Small Renal Cancers Research Articles

Developments in the Use of Antibody-Drug Conjugates

With the recent approvals of brentuximab for the treatment of refractory Hodgkin lymphoma and ado-trastuzumab emtansine for relapsed metastatic HER2+ breast cancer, the hope for delivering targeted chemotherapy in the form of an antibody-drug conjugate (ADC) against many cancers is rapidly growing. The strategy of delivering a potent cytotoxic via a monoclonal antibody to a tumor has been made feasible by marked advances in the technology of formulating and manufacturing these ADCs. The development of stable linkers together with the identification of relevant biomarkers has been a key to the success of this class of agent. The possibilities for deploying this technology in the treatment of a wide range of solid cancers are limited only by the discovery of suitable targets, those which are highly expressed on cancer cells and not, or minimally, on normal tissues. That said, with the improved linker engineering, the ADC affords the best opportunity at shrinking tumors while minimizing side effects. A variety of ADCs are in clinical trials studying a number of different tumor types as diverse as small cell lung and renal cell cancer. A future of potent anticancer therapy with minimal toxicity appears closer to reality for our patients.

Gamma Knife surgery for the treatment of 5 to 15 metastases to the brain

It has been generally accepted that Gamma Knife surgery (GKS) is an effective primary or adjunct treatment for patients with 1-4 metastases to the brain. The number of studies detailing the use of GKS for 5 or more brain metastases, however, remains minimal. The aim of the current retrospective study was to elucidate the utility of GKS in patients with 5-15 brain metastases. Patients were chosen for GKS based on prior MRI of these metastatic lesions and a known primary cancer diagnosis. Magnetic resonance imaging was used post-GKS to assess tumor control; patients were also followed up clinically. Overall survival (OS) from the date of GKS was used as the primary end point. Statistical analysis was performed to identify prognostic factors related to OS. Between 2003 and 2012, 96 patients were treated for a total of 704 metastatic brain lesions. The histology of these lesions varied among non-small cell lung cancer (NSCLC), breast cancer, melanoma, renal cancer, and other more rare carcinomas. At the initial treatment, 18 of the patients (18.8%) were categorized in Recursive Partitioning Analysis (RPA) Class 1 and 77 (80.2%) in RPA Class 2; none were in RPA Class 3. The median number of treated lesions was 7 (mean 7.13), and the median planned treatment volume was 6.12 cm(3) (range 0.42-57.83 cm(3)) per patient. The median clinical follow-up was 4.1 months (range 0.1-40.70 months). Actuarial tumor control was calculated to be 92.4% at 6 months, 84.8% at 12 months, and 74.9% at 24 months post-GKS. The median OS was found to be 4.73 months (range 0.4-41.8 months). Multivariate analysis demonstrated that RPA class was a significant predictor of death (HR = 2.263, p = 0.038). Number of lesions, tumor histology, Graded Prognostic Assessment score, prior whole-brain radiation therapy, prior resection, prior chemotherapy, patient age, patient sex, controlled primary tumor, extracranial metastases, and planned treatment volume were not significant predictors of OS. In patients with 5-15 brain metastases at presentation, the number of lesions did not predict survival after GKS; however, the RPA class was predictive of OS in this group of patients. Gamma Knife surgery for such patients offers an excellent rate of local tumor control.

Oncologic Outcomes Using Real-Time Peripheral Thermometry-Guided Radiofrequency Ablation of Small Renal Masses

With the increased incidence of low-stage renal cancers, thermal ablation technology has emerged as a viable treatment option for extirpation in selected persons and is supported by the current American Urological Association guidelines. We present a 9-year, single institution experience with radiofrequency ablation (RFA) using real-time peripheral temperature monitoring of small renal masses focusing on oncologic outcomes. We reviewed our prospectively collected database of patients with renal masses who were treated between November 2001 and January 2011 with laparoscopic (LRFA) or CT-guided percutaneous RFA (CTRFA) with simultaneous real-time peripheral fiberoptic thermometry. Patients were followed radiographically at 1 month, 6 months, 1 year, and then annually. Clinicopathologic outcomes were collected and analyzed. A total of 274 patients (211 male) aged 18 to 88 years (mean 67 years) with 292 renal tumors underwent LRFA (112) or CTRFA (180). Mean tumor size was 2.5 cm (0.7-5.3 cm). An intraoperative preablation biopsy showed 197 (67.4%) renal-cell carcinomas (RCC), and 77 (26.4%) benign tumors. Mean follow-up was 26 months (1-98 mos). The single ablation treatment radiographic success rate was 96% for all tumors and 94% for RCC. Metastatic RCC developed in one patient, who died. The Kaplan-Meier (KM) 3-year and 5-year cancer-specific survival was 100% and 98.6%, respectively. The KM 3-year and 5-year overall survival was 90.4% and 74.2%, respectively. RFA is a clinically effective and safe nephron-sparing treatment of patients with small renal masses. Our large cohort and intermediate-term experience adds to the building evidence for the efficacy of RFA for small renal cancers.

