Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Observational determination of surface radiative forcing by CO2 from 2000 to 2010.

The climatic impact of CO2 and other greenhouse gases is usually quantified in terms of radiative forcing, calculated as the difference between estimates of the Earth's radiation field from pre-industrial and present-day concentrations of these gases. Radiative transfer models calculate that the increase in CO2 since 1750 corresponds to a global annual-mean radiative forcing at the tropopause of 1.82 ± 0.19 W m(-2) (ref. 2). However, despite widespread scientific discussion and modelling of the climate impacts of well-mixed greenhouse gases, there is little direct observational evidence of the radiative impact of increasing atmospheric CO2. Here we present observationally based evidence of clear-sky CO2 surface radiative forcing that is directly attributable to the increase, between 2000 and 2010, of 22 parts per million atmospheric CO2. The time series of this forcing at the two locations-the Southern Great Plains and the North Slope of Alaska-are derived from Atmospheric Emitted Radiance Interferometer spectra together with ancillary measurements and thoroughly corroborated radiative transfer calculations. The time series both show statistically significant trends of 0.2 W m(-2) per decade (with respective uncertainties of ±0.06 W m(-2) per decade and ±0.07 W m(-2) per decade) and have seasonal ranges of 0.1-0.2 W m(-2). This is approximately ten per cent of the trend in downwelling longwave radiation. These results confirm theoretical predictions of the atmospheric greenhouse effect due to anthropogenic emissions, and provide empirical evidence of how rising CO2 levels, mediated by temporal variations due to photosynthesis and respiration, are affecting the surface energy balance.

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies.

BACKGROUND: The clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC. PATIENTS AND METHODS: Baseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS). RESULTS: Eighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC. CONCLUSIONS: A subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.

Local staging of anal and distal colorectal tumors with the magnetic resonance endoscope.

BACKGROUND: We prospectively assessed the feasibility and accuracy of endoscopic magnetic resonance (EMR) scanning in the local staging of anal and colorectal cancer as compared to endosonography. METHODS: Fifteen patients with biopsy-proven anal (n = 2), rectal (n = 11), and distal colonic (n = 2) cancer underwent endosonography followed by EMR imaging. Scans were acquired using the magnetic resonance receiver coil incorporated into the tip of the non-ferromagnetic endoscope. Blinded to endosonography results, two radiologists interpreted the EMR images using the TNM system. Staging results were compared to endosonography in all patients and to histopathology in the 13 colorectal cases. RESULTS: EMR imaging, well tolerated in all patients, correlated with endosonography in 10 of 15 and 12 of 15 cases for T- and N-staging, respectively. In the 13 colorectal patients with available histopathology, accuracy of EMR and of endosonography in T-staging was 77% and 85%, respectively; N-staging accuracy was 62% for both. CONCLUSIONS: For anal and distal colorectal neoplasms, EMR imaging is feasible and provides local staging comparable to endosonography.

Local staging of esophageal cancer using endoscopic magnetic resonance imaging: prospective comparison with endoscopic ultrasound.

BACKGROUND AND STUDY AIMS: The magnetic resonance endoscope consists of a non-ferrous endoscope with a radiofrequency receiver coil incorporated into its tip. The aim of this study was to assess the accuracy of endoscopic magnetic resonance imaging for the local staging of esophageal cancer. PATIENTS AND METHODS: Prospectively, 15 patients with biopsy-proven cancer of the esophagus (n = 9) or gastroesophageal junction (n = 6) underwent endosonography followed by imaging by the magnetic resonance endoscope. The results of endoscopic magnetic resonance imaging were assessed blindly, then compared with those of endosonography, which served as the gold standard. RESULTS: Endoscopic magnetic resonance imaging of transmural tumor invasion agreed with ultrasonography in 11/15 cases and of nodal state in 12/15 cases. Endoscopic magnetic resonance images were inadequate in four cases as a result of motion artifacts. CONCLUSIONS: Endoscopic magnetic resonance imaging of esophageal cancer diagnoses local staging that is comparable to endosonography. In future, the combination of endoscopic and conventional magnetic resonance scanning may provide comprehensive staging of esophageal cancer.

