Percent Of Tumors Research Articles

Percent tumor volume vs American Joint Committee on Cancer staging system subclassification for predicting biochemical recurrence in patients with pathologic T2 prostate cancer

Here, we re-checked the American Joint Committee on Cancer 7th edition subclassification and confirmed the possibility of percent tumor volume as a prognostic factor for biochemical recurrence in the 8th edition subclassification. A total of 1073 patients with pathologic T2 stage disease who underwent radical prostatectomy were included. Exclusion criteria were neoadjuvant therapy and pathologic T3 and N1 disease. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method. Cox hazard regression was used to predict biochemical recurrence. According to the 7th edition subclassification, 141 patients (13.1%) had T2a, 43 (4.0%) had T2b, and 889 (82.9%) had T2c disease. The 7th edition subclassification did not differ significantly on Kaplan-Meier analysis (p = 0.502). Mean percent tumor volume was 8.7 ± 8.0% (interquartile range, 5-10%). Percent tumor volume was positively correlated with initial prostate-specific antigen, grade group, surgical margin, and T2 subclassification (all p < 0.001). The 7th edition subclassification was not a significant factor, whereas percent tumor volume was (hazard ratio, 1.023; 95% confidence interval, 1.005-1.041; p = 0.0128) on multivariate analysis. On Kaplan-Meier analysis, percent tumor volume (> 7.5% vs ≤ 7.5%) differed significantly for biochemical recurrence-free survival (p < 0.001). The 7th edition pathologic T2 subclassification had poor prognostic value for biochemical recurrence in our cohort. Elimination of the 8th edition subclassification was suitable. Percent tumor volume classified biochemical recurrence prognosis in pathologic T2 stage. Therefore, percent tumor volume can be a candidate factor for the next T2 subclassification.

Therapeutic Efficacy and Dosimetry of Targeted Alpha Therapy using 225Ac-PSMA-617 in a Murine Model of Prostate Cancer

Targeted alpha therapy shows promise as a treatment in metastatic castration-resistant prostate cancer (mCRPC), owing to the high dose deposition and short range characteristics of alpha particle radiation. Ac-225 decays via multiple alpha particles – each capable of inducing irreparable DNA double-strand breaks in cell nuclei. PSMA-617 is a targeting ligand with specific affinity for prostate-specific membrane antigen (PSMA), a protein that is overexpressed in mCRPC but has low expression in normal tissues. Coupled with the lethal effects of alpha radiation, 225Ac-PSMA-617 is potentially highly cytotoxic to mCRPC while sparing normal tissues. The objective of this study was to evaluate the efficacy of alpha-particle radioligand therapy in a mouse model of mCRPC. Radiation dosimetry analysis was carried out to determine tumor dose as well as dose-limiting organs. NSG mice bearing subcutaneous PSMA-expressing C4-2 tumors were injected with escalating activities of 225Ac-PSMA-617: 20, 40, and 100 kBq/mouse (n=8/group). The tumor volumes were assessed over time by weekly low-dose microCT and compared with an untreated control group. In parallel, twenty-five NSG mice were used in a biodistribution study at five time points – 1, 4, 24, 48, and 168 hours post-administration of 40 kBq of the radiopharmaceutical. After sacrifice, percent tumor and organ radioactivity uptake was measured using gamma spectroscopy. Biexponential curve-fitting was used to fit the time-activity curves for the tumor and each organ, and integrated according to standard medical internal radiation dose methods to estimate the tumor and organ doses. Significant tumor growth retardation was observed in all treatment groups compared with the untreated group. Mice treated with 100 kBq exhibited some weight loss, while the mice treated with lower activities experienced only transient weight loss. There was a significant survival benefit conferred on tumor-bearing mice treated with 225Ac-PSMA617. The biodistribution over five time points showed high uptake and slow tumor activity clearance, and low uptake with fast clearance in non-target organs. The salivary glands, a dose-limiting organ in humans, did not show high uptake in mice, possibly due to lower PSMA expression. Estimates of the absorbed dose to the tumor and organs are reported. An administered activity of 40 kBq per mouse of the peptidomimetic 225AcPSMA-617 is well-tolerated and results in significant tumor growth retardation and improved survival. This work provides a preclinical foundation for further studies towards a more effective treatment option for advanced castration-resistant prostate cancer.

