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We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER) + /HER2 - advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity. Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up. Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER + /HER2 - advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACR See related commentary by Jordan, p. 3480 ., (©2018 American Association for Cancer Research.)

Purpose: To retrospectively evaluate gadoxetic acid-enhanced magnetic resonance angiography (MRA) using controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) technique for mapping hepatic vascular anatomy in potential living liver donors, with CT angiography (CTA) as reference standard., Methods: 82 potential living liver donors who underwent MRA and CTA were enrolled in this HIPAA-compliant IRB-approved study. MRA and CTA images were evaluated by two reviewers in consensus with respect to (1) image quality scores for depiction of the hepatic vessels and (2) accuracy of MRA for determining the hepatic vascular variants with CTA as reference standard. The image quality scores were compared using Fisher's exact test between MRA and CTA., Results: The accuracy for determining the hepatic arterial, portal, and hepatic venous variants and segment IV arterial origin was 73, 90, 79, and 55%, respectively, compared to CTA. However, subjective image quality for depiction of hepatic arteries in MRA was significantly lower than CTA (p < 0.001). The portal and hepatic venous image quality was almost equal in both modalities (p = 0.059) except left hepatic vein being depicted better on CT images (p = 0.023)., Conclusion: Gadoxetic acid-enhanced MRA using CAIPIRINHA technique is feasible for mapping hepatic vasculature in potential living liver donors, with moderate accuracy for arterial variants and good to excellent results for hepatic and portal vein variants, compared with CTA. However, the specific delineation of segment IV arterial origin was possible in just over half of the liver donors with MRA.

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of 89 Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with 89 Zr. Patients underwent PET/CT with 74 MBq of 89 Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered 89 Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. 89 Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, 89 Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the 89 Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with 89 Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To correlate qualitative and quantitative diffusion weighted imaging (DWI) characteristics of intrahepatic cholangiocarcinoma (ICC) with histopathologic tumour grade and fibrosis content., Methods: Fifty-one patients (21M/30F; mean age 61y) with ICC and MRI including DWI were included in this IRB-approved multicentre retrospective study. Qualitative tumour features were assessed. Tumour apparent diffusion coefficient (ADC) mean, minimum, and normalized (nADC liver ) values were computed. Tumour grade [well(G1), moderately(G2), or poorly differentiated(G3)] and tumour fibrosis content [minimal(1), moderate(2), or abundant(3)] were categorized pathologically. Imaging findings and ADC values were compared with pathologic measures. Utility of ADC values for predicting tumour grade was assessed using ROC analysis., Results: 51 ICCs (mean size 6.5±1.1 cm) were assessed. 33/51(64%) of ICCs demonstrated diffuse hyperintensity and 15/51(29%) demonstrated target appearance on DWI. Infiltrative morphology (p=0.02) and tumour size (p=0.04) were associated with G3. ADCmean and nADCmean of G3 (1.32±0.47x10 -3 mm 2 /sec and 0.97±0.95) were lower than G1+G2 (1.57±0.39x10 -3 mm 2 /sec and 1.24±0.49; p=0.03 and p=0.04). ADCmean and nADCmean were inversely correlated with tumour grade (p<0.025). No correlation was found between ADC and tumour fibrosis content. AUROC, sensitivity and specificity of nADCmean for G3 versus G1+G2 were 0.71, 89.5% and 55.5%., Conclusion: ADC quantification has reasonable accuracy for predicting ICC grade., Key Points: • ADC quantification was useful for predicting ICC tumour grade. • Infiltrative tumour morphology and size were associated with poorly differentiated ICCs. • ADC values depended more on ICC tumour grade than fibrosis content. • Ability to predict ICC tumour grade non-invasively could impact patient management.