Developments in the Use of Antibody-Drug Conjugates

With the recent approvals of brentuximab for the treatment of refractory Hodgkin lymphoma and ado-trastuzumab emtansine for relapsed metastatic HER2+ breast cancer, the hope for delivering targeted chemotherapy in the form of an antibody-drug conjugate (ADC) against many cancers is rapidly growing. The strategy of delivering a potent cytotoxic via a monoclonal antibody to a tumor has been made feasible by marked advances in the technology of formulating and manufacturing these ADCs. The development of stable linkers together with the identification of relevant biomarkers has been a key to the success of this class of agent. The possibilities for deploying this technology in the treatment of a wide range of solid cancers are limited only by the discovery of suitable targets, those which are highly expressed on cancer cells and not, or minimally, on normal tissues. That said, with the improved linker engineering, the ADC affords the best opportunity at shrinking tumors while minimizing side effects. A variety of ADCs are in clinical trials studying a number of different tumor types as diverse as small cell lung and renal cell cancer. A future of potent anticancer therapy with minimal toxicity appears closer to reality for our patients.

Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases

We tested the validity of two prognostic indices for stereotactic radiosurgically (SRS)-treated patients with brain metastases (BMs) from five major original cancer categories. The two indices are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) and our Modified Recursive Partitioning Analysis (RPA). Forty-six hundred and eight BM patients underwent gamma knife SRS during the 1998-2011 period. Primary cancer categories were non-small cell lung cancer (NSCLC, 2827 patients), small cell lung cancer (SCLC, 460), gastro-intestinal cancer (GIC, 582), breast cancer (BC, 547) and renal cell cancer (RCC, 192). There were statistically significant survival differences among patients stratified into four groups based on the DS-GPA systems (p < 0.001) in all five original cancer categories. In the NSCLC category, there were statistically significant mean survival time (MST) differences (p < 0.001) among the four groups without overlapping of 95 % confidence intervals (CIs) between any two pairs of groups with the DS-GPA system. However, among the SCLC, GIC, BC and RCC categories, MST differences between some pairs of groups failed to reach statistical significance with this system. There were, however, statistically significant MST differences (p < 0.001) among the three groups without overlapping of 95 % CIs between any two pairs of groups with the Modified RPA system in all five categories. The DS-GPA system is applicable to our set of patients with NSCLC only. However, the Modified RPA system was shown to be applicable to patients with five primary cancer categories. This index should be considered when designing future clinical trials involving BM patients.

Can Renal Biopsy Accurately Predict Histological Subtype and Fuhrman Grade of Renal Cell Carcinoma?

We determined the accuracy of renal biopsy in predicting histological subtype and final Fuhrman nuclear grade in small (4 cm or smaller) renal cancers, and evaluated the concordance between renal biopsy and surgery for these 2 criteria. A total of 187 percutaneous needle biopsies of small renal tumors, guided by computerized tomography with gauge needles and a coaxial technique, were consecutively performed between 2006 and 2011. Renal cell carcinoma was diagnosed in 132 tumors. Partial or radical nephrectomy was performed for 61 of these carcinomas. Preoperative biopsy results for the operative specimens were compared with respect to histological subtype and Fuhrman nuclear grade. In addition, Kappa values were calculated as a measure of agreement between biopsy and surgical specimens, with correction for chance agreement to evaluate the concordance between biopsy and surgical classification for these criteria. Biopsy accuracy and the concordance between biopsy and surgery were excellent for determining histological subtype. The biopsy correctly identified the grade in 75% of cases, and in 93% when pooling renal cell carcinoma in low (1 or 2) and high (3 or 4) grade cases. The agreement between biopsy and surgery for Fuhrman nuclear grade was moderate (Kappa = 0.52) and substantial (Kappa = 0.71) when pooling low and high grade carcinoma, respectively. Although the concordance between grading on biopsy and with surgical specimens was moderate, likely because of the reproducibility of the grading system, the accuracy of biopsy for differentiating high and low grade small renal tumors was high, which may greatly impact decision making in cases of small renal cancer.

