Citations

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.

Deletion of 15q11.2‐q13 results in either Prader–Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent‐of‐origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain. © 2014 Wiley Periodicals, Inc.

AbstractObjectivesPatient throughput is an increasingly important cause of emergency department (ED) crowding. The authors previously reported shorter patient length of stay (LOS) when adding a triage liaison provider, which required additional personnel. Here, the objective was to evaluate the effect of moving a fast‐track provider to the triage liaison role.MethodsThis was a prospective observational before‐and‐after study design with predefined outcomes measures. A “standard staffing” situation (where an advanced practice provider staffed treatment rooms in the fast track) was compared with an advanced practice provider performing the triage liaison staffing role, with no additional staff. Eleven intervention (“triage liaison staffing”) days were compared with 11 matched control (“standard staffing”) days immediately preceding the intervention. Total LOS was measured for all adult Emergency Severity Index (ESI) 3, 4, and 5 patients (excluding behavioral health patients), and results were compared using Wilcoxon rank‐sum and chi‐square tests.ResultsA total of 681 patients registered on control days and 599 on intervention days. There was no significant difference in total patient LOS: median = 273 minutes, interquartile range (IQR) 176 to 384 minutes on intervention days versus median = 253 minutes, IQR = 175 to 365 minutes on control days (p = 0.20). There was no difference in left‐without‐being‐seen (LWBS) rates (n = 48, 7% on control days vs. n = 35, 6% on intervention days; p=0.38). Secondary analysis of only ESI 3 patients showed no difference in total LOS between periods (median = 284 minutes, IQR = 194 to 396 minutes on intervention days vs. median = 290 minutes, IQR = 217 to 397 minutes on control days; p = 0.22). There was, however, significantly greater total LOS for ESI 4 and 5 patients during the intervention period (median = 238 minutes, IQR = 124 to 350 minutes on intervention days vs. median = 192 minutes, IQR = 124 to 256 minutes on control days; p = 0.011).ConclusionsThe previously reported benefits on patient LOS and LWBS rates after adding a triage liaison (resource additive) were lost when that provider was moved from fast track to the triage role (resource neutral). While the triage liaison provider role may be a way to improve ED throughput when additional resources are available, as evidenced by our prior study, the triage liaison model itself does not appear to replace the staffing of treatment rooms, as evidenced by this study.

Objective To determine if massive renal size should be a contraindication for attempting a laparoscopic approach to bilateral native nephrectomies in patients with autosomal dominant polycystic kidney disease ( ADPKD ). Patients and Methods We retrospectively reviewed all laparoscopic bilateral nephrectomies performed for ADPKD at our institution from 1 J anuary 2000 to 31 D ecember 2012. We stratified patients by kidney weight (with or without at least one kidney weighing >2500 g) and compared perioperative data, complications, and status of kidney allografts. Additionally, the subset of patients with at least one kidney weighing >3500 g was compared with the rest of the cohort. Results We identified 68 patients; mean (range) individual kidney weight was 1984 (197–5042) g. In all, 24 patients had at least one kidney weighing >2500 g, yet patients in this group were not significantly different from the rest of the cohort for complications, estimated blood loss, transfusion rate, or duration of hospitalisation. For those who underwent simultaneous renal allotransplantation, native kidney size was not associated with graft outcomes. Additionally, of the six patients with at least one kidney weighing >3500 g, only one required a blood transfusion, and the group had no intraoperative or postoperative Clavien grade ≥3 complications. None of the cohort required conversion to open surgery. Conclusion Massive size of polycystic kidneys is not a contraindication to attempting a laparoscopic approach to bilateral nephrectomies in an experienced, high‐volume centre.