The purpose of this study is to determine whether magnetic resonance (MR)-proton density fat fraction (PDFF) estimate of negligible hepatic fat percentage (<5%) can exclude significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy and to perform intraindividual comparisons between MR-PDFF techniques for hepatic steatosis quantification. In an ethics-approved retrospective study, 144 liver donor candidates with magnetic resonance spectroscopy (MRS) and 6-echo Dixon magnetic resonance imaging (MRI) between 2013 and 2015 were included. A subset of 32 candidates underwent liver biopsy. Hepatic fat percentage was determined using MR-PDFF and histopathology-determined fat fraction as the reference standard. A receiver operating characteristic analysis with positive predictive value, negative predictive value (NPV), sensitivity, and specificity was performed to discriminate between clinically significant steatosis (≥10%) or not (<10%) at MRS-PDFF and MRI-PDFF thresholds of 5% and 10%. Pearson correlation and Bland-Altman analyses between MRS-PDFF and MRI-PDFF were performed for intraindividual comparison of hepatic steatosis estimation. There was significant association between MRS-PDFF and MRI-PDFF with HP-FP. High NPV of 95% (95% confidence interval [CI], 78%-99%) and 100% (95% CI, 76%-100%) as well as an area under the curve of 0.90 (95% CI, 0.79-1.0) and 0.93 (95% CI, 0.84-1.0) were obtained with a cutoff threshold of 5% MRI-PDFF and MRS-PDFF, respectively, to exclude clinically significant steatosis (≥10%). Intraindividual comparison between MRS-PDFF and MRI-PDFF showed a Pearson correlation coefficient of 0.83. Bland-Altman analysis showed a mean difference of 1% with 95% limits of agreement between -1% and 3%. MR-PDFF estimate of negligible hepatic fat percentage (<5%) has sufficient NPV for excluding clinically significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy. It may be sufficient to acquire only the multiecho Dixon MRI-PDFF for hepatic steatosis estimation. Liver Transplantation 24 470-477 2018 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Theoretically driven smartphone-delivered behavioral interventions that target mechanisms underlying eating behavior are lacking. In this study, we administered a 28-day self-paced smartphone-delivered intervention rooted in an operant conditioning theoretical framework that targets craving-related eating using mindful eating practices. At pre-intervention and 1-month post-intervention, we assessed food cravings among adult overweight or obese women (N = 104; M age = 46.2 ± 14.1 years; M BMI = 31.5 ± 4.5) using ecological momentary assessment via text message (SMS), self-reported eating behavior (e.g., trait food craving), and in-person weight. Seventy-eight participants (75.0%) completed the intervention within 7 months ('all completers'), and of these, 64 completed the intervention within 3 months ('timely completers'). Participants experienced significant reductions in craving-related eating (40.21% reduction; p < .001) and self-reported overeating behavior (trait food craving, p < .001; other measures ps < .01). Reductions in trait food craving were significantly correlated with weight loss for timely completers (r = .30, p = .020), this pattern of results was also evident in all completers (r = .22, p = .065). Taken together, results suggest that smartphone-delivered mindful eating training targeting craving-related eating may (1) target behavior that impacts a relative metabolic pathway, and (2) represent a low-burden and highly disseminable method to reduce problematic overeating among overweight individuals. ClinicalTrials.gov registration: NCT02694731.

Purpose: We evaluated intervention rates, progression and cancer specific survival outcomes in patients with complex renal cysts in a single center experience., Materials and Methods: We used the Montage™ radiology data mining system to retrospectively identify all reported cases of complex renal cyst at our institution from 2001 to 2013. The primary study end points were overall and cancer specific survival. The secondary end points included radiographic progression and upgrading, clinical progression and final histology on surgical pathology., Results: We identified 336 patients with a complex renal cyst, of whom 185 (55.1%), 122 (36.3%) and 29 (8.6%) had Bosniak IIF, III and IV cysts, respectively. Median followup was 67.1 months (range 34.4 to 101.6). In the 332 patients with followup there was 1 cancer specific death (0.3%) and overall mortality was 6.2%. Ten (5.4%), 37 (30.3%) and 18 patients (62.1%) with Bosniak IIF, III and IV, respectively, underwent surgical or ablative intervention. The indication for intervention was predominantly age (intervention vs no intervention mean ± SD age 50.1 ± 15.9 vs 62.5 ± 13.9 years) and complexity. Surgery with radical and partial nephrectomy (23 patients or 35% and 37 or 57%, respectively) was most common and favorable final pathology was identified. Two treated patients experienced recurrence during followup. When excluding patients with von Hippel-Lindau syndrome, the cancer specific survival rate was 100%., Conclusions: Cancer survival and overall survival in patients with Bosniak IIF to IV renal cysts was high with only 1 cancer specific death. No cancer deaths were recorded in patients who did not undergo intervention. Reconsidering management guidelines for complex renal cysts is warranted, particularly consideration for initial surveillance of Bosniak III cysts., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver tumor, which has overlapping imaging features with mass forming intra-hepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Previous studies reported imaging features more closely resemble ICC and the aim of our study was to examine the differential MRI features of cHCC-CC and ICC with emphasis on enhancement pattern observations of gadolinium enhanced MRI., Methods: Institutional review board approval with consent waiver was obtained for this retrospective bi-centric study. Thirty-three patients with pathologically proven cHCC-CC and thirty-eight patients with pathologically proven ICC, who had pre-operative MRI, were identified. MRI images were analyzed for tumor location and size, T1 and T2 signal characteristics, the presence/absence of: cirrhosis, intra-lesional fat, hemorrhage/hemosiderin, scar, capsular retraction, tumor thrombus, biliary dilatation, degree of arterial enhancement, enhancement pattern, pseudocapsule and washout. Associations between MRI features and tumor type were examined using the Fisher's exact and chi-square tests., Results: Strong arterial phase enhancement and the presence of: washout, washout and progression, intra-lesional fat and hemorrhage were all strongly associated with cHCC-CC (P < 0.001). While cHCC-CC had a varied enhancement pattern, the two most common enhancement patterns were peripheral persistent (n = 6) and heterogeneous hyperenhancement with washout (n = 6), compared to ICC where the most common enhancement patterns were peripheral hypoenhancement with progression (n = 18) followed by heterogeneous hypoenhancement with progression (n = 14) (P < 0.001)., Conclusion: The cHCC-CC enhancement pattern seems to more closely resemble HCC with the degree of arterial hyperenhancement and the presence of washout being valuable in differentiating cHCC-CC from ICC. However the presence of washout and progression, in the same lesion or a predominantly peripheral /rim hyperenhancing mass were also seen as important features that should alert the radiologist to the possibility of a cHCC-CC.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

Background and Purpose: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets., Methods: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3 + Helios + ) and other immune cell subsets were monitored during treatment and compared with healthy controls., Results: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naïve Tregs [greater than 2.5 (the median of the naïve Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naïve Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of  %CD4 + Naïve T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40)., Conclusion: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naïve Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.

Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.

Purpose: Diffusion-weighted imaging (DWI) and 18 F-fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET) independently correlate with malignancy in breast cancer, but the relationship between their structural and metabolic metrics is not completely understood. This study spatially correlates diffusion, perfusion, and glucose avidity in breast cancer with simultaneous PET/MR imaging and compares correlations with clinical prognostics., Methods: In this Health Insurance Portability and Accountability Act-compliant prospective study, with written informed consent and approval of the institutional review board and using simultaneously acquired FDG-PET and DWI, tissue diffusion (D t ), and perfusion fraction (f p ) from intravoxel incoherent motion (IVIM) analysis were registered to FDG-PET within 14 locally advanced breast cancers. Lesions were analyzed using 2D histograms and correlation coefficients between D t , f p , and standardized uptake value (SUV). Correlations were compared with prognostics from biopsy, metastatic burden from whole-body PET, and treatment history., Results: SUV||D t correlation coefficient significantly distinguished treated (0.11 ± 0.24) from nontreated (-0.33 ± 0.26) patients (P = 0.005). SUV||f p correlations were on average negative for the whole cohort (-0.17 ± 0.13)., Conclusion: Simultaneously acquired and registered FDG-PET/DWI allowed quantifiable descriptions of breast cancer microenvironments that may provide a framework for monitoring and predicting response to treatment. Magn Reson Med 78:1147-1156, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Background: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer., Methods: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m 2 ) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m 2 , 150 mg/m 2 , and a third cohort of 125 mg/m 2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy., Results: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2-4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8-55)., Conclusion: The RP2D of ganetespib is 150 mg/m 2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer., Trial Registration: ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

Hepatic fibrosis is potentially reversible; however early diagnosis is necessary for treatment in order to halt progression to cirrhosis and development of complications including portal hypertension and hepatocellular carcinoma. Morphologic signs of cirrhosis on ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) alone are unreliable and are seen with more advanced disease. Newer imaging techniques to diagnose liver fibrosis are reliable and accurate, and include magnetic resonance elastography and US elastography (one-dimensional transient elastography and point shear wave elastography or acoustic radiation force impulse imaging). Research is ongoing with multiple other techniques for the noninvasive diagnosis of hepatic fibrosis, including MRI with diffusion-weighted imaging, hepatobiliary contrast enhancement, and perfusion; CT using perfusion, fractional extracellular space techniques, and dual-energy, contrast-enhanced US, texture analysis in multiple modalities, quantitative mapping, and direct molecular imaging probes. Efforts to advance the noninvasive imaging assessment of hepatic fibrosis will facilitate earlier diagnosis and improve patient monitoring with the goal of preventing the progression to cirrhosis and its complications.