Organ Donors with Small Renal Cancer: Report of 3 Cases

Transmission of donor malignancies has been reported since the early days of clinical transplantation. Up to 1995, the Transplant Tumor Registry created by Penn included 155 cadaver and 29 living donor affected by tumors. The most common, excluding brain tumor, was renal cell carcinoma (RCC). RCC represents 2% of adult cancers, an incidence that increases with advancing age. The expansion of the criteria that define a suitable organ donor has as a consequence included donors that are older than in the past. Small RCCs are found during renal recovery from a cadaveric donor in ∼1% of cases. The use of such donors is a matter of debate; it has been suggested that donor kidneys with small RCC Fuhrman grade I/II may be transplanted after appropriate surgical excision. We report our experience with 3 donors with clear cell RCC: 2 contralateral kidneys were transplanted in 2 recipient and a third recipient received an affected kidney after a wide tumor excision. All of the patients we alive and free from recurrence at 14–48 months (mean 35 mo). In the third case, immunosuppression was achieved with a mammalian target of rapamycin inhibitor, which is currently used not only as an immunosuppressant to prevent rejection, but also as treatment for renal cancer. Our data confirmed that donors with small renal tumors may be used, because the risk of tumor recurrence is small and the benefits of a kidney transplantation are great.

2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazoles: Search for anticancer agents

In this study, some novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4 (a–i), 7 (a–p) and 11 (a–i) were synthesized from 5-substituted-1,3,4-thiadiazol-2-amine. The newly synthesized compounds 4a, 4b, 4c, 4e, 4g, 7j, 7l, 11b and 11c were evaluated in the National Cancer Institute for single dose in vitro primary cytotoxicity assay. Among the tested nine compounds, compound 4b (107166/760239) and 4c (107168/760240) were passed the criteria for activity in this assay and scheduled automatically for evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. 3-(2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)aniline (4c) exhibited significant in vitro anticancer activity against Non Small Cell Lung Cancer HOP-92 cell line (GI50: 0.114 μM) and Renal Cancer CAKI-1 cell line (GI50: 0.743 μM).

Living-donor transplantation after excision of unrecognized renal cancer diagnosed after transplant

Published data on kidneys transplanted after resecting small renal cancers during the transplantation surgery are very rare and, to the best of our knowledge, no pediatric cases have been reported in the literature. Our patient was diagnosed with a bilateral Wilms tumor when he was 15 months old. A total bilateral nephrectomy was required to control the disease. Two years later, a human leukocyte antigen (HLA)-identical living-donor transplant from his father was performed. A small mass in the father's left kidney was diagnosed as an angiomyolipoma during the pretransplant donor evaluation. During the surgery, the mass was excised and the kidney implanted. One week later, the pathological study revealed the mass to be a clear cell renal carcinoma. After joint discussion, the urologic and nephrologic teams and the family decided to maintain the transplant, managing the patient with monotherapy based on rapamycin and close ultrasound control. To date, 8 years after transplantation, no signs of malignancy have been detected, and renal function is normal. This is the first reported pediatric case of a living-donor graft with a small renal carcinoma excised in the operating room. No malignancy has been observed in 8 years of follow-up.

Editorial Comment to Overall mortality after radical nephrectomy in patients aged over 80 years with renal cancer: A retrospective study on preoperative prognostic factors

This article cannot answer the hypothesis that small renal cancer might not have to be removed or treated, as the growth speed is very slow in elderly patients, even when their general condition is good. Also, high Charlson Comorbidity Index (CCI) is reported to worsen the postoperative prognosis in all age groups in other malignancies. However, as shown in the Figure 5, postnephrectomy patients with high CCI had an apparently poor prognosis, and when considered with M stage and T stage, this article gives us a certain evidence that nephrectomy will not be beneficial for patients categorized in the “bad prognosis group”.