Background— Decision aids (DAs) increase patient knowledge, reduce decisional conflict, and promote shared decision making (SDM). The extent to which they do so across diverse sociodemographic patient groups is unknown. Methods and Results— We conducted a patient-level meta-analysis of 7 randomized trials of DA versus usual care comprising 771 encounters between patients and clinicians discussing treatment options for chest pain, myocardial infarction, diabetes mellitus, and osteoporosis. Using a random effects model, we examined the impact of sociodemographic patient characteristics (age, sex, education, income, and insurance status) on the outcomes of knowledge transfer, decisional conflict, and patient involvement in SDM. Because of small numbers of people of color in the study population, we were not powered to investigate the role of race. Most patients were aged ≥65 years (61%), white (94%), and women (59%); two thirds had greater than a high school education. Compared with usual care, DA patients gained knowledge, were more likely to know their risk, and had less decisional conflict along with greater involvement in SDM. These gains were largely consistent across sociodemographic patient groups, with DAs demonstrating similar efficacy when used with vulnerable patients such as the elderly and those with less income and less formal education. Differences in efficacy were found only in knowledge of risk in 1 subgroup, with greater efficacy among those with higher education (35% versus 18%; P =0.02). Conclusions— In this patient-level meta-analysis of 7 randomized trials, DAs were efficacious across diverse sociodemographic groups as measured by knowledge transfer, decisional conflict, and patient involvement in SDM. To the extent that DAs increase patient knowledge and participation in SDM, they have potential to impact health disparities related to these factors.

Objective To evaluate outcomes of the first 18 patients treated with robot‐assisted retroperitoneal lymph node dissection ( RA‐RPLND ) for non‐seminomatous germ cell tumours ( NSGCT ) and paratesticular rhabdomyosarcoma ( RMS ) at our institution. Patients and Methods Between M arch 2008 and M ay 2013, 17 patients underwent RA‐RPLND for NSGCT and one for paratesticular RMS . Data were collected retrospectively on patient demographics, preoperative tumour characteristics, and perioperative outcomes including open conversion rate, lymph node ( LN ) yield, rate of positive LNs , operative time, estimated blood loss ( EBL ), and length of stay ( LOS ). Perioperative outcomes were compared between patients receiving primary RA‐RPLND vs post‐chemotherapy RA‐RPLND . Medium‐term outcomes of tumour recurrence rate and maintenance of antegrade ejaculation were recorded. Results RA‐RPLND was completed robotically in 15 of 18 (83%) patients. LNs were positive in eight of 18 patients (44%). The mean LN yield was 22 LNs . For cases completed robotically, the mean operative time was 329 min, EBL was 103 mL, and LOS was 2.4 days. At a mean (range) follow‐up of 22 (1–58) months, there were no retroperitoneal recurrences and two of 17 (12%) patients with NSGCT had pulmonary recurrences. Antegrade ejaculation was maintained in 91% of patients with a nerve‐sparing approach. Patients receiving primary RA‐RPLND had shorter operative times compared with those post‐chemotherapy (311 vs 369 min, P = 0.03). There was no significant difference in LN yield (22 vs 18 LNs , P = 0.34), EBL (100 vs 313 mL, P = 0.13), or LOS (2.75 vs 2.2 days, P = 0.36). Conclusion This initial selected case series of RA‐RPLND shows that the procedure is safe, reproducible, and feasible for stage I – IIB NSGCT and RMS in the hands of experienced robotic surgeons. Larger studies are needed to confirm the diagnostic and therapeutic utility of this technique.

Abstract MUC1 (MUC1 in human and Muc1 in nonhumans) is a membrane-tethered mucin that interacts with Pseudomonas aeruginosa (PA) through flagellin. In this study, we compared PA pulmonary clearance and proinflammatory responses by Muc1−/− mice with Muc1+/+ littermates following intranasal instillation of PA or flagellin. Compared with Muc1+/+ mice, Muc1−/− mice showed increased PA clearance, greater airway recruitment of neutrophils, higher levels of TNF-α and KC in bronchoalveolar lavage fluid, higher levels of TNF-α in media of flagellin-stimulated alveolar macrophages, and higher levels of KC in media of tracheal epithelial cells. Knockdown of MUC1 enhanced flagellin-induced IL-8 production by primary human bronchial epithelial cells. Expression of MUC1 in HEK293T cells attenuated TLR5-dependent IL-8 release in response to flagellin, which was completely ablated when its cytoplasmic tail was deleted. We conclude that MUC1/Muc1 suppresses pulmonary innate immunity and speculate its anti-inflammatory activity may play an important modulatory role during microbial infection.