deep learning model achieved a sensitivity of 74.8%, specificity of 79.1%, accuracy of 77.0%, and an AUC of 0.852 in the test set. CONCLUSION: The deep learning model based on CEUS images can accurately differentiate between low-grade and high-grade ccRCC in a non-invasive manner.

Enhancement of Tumor Perfusion and Antiangiogenic Therapy in Murine Models of Clear Cell Renal Cell Carcinoma Using Ultrasound-Stimulated Microbubbles.

OBJECTIVE: To explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on enhancing antiangiogenic therapy in clear cell renal cell carcinoma. MATERIALS AND METHODS: We explored the effects of USMC with different mechanical indices (MIs) on tumor perfusion, 36 786-O tumor-bearing nude mice were randomly assigned into four groups: (i) control group, (ii) USMC0.25 group (MI = 0.25), (iii) USMC1.4 group (MI = 1.4) (iv) US1.4 group (MI = 1.4). Tumor perfusion was assessed by contrast-enhanced ultrasound (CEUS) before the USMC treatment and 30 min, 4h and 6h after the USMC treatment, respectively. Then we evaluated vascular normalization(VN) induced by low-MI (0.25) USMC treatment, 12 tumor-bearing nude mice were randomly divided into two groups: (i) control group (ii) USMC0.25 group. USMC treatment was performed, and tumor microvascular imaging and blood perfusion were analyzed by MicroFlow imaging (MFI) and CEUS 30 min after each treatment. In combination therapy, a total of 144 tumor-bearing nude mice were randomly assigned to six groups (n = 24): (i) control group, (ii) USMC1.4 group, (iii) USMC0.25 group, (iv) bevacizumab(BEV) group, (v) USMC1.4 +BEV group, (vi) USMC0.25 +BEV group. BEV was injected on the 6th, 10th, 14th, and 18th d after the tumors were inoculated, while USMC treatment was performed 24 h before and after every BEV administration. We examined the effects of the combination therapy through a series of experiments. RESULTS: Tumor blood perfusion enhanced by USMC with low MI (0.25)could last for more than 6h, inducing tumor VN and promoting drug delivery. Compared with other groups, USMC0.25+BEV combination therapy had the strongest inhibition on tumor growth, led to the longest survival time of the mice. CONCLUSION: The optimized USMC is a promising therapeutic approach that can be combined with antiangiogenic therapy to combat tumor progression.