Histological correlates to pig gastrointestinal wall layers imaged in vitro with the magnetic resonance endoscope.

BACKGROUND & AIMS: The magnetic resonance endoscope consists of a nonferromagnetic endoscope with a receiver coil incorporated into its tip. The aim of this study was to define the anatomic correlates of the gastrointestinal wall layers imaged in vitro with the magnetic resonance endoscope. METHODS: Twenty-two tissue specimens from various segments of the porcine gastrointestinal tract were imaged with the magnetic resonance endoscope using up to four different scanning sequences. Cyanoacrylate, serving as a marker, was randomly injected into the tissue strips before imaging. Histological sections were then compared with the magnetic resonance images. RESULTS: T1-weighted spin echo sequences yielded the highest image quality and typically showed three wall layers that corresponded to distinct histological layers. The mucosa showed high signal intensity, the submucosa low signal intensity, and the muscularis propria an intermediate signal intensity. In the esophagus and rectum, the muscularis propria could be visualized as separate circular and longitudinal layers. CONCLUSIONS: In vitro imaging with the magnetic resonance endoscope shows three to five wall layers of the porcine gastrointestinal tract depending on the segment scanned. This degree of gut wall resolution suggests that endoscopic magnetic resonance imaging may have potential for local staging of gastrointestinal tumors.

MR endoscopy: preliminary experience in human trials.

The authors performed local staging of esophageal and rectal cancer (without pathologic correlation) with use of a nonferromagnetic magnetic resonance (MR) endoscope with a 3-cm-long receive-only coil embedded in its tip in 16 patients (eight with esophageal cancer and eight with anorectal cancer). Results with spin-echo sequences were optimal in all cases [corrected].

Translational injuries in posterior elbow dislocation.

We describe a new plain radiographic finding in posterior elbow dislocation: a defect in the nonarticular posterior surface of the capitellum caused by impaction of the radial head during dislocation. The defect was visible on a lateral view unobscured by overlying bony structures in the unreduced state and confirmed on both an axial view after reduction and by magnetic resonance imaging. We propose that this lesion is analogous to the Hill-Sachs/Bankart lesion complex seen in translational glenohumeral injury.

[Initial experiences with magnetic resonance endoscopy]. / Erste Erfahrungen mit dem Magnetresonanz-Endoskop.

BACKGROUND: In contrast to endorectal surface coils used to assess pelvic tumors, the magnetic resonance endoscope (MR) has all the features of a standard endoscope. In ex-vivo imaging of the porcine gastrointestinal tract, endoscopic MR demonstrates distinct histological layers of the gastrointestinal wall. The aim of this study was to assess the feasibility and the accuracy of endoscopic MR in local staging of patients with esophageal and rectal cancer. METHODS: From April to August 1996, 12 patients (5 female and 7 male, mean age 63 [range 44-84] years) with histologically proven esophageal (n = 6) and rectal (n = 6) cancer prospectively underwent endoscopic ultrasound (EUS) followed by endoscopic MR. The two radiologists reviewing the endoscopic MR images were blinded to the EUS results. Assessment of T and N stages was compared to EUS and histology. RESULTS: Endoscopic MR was well tolerated in all patients and there were no complications. Image quality was sufficient in 75%. Endoscopic MR T-staging correlated with EUS and histology in 7/12 and 5/7 patients respectively. Discordance was due to overstaging by endoscopic MR. N-staging correlated with EUS and histology in 10/12 and 6/8 cases respectively. Non-correlation was due to a number of false negative results at endoscopic MR. CONCLUSION: These early results demonstrate endoscopic MR to be feasible and to produce comparable local staging to EUS in patients with esophageal and rectal cancer. The ultimate goal will be to combine endoscopic MR with body coil MR imaging (for the assessment of distant metastases) in order to provide "one-step staging" for the entire evaluation of gastrointestinal tumors.

