ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma

Background

Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting.

Objective

To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification.

Design, setting, and participants

A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina.

Outcome measurements and statistical analysis

Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence.

Results and limitations

The subtypes were significantly associated with RFS (p < 0.01), CSS (p < 0.01), and OS (p < 0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms.

Conclusions

The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients.

Patient summary

We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.     

Biomechanical characteristics of the horizontal mattress stitch: implication for double-row and suture-bridge rotator cuff repair

Background

We investigated the effects of bite-size horizontal mattress stitch (distance between the limbs passed through the tendon) on the biomechanical properties of the repaired tendon.

Methods

We anchored 20 bovine Achilles tendons to bone using no. 2 high-strength suture and 5-mm titanium suture anchors in a mattress–suture technique. Tendons were allocated randomly into two groups of ten each to receive stitches with a 4- or 10-mm bite. Specimens underwent cyclic loading from 5 to 30 N at 1 mm/s for 30 cycles, followed by tensile testing to failure. Gap formation, tendon strain, hysteresis, stiffness, yield load, ultimate load, energy to yield load, and energy to ultimate load were compared between groups using unpaired t tests.

Results

The 4-mm group had less (p < 0.05) gap formation and less (p < 0.05) longitudinal strain than did the 10-mm group. Ultimate load (293.6 vs. 148.9 N) and energy to ultimate load (2,563 vs. 1,472 N-mm) were greater (p < 0.001) for the 10-mm group than the 4-mm group. All tendons repaired with 4-mm suturing failed at the suture–tendon interface, with sutures pulling through the tendon, whereas the suture itself failed before the tendon did in seven of the ten specimens in the 10-mm group.

Conclusions

Whereas a 4-mm bite fixed the tendon more tightly but at the cost of decreased ultimate strength, a 10-mm bite conveyed greater ultimate strength but with increased gap and strain. These results suggest that for the conventional double-row repair, small mattress stitches provide a tighter repair, whereas large stitches are beneficial to prevent sutures from pulling through the tendon after surgery. For suture-bridge rotator cuff repair, large stitches are beneficial because the repaired tendon has a higher strength, and the slightly mobile medial knot can be tightened by lateral fixation.     

Thymic carcinoma with rhabdoid features

A case of thymic carcinoma with rhabdoid differentiation is presented. A 67-year-old man who presented with chest pain and hemoptysis was referred to The University of Texas M. D. Anderson Cancer Center (Houston, TX). Radiologic studies revealed a large anterior mediastinal mass. After the initial biopsy and preoperative chemotherapy, a radical thymectomy revealed a stage III thymic carcinoma with a rhabdoid component. The rhabdoid component was characterized by large cells with an eccentric nucleus, prominent nucleolus, and typical paranuclear cytoplasmic inclusions. Immunohistochemical and electron microscopic studies confirmed the presence of rhabdoid cells with the paranuclear cytoplasmic inclusions staining for both pancytokeratin and vimentin. The patient was given postoperative chemotherapy and radiation. He has since developed metastases to the pelvis and is alive with disease at 20 months of follow-up. To our knowledge, this is the first reported case of thymic carcinoma with rhabdoid features.     

Incense stick ash as a novel and sustainable adsorbent for sequestration of Victoria Blue from aqueous phase

The present investigation assessed the applicability of incense stick ash, a novel and sustainable adsorbent for remediation of Victoria Blue dye from wastewater. Incense stick ash, without any physical and chemical treatment has been applied to investigate the influence of various experimental parameters as pH, loading of adsorbent, concentration, shaking time, temperature and ionic strength on Victoria Blue remediation in a batch operation. Incense stick ash was characterized using BET, DLS, SEM-EDS, FTIR and XRD techniques. BET surface area, pore volume and pore diameter of incense stick ash are obtained as 2.245 m² g^?1, 0.0118 cm³ g^?1 and 21.02 nm, respectively. Average particle size of the adsorbent is obtained as 293.2 nm. Goodness of the fit of isotherm and kinetic model to the reported data was identified based on chi squared and coefficient of determination values. Isotherm and kinetic behavior was best represented by Freundlich and pseudo 2nd order equation, respectively. Boyd model confirmed involvement of film diffusion mechanism along with intra-particle for adsorption of Victoria Blue on incense stick ash. Maximum dye uptake was reported as 105.57 mg g^?1. Thermodynamic study revealed spontaneous and favorable adsorption of Victoria Blue on incense stick ash at higher temperature. The performed elution and subsequent regeneration study implied desorption capability of incense stick ash and its applicability as a fresh adsorbent for further cycle of adsorption. The overall study implied scavenging potential of incense stick ash, a novel and sustainable adsorbent available at zero cost towards Victoria Blue removal.     

Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.     