135 Significant regional differences in the treatment of small renal cancers in Sweden

135 Significant regional differences in the treatment of small renal cancers in Sweden

Cryothérapie des tumeurs rénales par approche laparoscopique

Partial nephrectomy is the gold standard in small renal cancer treatment, for which overall incidence is steadily rising, due to the progress in imaging techniques allow to discover small renal tumors incidentally in a population of patients more older and with several comorbidities. Minimally invasive techniques have developed (cryotherapy or radiofrequency ablation), ablative therapy now valided done by a laparoscopic or an image-guided percutaneous approach (with computed tomography or magnetic resonance). This article will make a review of cryotherapy done by a laparoscopic approach, which is a reliable therapeutic alternative for small renal tumors with low morbidity and reasonable middle-term oncological results.

Primary genitourinary small cell carcinoma: Clinicopathologic and survival outcomes from SEER database.

200 Background: Small cell carcinoma of genitourinary system (SCC) is a highly aggressive and rare entity. The aim of the study is to characterize the clinicopathologic characteristics and evaluate the treatment outcomes of SCC in adult patients. Methods: Retrospective analysis of 732 patents diagnosed with small cell carcinoma of bladder from 1973 to 2007 was done via SEER database. Demographics, stage, type of treatment received and cancer-specific mortality were examined. Results: 732 patients were identified with SCC of genitourinary tract of which 341 were small cell bladder cancer, 336 were small cell prostate cancer and 55 were small cell renal cancer. Of these 644 patients were males and 88 were females. Median age of diagnosis is 73 years for bladder, 72 years for prostate and 70 years for renal cancer. Majority of the patients were Caucasians (89%) followed by African Americans (6%) and other races (4.98%). Grading of the tumor revealed that 12 patients had well differentiated tumor, 18 patients had moderately differentiated tumor, 191 patients had poorly differentiated, 292 patients had undifferentiated tumor and 219 patients had unknown grade. Pathological T-stages were as follows: T1= 34 (4.6%), T2= 102 (14%), T3= 43 (9%), T4= 41 (5.6%), 38.4% unknown T stage and 67 (9%) patients had metastatic disease. In majority of the patients the treatment received was unknown (565), 90 patients received external beam radiation, and 76 patients received surgery. Cancer-specific mortality was 54% in bladder cancer, 71% in prostate cancer and 78.6% in renal cancer. Median overall survival for all stages was 15.8 months in bladder cancer, 11.3 months in prostate cancer and 8 months in renal cancer. Conclusions: Results show that SCC is a highly aggressive tumor with poor prognosis. Clinical trials involving multiple institutes are needed to accrue enough patients so that treatment paradigms for this uncommon disease can be developed. No significant financial relationships to disclose.

Extracorporeal high intensity focused ultrasound for renal tumours: a 3‐year follow‐up

To determine whether primary extracorporeal high-intensity focused ultrasound (HIFU) is safe, feasible and effective for managing small renal tumours. Although surgery currently remains the standard treatment for localized renal cell carcinoma (RCC), the increasing incidence of small renal cancers has led to a shift towards nephron-sparing surgery, with associated morbidity in 20-25% of cases, and minimally invasive ablative therapies present an alternative management. HIFU results in 'trackless' homogenous tissue ablation and when administered via an extracorporeal device, is entirely noninvasive. The study comprised 17 patients (mean tumour size 2.5 cm) with radiologically suspicious renal tumours who underwent extracorporeal HIFU using the Model-JC System (Chongqing HAIFU™, China), under general anaesthesia with one overnight hospital stay. Real-time diagnostic ultrasonography was used for targeting and monitoring. Patients were followed with a clinical review and gadolinium-enhanced magnetic resonance imaging at 12 days and every 6 months for a mean of 36 months. The outcomes measures were patient morbidity and oncological efficacy of HIFU treatment. Of the 17 patients, 15 were treated according to protocol; two procedures were abandoned due to intervening bowel. There were no major complications related to HIFU. Radiological evidence of ablation was apparent at 12 days in seven of the 15 patients. Before the 6-month follow-up one patient had surgery due to persisting central enhancement. Fourteen patients were evaluated at the 6-month follow-up; eight tumours had involuted (mean 12% decrease in tumour area). Four patients had irregular enhancement on imaging and had alternative therapies. Ten patients remain on follow-up at a mean (range) of 36 (14-55) months after HIFU (mean 30% decrease in tumour area). There was central loss of enhancement in all. Renal HIFU achieves stable lesions in two-thirds of patients, with minimal morbidity, and might be appropriate in selected cases. Further trials with accurate histological follow-up are essential to fully evaluate this novel technique.

