Citations

Abstract Purpose: The RANO criteria have not been assessed using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma from the randomized phase II trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation as per RANO criteria on measurements of objective response rates (ORRs) and progression-free survival (PFS) compared with assessment based on contrast enhancement (Macdonald criteria). Experimental Design: The ORRs and median PFS were determined using the RANO criteria and compared with those obtained using the Macdonald criteria. Landmark analyses were performed at 2, 4, and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival. Results: The ORRs were 0.331 [95% confidence interval (CI), 0.260–0.409] and 0.393 (95% CI, 0.317–0.472) by RANO and Macdonald criteria, respectively (P < 0.0001). The median PFS was 4.6 months (95% CI, 4.1–5.5) using RANO criteria, compared with 6.4 months (95% CI, 5.5–7.1) as determined by Macdonald criteria (P = 0.01). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by either RANO or Macdonald criteria were predictive of overall survival [OS; hazard ratios for 4-month landmark (OR HR = 1.93, P = 0.0012; PFS HR, 4.23, P < 0.0001)]. Conclusions: The inclusion of T2/FLAIR assessment resulted in statistically significant differences in median PFS and ORRs compared with assessment of solely enhancing tumor (Macdonald criteria), although OR and PFS determined by both RANO and Macdonald criteria correlated with OS. Clin Cancer Res; 22(3); 575–81. ©2015 AACR.

ABSTRACT Varicella-zoster virus (VZV) is a highly neurotropic virus that can cause infections in both the peripheral nervous system and the central nervous system. Several studies of VZV reactivation in the peripheral nervous system (herpes zoster) have been published, while exceedingly few investigations have been carried out in a human brain. Notably, there is no animal model for VZV infection of the central nervous system. In this report, we characterized the cellular environment in the temporal lobe of a human subject who recovered from focal VZV encephalitis. The approach included not only VZV DNA/RNA analyses but also a delineation of infected cell types (neurons, microglia, oligodendrocytes, and astrocytes). The average VZV genome copy number per cell was 5. Several VZV regulatory and structural gene transcripts and products were detected. When colocalization studies were performed to determine which cell types harbored the viral proteins, the majority of infected cells were astrocytes, including aggregates of astrocytes. Evidence of syncytium formation within the aggregates included the continuity of cytoplasm positive for the VZV glycoprotein H (gH) fusion-complex protein within a cellular profile with as many as 80 distinct nuclei. As with other causes of brain injury, these results suggested that astrocytes likely formed a defensive perimeter around foci of VZV infection (astrogliosis). Because of the rarity of brain samples from living humans with VZV encephalitis, we compared our VZV results with those found in a rat encephalitis model following infection with the closely related pseudorabies virus and observed similar perimeters of gliosis. IMPORTANCE Investigations of VZV-infected human brain from living immunocompetent human subjects are exceedingly rare. Therefore, much of our knowledge of VZV neuropathogenesis is gained from studies of VZV-infected brains obtained at autopsy from immunocompromised patients. These are not optimal samples with which to investigate a response by a human host to VZV infection. In this report, we examined both flash-frozen and paraffin-embedded formalin-fixed brain tissue of an otherwise healthy young male with focal VZV encephalitis, most likely acquired from VZV reactivation in the trigeminal ganglion. Of note, the cellular response to VZV infection mimicked the response to other causes of trauma to the brain, namely, an ingress of astrocytes and astrogliosis around an infectious focus. Many of the astrocytes themselves were infected; astrocytes aggregated in clusters. We postulate that astrogliosis represents a successful defense mechanism by an immunocompetent human host to eliminate VZV reactivation within neurons.