Noncontrast T2-Weighted Magnetic Resonance Imaging Sequences for Long-Term Monitoring of Asymptomatic Convexity Meningiomas

Gadolinium-based contrast agents (GBCAs) used to enhance magnetic resonance imaging (MRI) scans have been linked to tissue deposition, including in the brain. The management of indolent tumors such as meningiomas requires frequent MRI scans to monitor for interval growth. Given concern regarding GBCA deposition, we sought to determine if noncontrast MRI scans in patients with asymptomatic meningiomas were equivalent to GBCA-enhanced MRI scans in surveillance monitoring. This institutional review board-approved retrospective chart review included 106 MRI sequences from 18 patients. Inclusion criteria were adult patients with asymptomatic meningiomas who received baseline contrast-enhanced and noncontrast axial brain MRI scan. Exclusion criteria included the following: 1) baseline or follow-up axial images were not available for review, 2) baseline scan was obtained without contrast, and 3) diagnosis of meningioma was uncertain. Percent tumor growth was measured by comparing cross-sectional area at maximum tumor diameter from the earliest and most recent scans. For each patient, change in tumor size over time was compared using T1+ contrast, T2, and T2 fluid-attenuated inversion recovery (FLAIR) sequences. These were compared with a qualitative consensus reading by a neurosurgeon and a neuroradiologist. Measured change of greater than 10% was taken to represent tumor growth. In 17 out of 18 patients, measurement of noncontrast studies (T2 and T2 FLAIR) matched consensus. For one patient, imaging on T2 suggested 11% growth, whereas T2 FLAIR and overall consensus was stability. Our study provides evidence that noncontrasted MRI scans are equivalent to contrast-weighted MRI scans to follow change in tumor size over time in asymptomatic meningiomas.

ANGI-11. SEX DIFFERENCES IN IMAGING-BASED ASSESSMENT OF GLIOBLASTOMA INVASION

Abstract INTRODUCTION Neuroimaging dogma for glioblastoma asserts that hyperintensity on T1Gd MRI reveals the bulk of the tumor, while T2/FLAIR signal indicates edema. However, it is unclear whether this edema results from immune response or increased tumor cells. Further, one significant driver of the known sex differences in glioblastoma may be differences in immune response, due to the X-linkage of many immune genes. Based on this, we hypothesized that assumptions regarding tumor cellularity in T2/FLAIR images should be tailored to the biological sex of the patient. METHODS Using a retrospective cohort of 18 primary glioblastoma patients receiving multiple image-localized biopsies (82 total) and standard MRI, we assessed: distance of biopsy from T1Gd and T2 areas; a pathologist’s score of percent tumor cell density; and an imaging-based invasion metric, D/ρ. This metric is derived from the biomathematical Proliferation-Invasion model of glioma growth, which features two parameters, net growth rate (ρ) and net invasion rate (D). Their ratio D/ρ is related to degree of invasion, and is estimated from volumetric measurements of MRI abnormalities. Additionally, 25 patient-derived xenograft models implanted in females were grown until moribund, at which point brains were excised and stained for DAPI (to show all cells) and Lamin (to highlight tumor cells). Image processing of lamin-stained sections defines contours of intensity correlating with cell density. RESULTS Outside both the T1Gd and T2 region, male patient biopsies had higher tumor cell densities than females. Males also tended to have higher invasion metrics. Although each set derived from different patients, preclinical metrics of invasion were positively correlated with clinical invasion in females but negatively correlated in males. CONCLUSION Our preliminary finding that cell distribution patterns correlate with imaging metrics differently between the sexes supports the hypothesis that the degree of tumor cell density represented on certain MRI sequences may be sex-specific.

Calculating the Tumor Nuclei Content for Comprehensive Cancer Panel Testing.