87 Robot-assisted renal tumorectomy for a small renal cell cancer

87 Robot-assisted renal tumorectomy for a small renal cell cancer

Delay surgery for small renal cancers to week 32 of gestation

Delay surgery for small renal cancers to week 32 of gestation

Pharmacognostic profile and &lt;i&gt;in vitro&lt;/i&gt; cytotoxic activity of &lt;i&gt;Adenema hyssopifolium&lt;/i&gt; G. Don

Pharmacognostic study of Adenema hyssopifolium was carried out to establish standards in agreement with those of WHO for vegetable drugs. Parameters examined include morphology, quantitative micrographic parameters, physical constant values, extractive values, behavior on treatment with different chemical reagents and fluorescence characters under ultraviolet light after treatment with different reagents. Phytochemical screening of the chloroform, ethyl acetate and ethanol extracts revealed the presence of flavones and iridoids. Chloroform, ethyl acetate and ethanolic extracts were investigated for in vitro cytotoxic activity against nine different types of human cancer panel of 60 different strains of tumor cell lines using the sulforhodamine-B (SRB) binding assay. The chloroform extract showed potent cytotoxicity against non small cell lung cancer cell, leukemia cell, ovarian cancer cell, prostate cancer cell and breast cancer cell lines with the GI50 of 2.66, 10, 10.8, 13 and 10.1 &mu;g/mL in NCI-H223, HL-60(TB), OVCAR-3, PC-3 and MDA-MB-231/ATCC cell lines respectively. Ethyl acetate extract exhibited potent cytotoxicity against non small cell lung cancer cell, colon, melanoma, renal and breast cancer cell lines with the GI50 of 12.7, 10.2, 10, 10.2 and 10.6 &mu;g/mL in EKVX, HCT-15, SK-MEL2, VO-31 and MCF7 cell lines respectively. The information from this study can explain the use of this plant in Indian traditional medicine and suggests great potential for further development into new pharmaceuticals.Keywords: Adenema hyssopifolium; Cytotoxic activity, Human cell lines, Iridoid glycosides; Microscopy

Editorial Comment

This is a very thought-provoking manuscript, with important information for the readership. The Surveillance, Epidemiology, and End Results (SEER) database is the gold standard for our epidemiologic research. The statistics and trends reported there are widely quoted in research articles and text books, and form the bases of our eduction. Coded Tumor Size May Be Unreliable for Small Metastatic Renal Cancers in the Surveillance, Epidemiology, and End Results DatasetUrologyVol. 75Issue 2PreviewTo report a weakness in the April 2006 release of the Surveillance, Epidemiology, and End Results (SEER) dataset, in which the primary tumor size of small (<1.8 cm) metastatic renal cancers was often incorrectly coded into the dataset from the measurement as listed in the patient's chart. Full-Text PDF

Bevacizumab Safety in Patients with Central Nervous System Metastases

Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified. A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified. In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage. In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non-small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials.

Coded Tumor Size May Be Unreliable for Small Metastatic Renal Cancers in the Surveillance, Epidemiology, and End Results Dataset

To report a weakness in the April 2006 release of the Surveillance, Epidemiology, and End Results (SEER) dataset, in which the primary tumor size of small (< 1.8 cm) metastatic renal cancers was often incorrectly coded into the dataset from the measurement as listed in the patient's chart. In the SEER dataset, 167 patients with tumor size < or = 2.5 cm had metastatic disease at presentation in 1998-2003. Each patient's chart was individually re-examined by SEER registries to determine the correct primary tumor size. This confirmed data were compared with the coded tumor size in the SEER dataset. Of the 167 re-examined cases, 2 had incorrect histology and 6 could not be verified. Of the remaining 159 cases, 87 (55%) were correctly coded for primary tumor size while 72 (45%) were incorrect. The error rate decreased with increasing size; for tumors < or = 1 cm, > 1-2 cm, and > 2-2.5 cm, error rates were 88%, 53%, and 6.8%, respectively (P < .001). A breakpoint in error rate occurred between tumor sizes < 1.8 cm (78%) and > or = 1.8 cm (10%) (P < .001). Most errors (72%) were miscoded by a factor of 10. Analysis of the latest April 2009 release suggests that most corrections have been incorporated into the public access dataset. Coded primary tumor sizes in the April 2006 release SEER dataset for metastatic renal tumors < 1.8 cm from 1998 to 2003 were often inaccurate. Verification of tumor size in this subset was essential to insure data accuracy and quality of research. Researchers should recognize potential limitations of population-based cancer registries.