The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial.
To assess if CN versus no CN is associated ...with improved overall survival (OS) in patients with mRCC treated in the TT era and beyond, characterize the morbidity of CN, identify prognostic and predictive factors, and evaluate outcomes following treatment sequencing.
Medline, EMBASE, and Cochrane databases were searched from inception to June 4, 2018 for English-language clinical trials, cohort studies, and case-control studies evaluating patients with mRCC who underwent and those who did not undergo CN. The primary outcome was OS. Risk of bias was evaluated using the Cochrane Collaborative tools.
We identified 63 reports on 56 studies. Risk of bias was considered moderate or serious for 50 studies. CN was associated with improved OS among patients with mRCC in 10 nonrandomized studies, while one randomized trial (CARMENA) found that OS with sunitinib alone was noninferior to that with CN followed by sunitinib. The risk of perioperative mortality and Clavien ≥3 complications ranged from 0% to 10.4% and from 3% to 29.4%, respectively, with no meaningful differences between upfront CN or CN after presurgical systemic therapy (ST). Notably, 12.9–30.4% of patients did not receive ST after CN. Factors most consistently prognostic of decreased OS were progression on presurgical ST, high C-reactive protein, high neutrophil-lymphocyte ratio, poor International Metastatic renal cell carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) risk classification, sarcomatoid dedifferentiation, and poor performance status. At the same time, good performance status and good/intermediate IMDC/MSKCC risk classification were most consistently predictive of OS benefit with CN. In a randomized trial investigating the sequence of CN and ST (SURTIME), an OS trend was observed with CN after a period of ST in patients without progression compared with upfront CN. However, the study was underpowered and results are exploratory.
Currently, ST should be prioritized in the management of patients with de novo mRCC who require medical therapy. CN maintains a role in patients with limited metastatic burden amenable to surveillance or metastasectomy, and may potentially be considered in patients with favorable response after initial ST or for symptom's palliation.
In the contemporary era, receiving systemic therapy is the priority in metastatic kidney cancer. Nephrectomy still has a role in patients with limited burden of metastases, well-selected patients based on established prognostic and predictive factors, and patients with a favorable response after initial systemic therapy.
In the targeted therapy era and beyond, systemic therapy is a priority in the management of de novo metastatic renal cell carcinoma. However, cytoreductive nephrectomy still has a role in patients with limited metastatic burden amenable to surveillance or metastasectomy, well-selected patients based on established prognostic and predictive factors, and patients with a favorable response after initial systemic therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We have used the quantitative polymerase chain reaction (qPCR) to measure the extent of oxidative DNA damage under varying reaction conditions used for copper(I)-catalyzed click chemistry. We ...systematically studied how the damage depends on a number of key reaction parameters, including the amounts of copper, ascorbate, and ligand used, and found that the damage is significant under nearly all conditions tested, including those commonly used for bioconjugation. Furthermore, we discovered that the addition of dimethyl sulfoxide, a known radical scavenger, into the aqueous mixture dramatically suppresses DNA damage during the reaction. We also measured the efficiency of cross-linking two short synthetic oligonucleotides via click chemistry, and found that the reaction could proceed reasonably efficiently even with DMSO present. This approach for screening both DNA damage and reactivity under a range of reaction conditions will be valuable for improving the biocompatibility of click chemistry, and should help to extend this powerful synthetic tool for both in vitro and in vivo applications.
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IJS, KILJ, NUK, PNG, UL, UM
Clear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer associated with the development of abnormal tumor angiogenesis. Although multiple anti-angiogenic therapies have been ...developed, responses to individual treatment are highly variable between patients. Thus, the use of one-patient clinical trials has been suggested as an alternative to standard trials. We used a microfluidic device to generate organotypic primary patient-specific blood vessel models using normal (NEnC) and tumor-associated primary CD31
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selected cells (TEnC). Our model was able to recapitulate differences in angiogenic sprouting and vessel permeability that characterize normal and tumor-associated vessels. We analyzed the expression profile of vessel models to define vascular normalization in a patient-specific manner. Using this data, we identified actionable targets to normalize TEnC vessel function to a more NEnC-like phenotype. Finally, we tested two of these drugs in our patient-specific models to determine the efficiency in restoring vessel function showing the potential of the model for single-patient clinical trials.
Identification and testing of personalized anti-angiogenic treatments for clear cell renal cell carcinoma using patient-derived microfluidic models of normal and tumor-associated blood vessels.
The purpose of the present study is to determine whether CT texture features of newly diagnosed primary renal cell carcinomas (RCCs) correlate with pathologic features and oncologic outcomes.
CT ...texture analysis was performed on large (> 7 cm; mean size, 9.9 cm) untreated RCCs in 157 patients (52 women and 105 men; mean age, 60.3 years). Measures of tumor heterogeneity, including entropy, kurtosis, skewness, mean, mean of positive pixels, and SD of pixel distribution histogram were derived from multiphasic CT using various filter settings: unfiltered (spatial scaling factor, 0), fine (spatial scaling factor, 2), medium (spatial scaling factor, 3-4), or coarse (spatial scaling factor, 5-6). Texture values were correlated with histologic subtype, nuclear grade, pathologic stage, and clinical outcome.