Aim: To determine whether a combination of clinical factors, the future liver remnant (FLR) ratio, and hepatic uptake of gadoxetic acid can be used to predict post-hepatectomy liver failure (PHLF) and other major complications (OMC)., Materials and Methods: Sixty-five consecutive patients who underwent pre-hepatectomy gadoxetic acid-enhanced magnetic resonance imaging (MRI) between October 2010 and December 2013 were included. The relative liver enhancement (RLE) of gadoxetic acid was calculated from regions of interest on MRI, and FLR ratios were obtained from computed tomography (CT). PHLF and OMC were defined by the International Study Group of Liver Surgery criteria and Clavien-Dindo grade of ≥3, respectively. Multivariate logistic regression modelling was performed to identify predictors of PHLF and OMC, including RLE, FLR ratio, age, sex, chemotherapy history, intra-operative blood loss, and intra-operative transfusion., Results: Nine patients experienced PHLF and another nine patients experienced OMC. RLE was comparable to the FLR ratio in predicting PHLF (areas under the receiver operating characteristic [AUROC] curves, 0.665 and 0.705), but performed poorly in predicting OMCs (AUROCs, 0.556 and 0.702). Combining all clinical and imaging parameters as predictors yielded the best performing predictive models (AUROCs, 0.875 and 0.742 for PHLF and OMC, respectively)., Conclusion: A model based on clinical parameters, the FLR ratio, and RLE of gadoxetic acid may improve pre-hepatectomy risk assessment., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the feasibility of semi-LASER renal magnetic resonance spectroscopy (MRS) in healthy volunteers and establish signature chemical composition of normal renal tissue towards future application for renal carcinoma characterization and grading., Materials and Methods: 14 healthy volunteers were recruited after informed consent. Single voxel 1 H spectra were acquired on a 3T MRI system using a semi-LASER sequence, employing outer-volume suppression and VAPOR water suppression with multiple averages in multiple breath-holds. Off-line processing and automatic correction for zero-order phase and frequency using the water resonance or residual water resonance for water-suppressed acquisitions was performed., Results: 11 volunteers successfully completed the entire examination. Phase and frequency correction was necessary to obtain optimal data quality prior to signal summation in few datasets. No lipid resonance was observed in any spectra from the unsuppressed water acquisitions, either in individual transients or in corrected summed spectra opposed to previously reported studies. No signal from other metabolites, such as choline-containing compounds, was observed in any dataset., Conclusion: Semi-LASER renal MRS is technically feasible. Normal renal parenchyma does not demonstrate detectable levels of lipid or choline. This may provide a reference point for future application of this technique for noninvasive renal carcinoma histologic subtype characterization and grade., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Motivation is an integral factor in substance use treatment and long-term recovery. However, it is unclear what role intrinsic and extrinsic motivation play across different treatment modalities. A meta-analysis (N = 84) was performed to estimate the pooled effect size of Motivational Interviewing (MI; primarily targeting intrinsic motivation) and contingency management (CM; primarily targeting extrinsic motivation) at different follow-up periods. Collapsed across all substance types, CM had a significant effect at 3-month follow-up, only. In contrast, MI had a significant effect at 6-month follow-up, only. CM had small and medium effects on multiple substances at 3-month follow-up (i.e., tobacco, marijuana, stimulants, polysubstances), but not at 6-month follow-up. MI had 1 significant medium effect at 3-month follow-up (i.e., marijuana), but several significant small effects at 6-month follow-up (i.e., alcohol, tobacco, polysubstances). This meta-analysis suggests that both CM and MI promote reductions in a range of substances, even several months after the intervention concludes. Further, these results provide some evidence that extrinsically focused CM may produce medium follow-up effects in the short run, but intrinsically focused MI may produce small but durable follow-up effects. However, this interpretation is complicated by the differences between the MI and CM studies that preclude statistical tests comparing effect sizes, and few studies assessed motivation itself. Future researchers should investigate how motivational dynamics impact lasting outcomes in substance use treatment. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Although a common occurrence, cystic lesions of the pancreatico-biliary tree (PBT) may pose a diagnostic dilemma because they encompass a large number of neoplastic and benign processes with varied clinical symptoms. Knowledge of lesion classification and characterization are essential in making an accurate prospective diagnosis. This is necessary for identifying clinically significant cystic masses, which at times may require invasive intervention from indolent, nonneoplastic lesions, for which surveillance may suffice. Today, there is an arsenal of modalities for assessing the PBT, however, magnetic resonance imaging (MRI) remains at the forefront for characterizing cystic morphology and fluid content, internal septations, solid component, enhancement patterns, as well as assessing the surrounding normal structures. This pictorial review aims to review the spectrum of MRI features, which will aid in the differential diagnoses of cystic lesions of the PBT and mimickers, enabling the radiologist to reach a more confident diagnosis., Competing Interests: There are no conflicts of interest.

Purpose To compare fluorine 18 ((18)F) fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and magnetic resonance (MR) imaging with (18)F FDG combined PET and computed tomography (CT) in terms of organ-specific metastatic lesion detection and radiation dose in patients with breast cancer. Materials and Methods From July 2012 to October 2013, this institutional review board-approved HIPAA-compliant prospective study included 51 patients with breast cancer (50 women; mean age, 56 years; range, 32-76 years; one man; aged 70 years) who completed PET/MR imaging with diffusion-weighted and contrast material-enhanced sequences after unenhanced PET/CT. Written informed consent for study participation was obtained. Two independent readers for each modality recorded site and number of lesions. Imaging and clinical follow-up, with consensus in two cases, served as the reference standard. Results There were 242 distant metastatic lesions in 30 patients, 18 breast cancers in 17 patients, and 19 positive axillary nodes in eight patients. On a per-patient basis, PET/MR imaging with diffusion-weighted and contrast-enhanced sequences depicted distant (30 of 30 [100%] for readers 1 and 2) and axillary (eight of eight [100%] for reader 1, seven of eight [88%] for reader 2) metastatic disease at rates similar to those of unenhanced PET/CT (distant metastatic disease: 28 of 29 [96%] for readers 3 and 4, P = .50; axillary metastatic disease: seven of eight [88%] for readers 3 and 4, P > .99) and outperformed PET/CT in the detection of breast cancer (17 of 17 [100%] for readers 1 and 2 vs 11 of 17 [65%] for reader 3 and 10 of 17 [59%] for reader 4; P < .001). PET/MR imaging showed increased sensitivity for liver (40 of 40 [100%] for reader 1 and 32 of 40 [80%] for reader 2 vs 30 of 40 [75%] for reader 3 and 28 of 40 [70%] for reader 4; P < .001) and bone (105 of 107 [98%] for reader 1 and 102 of 107 [95%] for reader 2 vs 106 of 107 [99%] for reader 3 and 93 of 107 [87%] for reader 4; P = .012) metastases and revealed brain metastases in five of 51 (10%) patients. PET/CT trended toward increased sensitivity for lung metastases (20 of 23 [87%] for reader 1 and 17 of 23 [74%] for reader 2 vs 23 of 23 [100%] for reader 3 and 22 of 23 [96%] for reader 4; P = .065). Dose reduction averaged 50% (P < .001). Conclusion In patients with breast cancer, PET/MR imaging may yield better sensitivity for liver and possibly bone metastases but not for pulmonary metastases, as compared with that attained with PET/CT, at about half the radiation dose. (©) RSNA, 2016 Online supplemental material is available for this article., Competing Interests: of Conflicts of Interest: A.N.M. disclosed no relevant relationships. R.A.R. disclosed no relevant relationships. A.C.P. disclosed no relevant relationships. F.D.P. disclosed no relevant relationships. K.M.P. disclosed no relevant relationships. K.J. disclosed no relevant relationships. J.S.B. disclosed no relevant relationships. E.E.S. disclosed no relevant relationships. S.G.K. disclosed no relevant relationships. L.A.M. disclosed no relevant relationships.