Magnetic resonance cholangiopancreatography: a novel approach to the evaluation of suspected pancreaticobiliary neoplasms.

BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) is a new noninvasive diagnostic method for pancreaticobiliary (PB) imaging without endoscopy, sedation, or iodinated contrast. The purpose of this study was to evaluate the ability of MRCP to depict pancreatic and biliary ductal anatomy compared to that of endoscopic retrograde cholangiopancreatography (ERCP) and to evaluate the ability of MRCP to accurately diagnose PB neoplasms. METHODS: Twenty patients had MRCP, and 17 also had ERCP. All studies were read prospectively by experienced reviewers blinded to other imaging data. Pathologic diagnosis was made in all patients. RESULTS: Bile duct dilatation seen by ERCP in 14 of 17 patients was correctly identified by MRCP in all 14 patients, and normal ducts were correctly identified by MRCP in the other 3 patients. The pancreatic duct was visible on MRCP in the pancreatic head in 17 of 20 patients, the body in 17 of 20 patients, and the tail in 15 of 20 patients. At ERCP, pancreatic duct dilatation was present in 11 cases and was identified by MRCP in 10 of them. Eighteen of 20 patients had malignant PB neoplasms. MRCP indicated PB neoplasm in 19 patients. Seventeen of these 19 patients had histologically confirmed malignant neoplasms pathologically, whereas 2 had benign pathology (both chronic pancreatitis). Among the 17 patients who also had ERCP, MRCP and ERCP correctly agreed on a final diagnosis of malignant neoplasm in 14 cases. In the three cases in which MRCP and ERCP disagreed on a final diagnosis, MRCP was correct in one and incorrect in two. CONCLUSIONS: MRCP can accurately and noninvasively delineate PB ductal anatomy and diagnose PB neoplasms comparably to ERCP. MRCP is an interesting new noninvasive method for evaluating patients with suspected PB neoplasms.

Multicentric Castleman's disease: imaging findings.

Multicentric Castleman's disease is an unusual lymphoproliferative lesion typically associated with systemic manifestations and specific histopathology. We describe two cases of pathologically proven multicentric Castleman's disease along with radiographic and ultrasonographic findings.

Pseudostripe sign in lobar collapse.

The stripe sign in perfusion lung scanning refers to an area of focal hypoperfusion that fails to extend to the pleural surface, leaving a peripheral rim of perfused parenchyma. Although experimental evidence suggests that the stripe sign is caused by central pulmonary emphysema, we report a case of an identical perfusion defect related to a completely collapsed left lower lobe. This etiology should be considered in the differential diagnosis of the stripe sign.

Trans-jugular extraction of bullet embolus to the heart.

Bullet emboli to the heart are rare and are typically treated by operative extraction through a median sternotomy and cardiotomy. This report details the case of an 18-year-old male who sustained two gunshot wounds, one of which lodged in his left renal vein. At laparotomy, the bullet embolized to the right atrium via the inferior vena cava. Under fluoroscopic guidance the bullet was retrieved with a snare introduced percutaneously through the right internal jugular vein. Sternotomy and possible cardiopulmonary bypass were avoided.

Crutch-induced axillary artery injury.

PURPOSE: To describe the spectrum of radiologic findings in crutch-induced axillary artery injury and the effects of its unique pathophysiology on diagnostic evaluation and treatment. METHODS: Three patients with axillary crutch-induced axillobrachial injury were studied angiographically and percutaneous intervention was performed in two cases. RESULTS: One patient required surgical bypass of a thrombosed axillary artery aneurysm. One patient responded to percutaneous transluminal angioplasty (PTA) of a focal axillary artery stenosis. One patient with an axillary artery aneurysm and distal thromboembolic disease was treated by both thrombolysis and surgical thromboembolectomy and later by PTA of an axillary artery intimal disruption. CONCLUSION: Chronic axillary crutch use may be associated with axillary artery stenosis, aneurysm formation, and secondary axillobrachial thromboembolic disease. Mural injury can be successfully treated by PTA and thromboembolic disease by thrombolytic therapy. Early identification of the axillary artery lesion is critical for long-term therapeutic results.