Unexpected atypical findings on CT after radiofrequency ablation for small renal-cell carcinoma and the role of percutaneous biopsy

Radiofrequency ablation is a safe and effective treatment for small renal-cell carcinoma (RCC) in selected patients. After ablation, computed tomography or magnetic resonance imaging is used to confirm complete eradication or the presence of residual unablated tumor. The characteristic findings associated with these imaging techniques have been described previously. When the appearance of the ablated tumor deviates from expected findings, percutaneous biopsy is necessary to further evaluate the ablation zone. The present report describes three patients whose atypical findings after ablation of small RCC prompted percutaneous biopsy.     

Current medical therapy for chronic inflammatory bowel diseases

Chronic idiopathic inflammatory bowel diseases (IBD) include Crohn's disease (CD), ulcerative colitis (UC), and colonic IBD type unclassified (IBDU). This article focuses upon current medical therapies for adult CD and UC, and is organized according to therapy for the corresponding disease type, stage, and severity.     

Cytoreductive nephrectomy in the elderly patient: the M. D. Anderson Cancer Center experience

PURPOSE: Cytoreductive nephrectomy as part of a multidisciplinary approach may be considered in patients with metastatic renal cell carcinoma. The benefit in the elderly population (75 years or older) is unclear. We reviewed our experience to help determine if it is of benefit in this patient population. MATERIALS AND METHODS: Of 404 patients undergoing cytoreductive nephrectomy from 1995 and 2005 we identified 24 elderly patients. Outcomes in these elderly patients were analyzed and compared to outcomes in the remaining 380 who were younger than 75 years. RESULTS: Median age in the elderly and younger groups was 77.5 and 57.0 years, respectively. Performance status, sex distribution, and tumor histology, stage, grade and size were comparable. Estimated blood loss, transfusion rates, surgical times and hospital stay were similar in the 2 groups. There were 5 perioperative deaths (21%) in elderly patients compared to 4 (1.1%) in younger patients (p<0.01). Estimated blood loss, units transfused and surgical time were greater in the patients who died perioperatively (p<0.05). Median survival was 16.6 months in the elderly group, which did not differ statistically from the 13.7 months in the younger group. CONCLUSIONS: Cytoreductive nephrectomy in the elderly population can be associated with the potential for significant morbidity and mortality. Despite this and as part of a multidisciplinary approach it may provide potential survival as well as other benefits, which may justify it in highly select and highly motivated patients who are 75 years or older. However, it must be performed carefully with realistic expectations on behalf of the patient and urologist.     

Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy

OBJECTIVE

Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB.

RESEARCH DESIGN AND METHODS

We studied 40 obese (BMI 48 ± 8 kg/m²) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity.

RESULTS

Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP.

CONCLUSIONS

Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.Of the estimated 26 million people in the U.S. with type 2 diabetes and the 79 million with prediabetes (1), ∼80% are overweight or obese. Roux-en-Y gastric bypass (RYGB) surgery for treatment of obesity leads to long-term diabetes remission in ∼80% of patients (2), whereas very limited effects are observed with lifestyle intervention (3). Improvements in diabetes are reported to occur immediately after RYGB (4), with ∼30% of patients being discharged from the hospital with discontinuation of all diabetes medications (5).Impaired insulin sensitivity (insulin resistance) at the liver and in the periphery (primarily skeletal muscle) is an underlying mechanism of and precursor to diabetes (6). Several studies have described a long-term improvement in peripheral and hepatic insulin sensitivity 6 months to 1 year after RYGB (7–9), which is considered to occur secondary to weight loss. The mechanisms of the immediate improvement in diabetes after RYGB, before substantial weight loss, are not well delineated. Improvements in insulin sensitivity are reported early after RYGB, by hyperglycemic clamp at 1 and 4 weeks postoperatively (10) or by intravenous glucose tolerance tests (11) and homeostasis model assessment (HOMA) during the first week postoperatively (11,12). These approaches to measure insulin sensitivity, however, cannot distinguish between peripheral and hepatic insulin sensitivity. The hyperinsulinemic-euglycemic clamp method in conjunction with isotopically labeled tracer infusion allows measurement of peripheral (primarily skeletal muscle) insulin sensitivity as well as hepatic glucose production (HGP) and hepatic insulin sensitivity. Two studies have used this technique to assess insulin sensitivity early after RYGB, and interestingly, did not find a significant improvement in peripheral insulin sensitivity 2 to 4 weeks after RYGB; however, hepatic insulin sensitivity was not assessed (13,14). Recently, Camastra et al. (7) reported that peripheral and hepatic insulin sensitivity did not change at 2 weeks after RYGB in patients with and without diabetes.Increased visceral fat is considered an important risk factor for diabetes and insulin resistance (15). We recently reported, however, that surgical removal of the greater omentum (omentectomy) in conjunction with RYGB did not augment the improvement in insulin sensitivity long-term after RYGB (8). Here we report the acute effects of RYGB with or without omentectomy on hepatic and skeletal muscle insulin sensitivity. This was assessed by hyperinsulinemic-euglycemic clamp with tracer infusion at 1 month after RYGB. We also tested the hypothesis that an early remission of diabetes after RYGB is associated with improved hepatic and peripheral insulin sensitivity.