Comprehensive genetic panel testing generally requires that the analyzed tissues have a percent tumor nuclei (%TN) content of 20% or more to achieve assay performance comparable to the validated specifications. Pathologists play a crucial role in ensuring that the optimal results are achieved by accurately assigning %TN content of the available specimens and selecting the best material to submit for sequencing. This study addresses the issues in evaluating %TN, such as intraobserver variability, and examines whether focused training and feedback can improve pathologist performance. Nine referring institution pathologists (all board-certified and working at the core institute and the alignment hospitals under the National Cancer Genome scheme) evaluated 18 tumors that had been subjected to comprehensive genetic panel testing with the FoundationOne CDx assay. The %TN estimates provided by referring institution pathologists were compared with two standards: %TN assigned by the tumor sequencing institution's pathologist (a board-certified pathologist at Foundation Medicine, Inc.) and the computational %TN estimated from the mutant allele frequencies after sequencing was completed. The pathologists generally overestimated %TN in the first pretraining round of the evaluation, and the differences in the averaged %TN from the tumor sequencing institution and computational standards werestatistically significant. However, the posttraining second-round results became significantly concordant with the standards. This study suggests that %TN content is empirically overestimated but the evaluation skill can be improved by providing a training and feedback program.

Beyond The T/C Ratio: Old And New Anticancer Activity Scores In Vivo.

Assessing the efficacy of anticancer agents in animal models remains a necessary step in the development of new treatment options and plays an important role in their optimization and comparison. Often, however, interpretation of the results is flawed by excessive trust in scores traditionally handed down, but whose origin and limitations have been lost. Here I examine the theories and assumptions underlying the most common rating scales, suggesting improvements to the old scores and proposing the adoption of multi-parameter analysis and interpretation of the results, considering different time-windows. I examined case examples of different scenarios of antiproliferative effects induced by treatment, demonstrating that common scores fail to distinguish between completely different responses to treatment or, in other circumstances, indicate a different outcome when the response is the same. I found that a combination of parameters, including the percent tumor growth between the start and end of treatment, the relative tumor burden at nadir and the absolute growth delay, may distinguish among the different cases and support a correct interpretation of the antitumor response. All these parameters can be derived from individual tumor growth curves in a simple way, without any change to common experimental procedures.

Development and analytical validation of a next-generation sequencing based microsatellite instability (MSI) assay.

We have developed and analytically validated a next-generation sequencing (NGS) assay to classify microsatellite instability (MSI) in formalin-fixed paraffin-embedded (FFPE) tumor specimens. The assay relies on DNA-seq evaluation of insertion/deletion (indel) variability at 29 highly informative genomic loci to estimate MSI status without the requirement for matched-normal tissue. The assay has a clinically relevant five-day turnaround time and can be conducted on as little as 20 ng genomic DNA with a batch size of up to forty samples in a single run. The MSI detection method was developed on a training set (n = 94) consisting of 22 MSI-H, 24 MSS, and 47 matched normal samples and tested on an independent test set of 24 MSI-H and 24 MSS specimens. Assay performance with respect to accuracy, reproducibility, precision as well as control sample performance was estimated across a wide range of FFPE samples of multiple histologies to address pre-analytical variability (percent tumor nuclei), and analytical variability (batch size, run, day, operator). Analytical precision studies demonstrated that the assay is highly reproducible and accurate as compared to established gold standard PCR methodology and has been validated through NYS CLEP. This assay provides clinicians with robust and reproducible NGS-based MSI testing without the need of matched normal tissue to inform clinical decision making for patients with solid tumors.

Limb-sparing in dogs using patient-specific, three-dimensional-printed endoprosthesis for distal radial osteosarcoma: A pilot study.

Limb-sparing for distal radial osteosarcoma has a high rate of complications. Using personalized three-dimensional (3D)-printed implants might improve outcome. The goals of this study were to optimize use of patient-specific, 3D-printed endoprostheses for limb-sparing in dogs in the clinical environment and to report the outcome. This was a pilot study where five client-owned dogs were enrolled. Computed tomography (CT) of the thoracic limbs was performed, which was used to create patient-specific endoprostheses and cutting guides, and repeated on the day of surgery. Intra-arterial (IA) carboplatin was introduced in the clinical management. Limb-sparing was performed. Outcome measures were time required to produce the endoprosthesis and cutting guide, fit between cutting guide and endoprosthesis with host bones, gait analysis, size of the tumour, percent tumour necrosis, complications, disease-free interval (DFI) and survival time (ST). Four dogs received IA carboplatin. Excessive tumour growth between planning CT and surgery did not occur in any dog. The interval between the CT and surgery ranged from 14 to 70 days. Fit between the cutting-guide and endoprosthesis with the host bones was good to excellent. At least one complication occurred in all dogs. Two dogs were euthanized with STs of 192 and 531 days. The other dogs were alive with a follow up of 534 to 575 days. IA chemotherapy is a promising strategy to minimize the risk of excessive tumour growth while waiting for the endoprosthesis and cutting-guide to be made. The design of the cutting-guide was critical for best fit of the endoprosthesis with host bones.