Multiple symmetrical lipomatosis: computed tomographic appearance.

In a case of localized multiple symmetrical lipomatosis (Madelung's disease), we examined the cervical fat accumulation by computed tomography. We describe the radiographic features of this process and briefly review the pathophysiology of this rare disorder.

Phosphatidylcholine hydrolysis stimulated by phorbol myristate acetate is mediated principally by phospholipase D in endothelial cells.

The mechanism of phosphatidylcholine (PC) degradation stimulated by phorbol myristate acetate (PMA) was investigated in bovine pulmonary artery endothelial cells prelabeled with [methyl-3H]choline ([3H]choline) or [9,10-3H]myristic acid ([3H]myristic acid). Both labels were selectively incorporated into PC, and addition of PMA stimulated comparable losses of 3H from PC in cells prelabeled with [3H]choline or [3H]myristate. In cells prelabeled with [3H]choline, the loss of 3H from PC correlated with a rapid increase in intracellular free [3H]choline. The increase in intracellular [3H]choline stimulated by PMA was not preceded by an increase in any other 3H-labeled PC degradation product. PMA did not stimulate the formation of PC deacylation products in cells prelabeled with [3H]choline. In permeabilized cells prelabeled with [3H]choline, PMA stimulated the formation of [3H]choline but not [3H]phosphocholine. In intact cells prelabeled with [3H]myristate, the loss of 3H from PC induced by PMA correlated with the formation of [3H]phosphatidic acid ([3H]PA) and [3H]diacylglycerol. In the presence of ethanol, PMA stimulated the formation of [3H]phosphatidylethanol ([3H]PEt) at the expense of [3H]PA. The time-course of [3H]PEt formation was similar to the time-course of intracellular [3H]choline formation in cells stimulated with PMA. These data taken together support the notion that PC degradation in endothelial cells stimulated with PMA is mediated principally by phospholipase D. PC breakdown via phospholipase D was not observed in cells treated with phorbol esters incapable of interacting with protein kinase C. Activation of phospholipase D by phorbol esters was inhibited by long-term pretreatment of cells with PMA to down-regulate protein kinase C and by pretreatment of the cells with staurosporine. These data support the notion that activation of phospholipase D by phorbol esters is dependent upon protein kinase C.

Long-term phorbol ester treatment dissociates phospholipase D activation from phosphoinositide hydrolysis and prostacyclin synthesis in endothelial cells stimulated with bradykinin.

Bovine pulmonary artery endothelial cells (BPAEC) were prelabeled with [3H]choline or [3H]myristic acid to selectively label endogenous phosphatidylcholine. BPAEC were stimulated with ATP and bradykinin (BK), and phospholipase D (PLD) activation was detected as a 4-fold increase in [3H]choline in cells prelabeled with [3H]choline or as a 2- to 3-fold increase in [3H]phosphatidylethanol in cells prelabeled with [3H]myristic acid and stimulated in the presence of ethanol. Pretreatment of BPAEC with 0.1 microM phorbol 12-myristate 13-acetate (PMA) for 22 hr completely inhibited agonist-induced PLD activation, whereas prostacyclin synthesis and [3H]phosphoinositide ([3H]PIns) hydrolysis were enhanced in pretreated cells. Long-term PMA treatment thus dissociates agonist-induced PLD activation from [3H]PIns hydrolysis, and agonist-induced prostacyclin synthesis is not dependent upon PLD activation.