Magnetic resonance (MR) imaging is increasingly being used for comprehensive evaluation of liver diseases in children because of the lack of radiation and better lesion detection and characterization. Liver examination involves routine sequences such as T2-weighted, balanced steady-state free precession, and in-phase and out-of-phase sequences. Dynamic imaging is an essential component of liver examination to characterize focal lesions and involves capturing snapshots of the passage of contrast material in the arterial, portal venous, equilibrium, and sometimes hepatobiliary phases, generally by using T1-weighted three-dimensional gradient-echo sequences. Optimal arterial phase imaging is important for detection and characterization of hypervascular lesions. In the equilibrium phase, the concentration of contrast material is similar in the microvasculature and the extracellular interstitial space. Some superficial, spreading, inflammatory lesions are better seen on equilibrium phase images. Meticulous attention to intravenous access and use of an appropriate timing method are critical for successful dynamic imaging. Commonly used contrast media for liver imaging include gadolinium-based extracellular contrast agents and hepatobiliary contrast agents. A portion of hepatobiliary contrast agents such as gadoxetate and gadobenate is taken up by hepatocytes and excreted through bile. Hepatobiliary phase images acquired after hepatobiliary contrast agent administration are increasingly used to characterize liver lesions in children, such as focal nodular hyperplasia. Interpretation of liver MR images involves synthesis of information acquired from evaluation of background hepatic parenchyma, detection of lesions, and evaluation of signal intensity characteristics on images obtained with various sequences to arrive at a diagnosis or reasonable differential diagnoses. Understanding the appropriate technique, sequences, and contrast media when performing pediatric liver MR imaging is important for high diagnostic yield. (©)RSNA, 2016.