Comparison of Radiographic Approaches to Assess Treatment Response in Pituitary Adenomas: Is RECIST or RANO Good Enough?

ContextPituitary adenomas (PA) are often irregularly shaped, particularly posttreatment. There are no standardized radiographic criteria for assessing treatment response, substantially complicating interpretation of prospective outcome data. Existing imaging frameworks for intracranial tumors assume perfectly spherical targets and may be suboptimal.ObjectiveTo compare a three-dimensional (3D) volumetric approach against accepted surrogate measurements to assess PA posttreatment response (PTR).DesignRetrospective review of patients with available pre- and postradiotherapy (RT) imaging. A neuroradiologist determined tumor sizes in one dimensional (1D) per Response Evaluation in Solid Tumors (RECIST) criteria, two dimensional (2D) per Response Assessment in Neuro-Oncology (RANO) criteria, and 3D estimates assuming a perfect sphere or perfect ellipsoid. Each tumor was manually segmented for 3D volumetric measurements. The Hakon Wadell method was used to calculate sphericity.SettingTertiary cancer center.Patients or Other ParticipantsPatients (n = 34, median age = 50 years; 50% male) with PA and MRI scans before and after sellar RT.InterventionsPatients received sellar RT for intact or surgically resected lesions.Main Outcome Measure(s)Radiographic PTR, defined as percent tumor size change.ResultsUsing 3D volumetrics, mean sphericity = 0.63 pre-RT and 0.60 post-RT. With all approaches, most patients had stable disease on post-RT scan. PTR for 1D, 2D, and 3D spherical measurements were moderately well correlated with 3D volumetrics (e.g., for 1D: 0.66, P < 0.0001) and were superior to 3D ellipsoid. Intraclass correlation coefficient demonstrated moderate to good reliability for 1D, 2D, and 3D sphere (P < 0.001); 3D ellipsoid was inferior (P = 0.009). 3D volumetrics identified more potential partially responding and progressive lesions.ConclusionsAlthough PAs are irregularly shaped, 1D and 2D approaches are adequately correlated with volumetric assessment.

Abstract 1946: Quantifying trastuzumab-induced alterations of intratumoral heterogeneity using MRI-derived tumor subregions in the preclinical setting