When a coarse filter setting (spatial scaling factor, 6) was used, entropy on portal venous phase CT images was positively associated with clear cell histologic findings (odds ratio OR, 134; 95% CI, 16-1110; p < 0.001) and was negatively associated with non-clear cell subtype findings (papillary spatial scale factor, 6; OR, 0.016; 95% CI, 0.002-0.132; p < 0.001). ROC curve analysis for entropy (on portal venous phase images obtained with a spatial scaling factor of 6) revealed an AUC of 0.943 (95% CI, 0.892-0.993) for clear cell histologic findings, with similar values noted for non-clear cell histologic findings. The mean of positive pixels and the SD of the pixel distribution histogram were statistically significantly associated with histologic cell type in a similar fashion. Entropy, the SD of the pixel distribution histogram, and the mean of positive pixels were associated with nuclear grade, most prominently when fine or medium texture filters were used (p < 0.05). There was a statistically significant association of texture features noted on unenhanced CT, including the SD of the pixel distribution histogram, the mean of positive pixels, and entropy, with the time to disease recurrence and death due to disease (e.g., for entropy noted on unenhanced CT images obtained with a spatial scaling factor of 6, the hazard ratio was 3.49 95% CI, 1.55-7.84; p = 0.002).
CT texture features (in particular, entropy, the mean of positive pixels, and the SD of the pixel distribution histogram) are associated with tumor histologic findings, nuclear grade, and outcome measures. The contrast phase does seem to affect heterogeneity measures.
Abstract Background Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. Objective ...To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. Design, setting, and participants A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. Measurements The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. Results and limitations Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. Conclusions TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although multiple active systemic treatments are now available for patients with metastatic kidney cancer, the tools to clearly identify patients who appear to benefit from cytoreductive surgery ...remain poorly defined or validated. To improve the level of evidence for future surgical research in metastatic renal cell cancer, it is imperative that specific tools be developed for advanced risk stratification in the context of evaluating the potential benefits from surgery.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Background Surgery for renal cell carcinoma (RCC) patients with inferior vena cava (IVC) thrombus above the hepatic veins is technically complex and associated with an increased risk of ...perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with poor outcomes. Objective To determine the preoperative predictors of major complications and 90-d mortality after surgery in RCC patients who have IVC thrombus above the hepatic veins. Design, setting, and participants We reviewed medical records of all RCC patients who had IVC tumor thrombus above hepatic veins and had had surgery between January 2000 and December 2012 at the Mayo Clinic, M.D. Anderson Cancer Center, University of Texas Southwestern Medical Center, and the University of Wisconsin Hospital. Outcome measurement and statistical analysis Major complications recorded were defined as ≥3A according to the Clavien-Dindo system within 90 d of surgery. Univariate and multivariate analyses were used to evaluate associations of preoperative variables with risk of major complications or 90-d mortality. Results and limitations A total of 162 patients were identified for study (level 3, 4 in 69, 93 patients, respectively, according to the Neves classification). Cardiopulmonary bypass was used in 60 of 162 patients (37.5%), and 40 patients (24.7%) had preoperative angioembolization. Major complications were reported in 55 patients (34.0%), with the most common being respiratory, cardiac, and hematologic issues. After multivariate analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with increased risk of major complications. Mortality was reported in 17 patients (10.5%) within 90 d after surgery. After multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low serum albumin were preoperative factors independently associated with increased risk of 90-d mortality. Conclusions Contemporary perioperative mortality and major complication rates for RCC patients who have upper-level thrombus are 10% and 34%, respectively. Patients who have ECOG PS >1 or low serum albumin have increased risk for perioperative mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of ...therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC‐specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD‐L1 and HLA‐I expression and correlated with patient response to therapy. CTC enumeration and expression of PD‐L1 and HLA‐I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker.
Circulating tumor cells (CTCs) were evaluated for their expression of programmed death ligand‐1 (PD‐L1) and human leukocyte antigen class I (HLA‐I), so that biomarkers of therapeutic resistance of clear cell renal cell carcinoma can be developed. CTCs were captured with antibody‐conjugated magnetic beads against EpCAM and CAIX then probed for CAXII and CK expression using microfluidic technology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose Identification of patient and tumor characteristics associated with nondiagnostic biopsies is necessary to improve prebiopsy counseling and patient selection. Materials and Methods We ...reviewed the clinical records and prebiopsy imaging of all patients treated with percutaneous biopsy for a renal mass 7 cm or less. Univariate and multivariate logistic regression models were constructed to examine the association between biopsy outcome and clinical/radiographic features. Results A total of 565 biopsies of renal tumors 7 cm or less in 525 patients were included in the study. There was no significant difference in age, body mass index, Charlson comorbidity score or gender between the patient cohorts with diagnostic and nondiagnostic biopsy. In 83 of 565 patients (14.7%) overall and in 72 of the 413 (17.4%) with a mass of 4 cm or less the biopsy findings were nondiagnostic. Overall 14.7% of masses were cystic and 85.3% were solid with a median tumor size of 2.75 cm (IQR 2.05–4.25). Independent predictors of nondiagnostic biopsy included cystic features, enhancement less than 20 HU, left tumor, tumor diameter and skin-to-tumor distance. The nondiagnostic rate of repeat biopsies was 20.8%, which did not statistically differ from the nondiagnostic rate at the initial renal mass biopsy attempt. Radiologist or pathologist experience was not associated with the biopsy nondiagnostic rate. In 7 of 565 patients (1.2%) hospital admission was required for adverse events after biopsy. Conclusions Nondiagnostic renal mass biopsies are more common in cystic, nonenhancing, small masses when patients have a skin-to-tumor distance of 13 cm or greater. Excluding patients with these criteria decreased the nondiagnostic rate from 14.7% to 8.7%.
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