Abstract Objectives: Hemostatic clip migration into the lower urinary tract is a potential complication of radical prostatectomy that may cause symptoms, anxiety, and functional concern. Our objective was to evaluate initial presentation, endoscopic management, and outcomes of patients with hemostatic clip migration following radical prostatectomy. Patients and Methods: We retrospectively identified all patients with hemostatic clip migration at our institution from 1977 to 2012. Patient records were then reviewed to identify causative factors, presentation, and long-term functional outcomes. Results: Seventeen patients were identified with clip migration following radical prostatectomy. Eight (47%) patients had undergone open retropubic radical prostatectomy, and 9 (53%) had received robot-assisted radical prostatectomy. Hemostatic clip migration was diagnosed at a median of 8 (range, 1–252) months after prostatectomy. The majority of patients ( n = 16, 94%) were symptomatic upon the diagnosis of clip migration. Symptoms included irritative urinary symptoms ( n = 14, 82%), perineal pain ( n = 3, 18%), hematuria ( n = 2, 12%), and infection ( n = 2, 12%). Five (29%) had concomitant bladder neck contracture. Fifteen (88%) underwent successful endoscopic clip removal, whereas 2 (13%) patients required a repeat operation for recurrent clip erosion. With a median follow-up of 1.6 years, the majority ( n = 13, 87%) had complete symptom resolution after clip removal, although 2 patients had recurrent bladder neck contracture. Conclusions: Hemostatic clip migration after prostatectomy is often symptomatic with irritative voiding complaints, perineal pain, hematuria, infection, or bladder neck contracture. Fortunately, clips can be removed endoscopically with expected symptom resolution in the vast majority of patients.

SummaryThe International Prognostic Score (IPS‐7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS‐7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS‐7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS‐7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS‐3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS‐3 outperformed the IPS‐7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS‐7 low risk patients were re‐classified as intermediate risk and 13% of IPS‐7 intermediate risk patients as low risk. For patients with advanced HL, the IPS‐3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

Abstract Purpose: Methylated DNA markers can discriminate upper from lower GI neoplasms (Gastroenterology 2013;144(5):S84). It is unknown if organ-specific molecular prediction of GI tumor site can be achieved. Experimental design: An unbiased search for neoplasm markers at each major GI organ site was conducted by reduced representation bisulfite sequencing. Top marker candidates were then blindly validated by methylation specific PCR on independent tissue DNA samples from normal mucosa [17 esophagus (E), 13 stomach (S), 33 pancreas (P), 35 bile duct/liver (BD), 21 colorectal (CR)] and neoplasia [42 E, 43 S, 36 P, 48 BD, 97 CR]. Recursive partitioning (rPart) trees modeled all stepwise combinations of single markers to classify controls vs neoplasms and then neoplasms by site (CR, gastroesophageal or pancreaticobiliary). A 2nd model was designed from tissue data for blinded clinical piloting on 42 independent plasma DNA samples (14 normal and 28 cancers (14 P, 14 CR). Results: From the top 100 markers, 95 were validated and used for rPart modeling. A 3- marker panel (chr12.133484978-5047, BMP3, chr11.123301058-255) was selected for the universal detection of GI neoplasms, as it classified neoplasms and control tissues with 95% accuracy. Two markers (chr7.25896389-501, QKI) then assigned lower vs upper GI neoplasms with 94% accuracy. Finally, 3 markers (PDGFD, ELOVL2, PCBP3) called pancreaticobiliary vs gastroesophageal neoplasms with 94% accuracy. All 8 markers applied in a single model (Table) accurately predicted control vs tumor by site [88% (p &lt;0.0001)]. In plasma, a 2-marker panel (BMP3, QKI) was 78% accurate in assigning patients to cancer or control groups (p&lt;0.0009) and 83% accurate in assigning cancer origin to CR or P sites (p&lt;0.0001). Predicted by ModelTissue SourceControlsColorectal neoplasiaPancreatico-biliary cancerGastro-esophageal neoplasiaControls1169102Colorectal neoplasia18617Pancreatico-biliary cancer10654Gastro-esophageal neoplasia12872 Conclusion: Panels of methylated DNA markers were identified for both universal detection of GI neoplasia and accurate prediction of tumor site. Pilot testing of these markers in plasma supports potential clinical feasibility. Citation Format: John B. Kisiel, William R. Taylor, Tracy C. Yab, Hassan M. Ghoz, Patrick H. Foote, Mary E. Devens, Douglas W. Mahoney, Thomas C. Smyrk, Lisa A. Boardman, Gloria M. Petersen, Navtej S. Buttar, Lewis R. Roberts, Graham P. Lidgard, David A. Ahlquist. Accurate site prediction of gastrointestinal cancer by novel methylated DNA markers: Discovery & validation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4252. doi:10.1158/1538-7445.AM2015-4252