Introduction: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors., Patients and Methods: Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test., Results: Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001)., Conclusion: Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The natural history of renal angiomyolipoma (AML) is unknown. Treatment recommendations are based on smaller case series, with selection bias towards symptomatic patients., Objective: To define the natural history of renal AML, including growth rates, size, and clinical presentation., Design, Setting, and Participants: We used a unique radiology data-mining system (Montage; Montage Healthcare Systems, Philadelphia, PA, USA) to retrospectively review the radiology database in an academic health centre between 2002 and 2013 to identify all renal AMLs. Of 2741 patients identified, 447 with 582 AMLs had three or more imaging studies suitable for analysis., Intervention: Angioembolisation, surgery, radiofrequency ablation, and mammalian target of rapamycin inhibitors., Outcome Measurements and Statistical Analysis: The primary end point was the growth rate of untreated AMLs. We used a linear mixed-effects model to determine change in growth rate over time. We evaluated the association among growth rate, size, and patient factors as well as interventions., Results and Limitations: The majority of untreated AMLs (>92%) had not grown at a median follow-up of 43 mo, with no difference in growth rates between AMLs ≤4 and >4cm. Most AMLs occurred in female participants (80%) and were asymptomatic (91%). Tuberous sclerosis complex (TSC) was confirmed in 3.8% (n=17) and presented at an earlier age. Median size was 1cm but was significantly larger for TSC (5.5cm; p<0.001). Interventions were performed in 5.6% of patients. Limitations of our study include the retrospective design, selection against fat-poor AMLs, and lack of histology., Conclusions: This large, single-institution series on AMLs confirms that lesions >4cm do not require early intervention based on size alone. The vast majority are sporadic, asymptomatic, and initially harmless, with a negligible growth rate. Our findings support a policy of initial active surveillance for all asymptomatic AMLs., Patient Summary: We evaluated the natural history and growth rates of renal AMLs. We found no difference in growth rates between AMLs >4 and ≤4cm. Initial AS appears to be a safe management option., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs)., Patients and Methods: Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed., Results: Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2., Conclusion: IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The success of breast cancer therapy is ultimately defined by clinical endpoints such as survival. It is valuable to have biomarkers that can predict the most efficacious therapies or measure response to therapy early in the course of treatment. Molecular imaging has a promising role in complementing and overcoming some of the limitations of traditional biomarkers by providing the ability to perform noninvasive, repeatable whole-body assessments. The potential advantages of imaging biomarkers are obvious and initial clinical studies have been promising, but proof of clinical utility still requires prospective multicenter clinical trials., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Since the approval of trastuzumab, a humanized monoclonal antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2), 3 other HER2-targeting agents have gained regulatory approval: lapatinib, pertuzumab, and trastuzumab-emtansine. These agents have revolutionized the management of HER2-positive breast cancer, highlighting the concept that targeted therapies are successful when patients exhibit tumor-selective expression of a molecular target-in this case, HER2. However, response prediction and innate or acquired resistance remain serious concerns. Predictive biomarkers of a response-which could help in the selection of patients who might benefit from a selected targeted therapy-are currently lacking. Molecular imaging with anti-HER2 probes allows the noninvasive, whole-body assessment of HER2 tumor burden and has the potential to improve patient selection, optimize the dose and schedule, and rationalize assessment of the response to anti-HER2 therapies. Furthermore, unlike biopsy-based HER2 assessment, this approach can reveal inter- or intratumoral heterogeneity as well as variations in HER2 expression over time. This review summarizes the available literature and the current status of molecular imaging as a tool for the assessment of HER2 (target) expression or the prediction of an early treatment response in early and advanced HER2-positive breast cancer., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objective: This review article explores recent advancements in PET/MRI for clinical oncologic imaging., Conclusion: Radiologists should understand the technical considerations that have made PET/MRI feasible within clinical workflows, the role of PET tracers for imaging various molecular targets in oncology, and advantages of hybrid PET/MRI compared with PET/CT. To facilitate this understanding, we discuss clinical examples (including gliomas, breast cancer, bone metastases, prostate cancer, bladder cancer, gynecologic malignancy, and lymphoma) as well as future directions, challenges, and areas for continued technical optimization for PET/MRI.

Objective: Rectal cancers are the second most common GI carcinoma. Prognosis and therapeutic decisions hinge on the extent of disease. We present a comprehensive structured approach for staging rectal cancer using MRI to ensure the clear, concise, and standardized communication of disease extent to guide optimal treatment planning., Conclusion: MRI is crucial for local staging of rectal cancer. A standardized approach to reporting of rectal MRI focused on communication of essential treatment planning and prognostic indicators ensures maximal added value to referring physicians to guide appropriate management.

Background: Although multidisciplinary cancer conferences have been reported to lead to improved patient outcomes, few studies have reported results of these for rectal cancer., Objective: The purpose of this work was to assess the quality of multidisciplinary cancer conferences, the effect of the conference on the initial treatment plan, compliance with the conference treatment recommendations, and clinical outcomes for rectal cancer., Design: This was a prospective, longitudinal study., Settings: The study was conducted at a tertiary care academic hospital., Patients: Patients with primary rectal cancer were included in this study., Intervention: The intervention was a rectal cancer-specific multidisciplinary cancer conference., Main Outcome Measures: The quality of the multidisciplinary cancer conference was assessed using the Cancer Care Ontario Multidisciplinary Cancer Conference standards score. A change in treatment plan was defined as a change from the initial treatment plan selected by the treating physician to an alternate treatment plan recommended at the conference., Results: Twenty-five multidisciplinary cancer conferences were conducted over a 10-month study period. The Cancer Care Ontario Multidisciplinary Cancer Conference standards score was 7 (from a maximum score of 9). Forty-two patients with primary rectal cancer were presented, and there was a 29% (12/42) change in the initial treatment plan. A total of 42% (5/12) of these changes were attributed to reinterpretation of the MRI findings. There was 100% compliance with the conference treatment recommendations. The circumferential resection margin was positive in 5.5% (2/36)., Limitations: Selection bias may have led to an overestimate of effect, and there is no control group for comparison of clinical outcomes., Conclusions: A high-quality rectal cancer-specific multidisciplinary cancer conference led to a 29% change in the treatment plan for patients with primary rectal cancer, with almost half of these changes attributed to reinterpretation of the magnetic resonance images.

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.

OBJECTIVE. This systematic review presents evidence-based consensus statements as reported by a multidisciplinary expert panel (six abdominal radiologists, four hepatobiliary surgeons, and two hepatologists) regarding the use of gadoxetic acid for liver MRI. CONCULSION. Although this review highlights the incremental diagnostic value of hepatobiliary phase imaging with gadoxetic acid-enhanced liver MRI in multiple clinical scenarios, there remains a need for further impact studies for some clinical applications, such as hepatocellular carcinoma in cirrhosis.

Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.

Tests to better characterize tumor genomic architecture are quickly becoming a standard of care in oncology. For breast cancer, the use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. In the last 5 years, more assays have become available to the practicing oncologist. Given the rapidity with which this field has evolved, it is prudent to review the tests, their indications, and the studies from which they have been validated. We present a comprehensive review of the available gene expression assays for early stage breast cancer. We review data for several individual tests and comparative studies looking at risk prediction and cost-effectiveness., (©AlphaMed Press.)

Background: Recent changes in healthcare delivery have necessitated residency education reform. To adapt to these changes, graduate medical education can adopt a chief resident-led clinical curriculum. Chief residents are ideal clinical instructors, as they are recent graduates who have excelled in their residency programs. To effectively use the limited time available for education, chief residents can implement active learning techniques. We present a chief resident-led, small-group, problem-based curriculum for teaching first-year internal medicine residents, and provide preliminary data supporting the efficacy of this approach., Methods: The seminar consisted of 11 4-week modules. Week 1 was a team-based crossword competition. Weeks 2-4 were small-group, problem-based clinical reasoning sessions taught by chief residents. The program was evaluated via pre- and post-module multiple-choice tests. Resident satisfaction data were collected via self-reported, anonymous surveys., Results: Preliminary results revealed a statistically significant increase from pre-test to post-test score for 9 of the 11 modules. The chest pain, fever, abdominal pain, shock, syncope, jaundice, dizziness, anemia, and acute kidney injury modules achieved statistical significance. Additionally, resident satisfaction surveys show that this teaching approach was an enjoyable experience for our residents., Discussion: Our chief seminar is an evidence-based, clinical reasoning approach for graduate medical education that uses active learning techniques. This is an effective and enjoyable method for educating internal medicine residents. Because of its reproducibility, it can be applied throughout residency education.

A workforce crisis for many pediatric specialties, particularly nephrology, is due to growing retirement rates, attrition during training, and retention difficulties. To obtain specific information regarding pediatric nephrology trainee shortages, we administered two cross-sectional surveys to non-renal pediatric subspecialty fellows and pediatric nephrology program directors. We characterized the fellows' experiences with nephrology and the program directors' experiences with their fellows as well as their outcomes in the last 10 years. We analyzed responses from 531 non-renal fellows (14.4% response rate). Overall, 317 (60%) fellows rated nephrology as difficult, particularly women (65.4% vs. 49.5%, p < 0.001), with American women medical graduates rating nephrology as more difficult compared to all others (p = 0.001). More men than women (24% vs. 8%, p < 0.001) considered the monetary benefit as not adequate. Program directors (25; 64% response rate) represented 57% of all USA fellows in training, and 15 (60%) found it difficult to recruit qualified applicants. Of the 183 graduates in the past 10 years, 35 (19%) were reported as not in the USA pediatric nephrology workforce. These findings support our belief that a strong effort needs to be made by the academic community to teach nephrology in more interesting and understandable formats. While these are national samples, we were unable to contact non-nephrology fellows directly and program directors from larger programs were underrepresented. Difficulties in attracting/retaining trainees (particularly women) to nephrology must be addressed systematically, identifying incentives to practice in this field. Bold concerted efforts are required and we propose seven steps to achieve this goal.

Background: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC., Patients and Methods: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1., Results: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable)., Conclusion: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors., Areas Covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents., Expert Opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

Pertuzumab, a humanized monoclonal antibody and the first in the class of agents called the HER2 dimerization inhibitors, impairs the ability of HER2 to bind to other members of the HER family. It has a unique and complimentary mechanism of action compared with trastuzumab, and the combination has resulted in the enhanced blockade of the HER signaling pathway. When pertuzumab was used in combination with docetaxel and trastuzumab in the first-line treatment of metastatic HER2(+) breast cancer, it led to an overall survival benefit. Pertuzumab has therefore been approved by the FDA and is currently used as a standard of care for this indication. It is also the first agent in oncology to receive accelerated FDA approval in the neoadjuvant setting. Randomized trials showed that the addition of pertuzumab to trastuzumab-based chemotherapy improves pathologic complete response rates in HER2(+) early-stage breast cancer. A randomized phase III clinical trial with disease-free survival as the primary end point is evaluating the safety and efficacy of pertuzumab in the adjuvant setting. This article describes the preclinical data, synthesizes available data from phase I-III clinical trials of pertuzumab in early stage and metastatic settings, and puts them into perspective with current treatment recommendations and future research developments.

Introduction: Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC)., Methods: The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus., Results: We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis., Conclusion: Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses., Trial Registrations: ClinicalTrials.gov NCT01127763.

Enteric drainage is the preferred method of exocrine diversion in simultaneous kidney-pancreas transplantation. Because of improvements in immunosuppression, enteric drainage has become the preferred method of pancreas transplantation in general. Although associated with less potential complications than bladder-drained pancreas, potentially lethal arterio-enteric fistulas in the setting of nonfunctioning allografts represent a constant threat. We herein present a case report, a review of the literature, and a call for caution.