Abstract Background: Epidemiologic studies have suggested that metformin use is associated with cancer death reduction. The results for pancreatic ductal adenocarcinoma (PDAC) are inconsistent. Retrospective studies of cancer survival may potentially have unintended biases; due to complexities of diabetes management, metformin use exposure is commonly categorized as simply “yes/no.” Nevertheless, in part based on epidemiologic studies, there are at least 20 open cancer clinical trials that include metformin in a treatment arm. We aimed to study metformin use and survival of patients with PDAC, addressing potential inherent biases. Methods: A retrospective cohort study for the years 2000-2011 was conducted using the patient database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. 1,360 PDAC patients (59% male; mean age 67) with diabetes were studied; overall survival was the primary outcome. Initiation and duration of metformin use was carefully abstracted from medical records. Patients were categorized into 5 groups based on metformin initiation: (A) Never used, n = 908 (reference group); (B) Metformin started &gt;1 year prior to PDAC diagnosis, n = 84; (C) Metformin started within 1 year prior to PDAC diagnosis, n = 212; (D) Metformin started &lt;30 days post-PDAC diagnosis, n = 104; (E) Metformin started &gt;30 days post PDAC diagnosis, n = 34. Hazard ratios (HR) and 95% confidence intervals (C.I.) for survival differences between groups were computed using Cox proportional hazards models, adjusting for age, sex, disease stage, body mass index, and diagnosis year group. Results: Median survival of patients in Groups B-E was 292 days compared to 308 for Group A; this was not significantly different. However, among 413 resectable patients, metformin users appeared to survive longer than non-users (782 vs. 612 days, p = 0.07). Survival in each group was 308, 245, 249, 243 and 818 days, respectively. Because Group E had already survived &gt;30 days, a bias existed. With Group E excluded, there was no survival difference among the other 4 groups (p = 0.18). Compared to Group A, HR and 95% C.I. for metformin use were 1.08 (0.85-1.37), 0.99 (0.85-1.17), 1.04 (0.83-1.31) and 0.49 (0.33-0.74), for Group B-E, respectively. Conclusions: Our thorough analysis suggests that metformin use does not improve survival of patients with PDAC. The benefit of metformin was observed only in patients who started metformin post-PDAC diagnosis; however, there is an inherent survival bias in this group of patients. Studies of medication exposure and cancer survival warrant very careful and detailed data collection. Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies. Citation Format: Roongruedee Chaiteerakij, David B. Zhen, Patrick A. Burch, Kari G. Chaffee, William R. Bamlet, Ann L. Oberg, Lewis R. Roberts, Gloria M. Petersen. Metformin use does not increase survival of pancreatic cancer patients: A cautionary lesson. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-183. doi:10.1158/1538-7445.AM2015-LB-183

Abstract Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. TROY expression increases with glial tumor grade and inversely correlates with patient survival. TROY stimulates GBM cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. Conversely, knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. In this study, we demonstrated that PPF decreases TROY protein expression in glioma cells, and subsequently suppress activation downstream signaling effectors including AKT, NF-κB, and Rac1. PPF treatment of glioma cells also suppressed glioma cell migration and invasion, demonstrated by transwell migration assay and reduced membrane ruffling. Finally, PPF treatment increased vulnerability of glioma cells to Temozolomide (TMZ) and radiation. In summary, this study demonstrates that PPF provides a pharmacologic approach to target TROY to inhibit glioma cell invasion and reduce therapeutic resistance to TMZ and radiation. Citation Format: Harshil D. Dhruv, Serdar Tuncali, Alison Roos, Patrick Tomboc, Nathan Jameson, Ashley Chavez, Joseph Loftus, Michael E. Berens, Nhan L. Tran. Propentofylline inhibits TROY/TNFRSF19 signaling to enhance therapeutic efficacy in invasive glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5366. doi:10.1158/1538-7445.AM2015-5366