There are few reports about the treatment of moderate to severe hyponatremia associated with malignant liver metastasis. Here, we report using intravenous salt poor albumin infusion to treat hypervolemic cirrhosis related hyponatremia. A 58-year-old female with ascites secondary to metastatic breast cancer was referred to our department with symptomatic hyponatremia (serum sodium concentration of 121 mEq/L). The serum sodium level was corrected slowly over 2 days with intravenous albumin infusion and the patient's symptoms - fatigue, nausea, dizziness and headache improved.

Women are often subjected to serum human chorionic gonadotropin (HCG) testing prior to diagnostic and therapeutic interventions. A positive result leads to further testing to rule out pregnancy and avoid possible fetal teratogenicity. The impact of chronic kidney disease (CKD) on HCG testing has not been studied. We report a series of 5 women out of 62 with CKD, who had a positive HCG test on routine pre-transplant screening at a single transplant center. We analyzed their case records retrospectively. Despite aggressive investigation, their elevated HCG levels remained unexplained. The positive test contributed to delays in transplantation and increased overall cost of treatment.

The aim of this study was to determine the prognostic value of quantitative fluorodeoxyglucose (FDG) measurements (maximum standardized uptake value [SUVmax ], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) in patients with newly diagnosed metastatic breast cancer (MBC). An IRB-approved retrospective review was performed of patients who underwent FDG positron emission tomography (PET)/computed tomography (CT) from 1/02 to 12/08 within 60 days of diagnosis MBC. Patients with FDG-avid lesions without receiving chemotherapy in the prior 30 days were included. Target lesions in bone, lymph node (LN), liver, and lung were analyzed for SUVmax , MTV, and TLG. Medical records were reviewed for patient characteristics and overall survival (OS). Cox regression was used to test associations between quantitative FDG measurements and OS. A total of 253 patients were identified with disease in bone (n = 150), LN (n = 162), liver (n = 48), and lung (n = 66) at the time of metastatic diagnosis. Higher SUVmax tertile was associated with worse OS in bone metastases (highest vs. lowest tertile hazard ratio [HR] = 3.1, P < 0.01), but not in LN, liver or lung (all P > 0.1). Higher MTV tertile was associated with worse OS in LN (HR = 2.4, P < 0.01) and liver (HR = 3.0, P = 0.02) metastases, but not in bone (P = 0.22) or lung (P = 0.14). Higher TLG tertile was associated with worse OS in bone (HR = 2.2, P = 0.02), LN (HR = 2.3, P < 0.01), and liver (HR = 4.9, P < 0.01) metastases, but not in lung (P = 0.19). We conclude measures of FDG avidity are prognostic biomarkers in newly diagnosed MBC. SUVmax and TLG were both predictors of survival in breast cancer patients with bone metastases. TLG may be a more informative biomarker of OS than SUVmax for patients with LN and liver metastases., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.

Objective: The purpose of this study is to evaluate the interval growth, tumor recurrence, and metastatic disease occurrence of cystic renal cell carcinoma (RCC)., Materials and Methods: Pre-and posttreatment imaging of 47 histologically proven cystic RCCs, with at least 6 months of pretreatment imaging monitoring or at least 2 years of posttreatment imaging follow-up, or both, was retrospectively reviewed. Tumor morphologic features, preoperative growth, histologic typing and grading, and the incidence of tumor recurrence or metastasis were evaluated. Growth rate of tumors were compared among various histologic subtypes and Fuhrman grades., Results: Of 47 tumors, 27 (57.5%) were clear cell RCCs, 12 (25.5%) were multilocular RCCs, and eight (17%) were papillary cystic RCCs. Overall, 26 (55.3%) tumors were graded as Fuhrman grade 2, 17 (36.1%) were Fuhrman grade 1, and one tumor was Fuhrman grade 3. Of the 26 tumors with a minimum of 6 months of pretreatment imaging monitoring, 19 (73%) did not show a significant increase in tumor size. The differences in mean growth among the Fuhrman grades and different subtypes were not statistically significant. The average duration of posttreatment follow-up was 51 months. There were no local recurrences among the 43 patients who underwent posttreatment imaging, except for one patient who had metastasis at preoperative clinical presentation., Conclusion: Cystic RCCs exhibit slow indolent growth, if any, and show no significant metastatic or recurrence potential, with excellent clinical outcomes. We raise the need for revisiting current imaging protocols that may involve frequent pre-and posttreatment imaging in cystic RCCs.

The Sanger Mouse Genetics Project generates knockout mice strains using the EUCOMM/KOMP-CSD embryonic stem (ES) cell collection and characterizes the consequences of the mutations using a high-throughput primary phenotyping screen. Upon achieving germline transmission, new strains are subject to a panel of quality control (QC) PCR- and qPCR-based assays to confirm the correct targeting, cassette structure, and the presence of the 3' LoxP site (required for the potential conditionality of the allele). We report that over 86 % of the 731 strains studied showed the correct targeting and cassette structure, of which 97 % retained the 3' LoxP site. We discuss the characteristics of the lines that failed QC and postulate that the majority of these may be due to mixed ES cell populations which were not detectable with the original screening techniques employed when creating the ES cell resource.