Abstract Introduction: Heterogeneity in the tumor microenvironment affects therapeutic delivery, providing a major challenge for cancer treatment. We investigate the ability of multi-parametric, voxel-based characterizations of tumor heterogeneity from quantitative magnetic resonance imaging (MRI) to spatially resolve physiological tumor subregions of response to anti-HER2 targeted therapy in a murine model of HER2+ breast cancer. Methods: BT474 cells were implanted in nude athymic mice (n=20) and tumors grown to ~225 mm3. Mice were randomly assigned to saline control or trastuzumab groups, with treatments given on days 0 and 3. Dynamic contrast enhanced (DCE) MRI and diffusion weighted (DW) MRI data were collected on days 0 (pre-treatment), 1 and 4. Tumors, excised on day 4, were processed for histology with anti-CD31 staining. Apparent diffusion coefficients (ADC, a measure of cell density) were extracted from DW-MRI data. DCE-MRI data was modeled to extract the extravascular, extracellular volume fraction, ve, and the volume transfer coefficients, Ktrans and kep, which correspond to the rate of wash-in and wash-out of contrast agent, respectively. Hierarchical clustering of tumor voxel data (ADC, ve, Ktrans, and kep) was used to identify physiological tumor subregions. The contribution of each subregion to tumor volume was quantified as percent tumor volume for each mouse and time point. Image analysis of histology data was used to generate vessel area and nuclei maps for whole-slice histology data. CD31 stained slices were subsequently divided into physiological subregions in terms of vessel and nuclei density, and the contribution of each subregion to the whole-slice area was quantified as percent tumor area. Results: Hierarchical clustering of the MRI data yielded four clusters: low vascularity - low cellularity (LV-LC), low vascularity - high cellularity (LV-HC), high vascularity - low cellularity (HV-LC), high vascularity - high cellularity (HV-HC). At day 0, no significant differences in cluster percent tumor volume were observed between control and treated tumors (p&amp;gt;0.05). At day 4, a significant decrease in LV-HC percent tumor volume was observed in treated tumors compared to control (mean 13.7% vs. 35.0%, p=0.04). Histology subregion analysis corroborated in vivo imaging findings, with treated tumors having significantly lower LV-HC percent tumor area compared to control (mean 26.8% vs 53.6%, p&amp;lt;0.01). Conclusion: High-dimensional analysis of quantitative MRI parameter maps can be utilized to identify physiological subregions of tumor response, and can be biologically validated using histology data. The results suggest trastuzumab therapy decreases the hypoxic (LV-HC) tumor volume. Quantifying tumor microenvironment alterations in response to therapy can potentially be used to predict response for patients with HER2+ breast cancer. Citation Format: Anum Syed, Jennifer Whisenant, Anna Sorace, Thomas Yankeelov. Quantifying trastuzumab-induced alterations of intratumoral heterogeneity using MRI-derived tumor subregions in the preclinical setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1946.

Abstract 3867: Microsomal prostaglandin E synthase-1: A therapeutic target in bladder cancer

Abstract Introduction and Objective: Prostaglandin E2 (PGE2) is a lipid-derived signaling agent that promotes tumorigenesis via increasing stemness, proliferation, and angiogenesis. PGE2 levels are elevated in multiple cancers, including bladder (BCa) where they may play a pathological role. PGE2 is generated in part by cyclooxygenase enzymes (COX-1/COX-2). Clinical trials using the COX-2 specific inhibitor celecoxib to prevent progression and recurrence of non-muscle invasive BCa report hazard ratio reductions; however, celecoxib fails to significantly outperform standard of care. These studies are dose-limited by cardiotoxicity present with COX inhibition, but have suggested higher doses of celecoxib may yield significant results. Microsomal PGE2 synthase-1 (mPGES-1) is one of two terminal enzymes (downstream of COX-1/2) associated with PGE2 production. Inhibition of mPGES-1 does not affect synthesis of the prostaglandins responsible for cardiotoxicity but still reduces PGE2 levels. Using a model of carcinogen induced BCa, we have previously established mPGES1-/- have significantly smaller bladder tumors by weight, reduced pathological stage, reduced PGE-2 metabolites, and reductions in percent tumor involvement in the bladder compared to WT mice. The purpose of this study was to further understand mPGES mediated tumorigenesis using in vitro cellular models. We hypothesized pharmacological inhibition with the mPGES-1 specific inhibitor MF63 would reduce PGE2 levels leading to reduced cellular proliferation and reduced PGE2 release in vitro. Methods: mPGES1 protein and RNA levels were measured in benign (UROtsa) or malignant BCa cell lines using western blotting and qPCR respectively. PGE2 levels were assessed by ELISA. Cell proliferation was assessed using the hexosaminidase assay and colony formation assays. Cell death was assessed using lactate dehydrogenase (LDH) release. Results: In vitro, BCa cell lines HT-1376, RT-4 and HTB-9 significantly upregulate mPGES1 as compared to a benign urothelial cell line (UROtsa). To assess the capacity of MF63 to effect PGE2 production, we treated HT-1376 and HTB-9 cells with MF63 at increasing concentrations and assessed PGE2 levels. MF63 significantly reduced PGE2 production after 24h in both cell lines. Furthermore, pharmacological inhibition of mPGES1 with MF63 at concentrations of 10µM and above significantly reduced cellular proliferation after 48 or 72 hours using both colony formation and the hexosaminidase assay to assess proliferation. Finally, concentrations of 50µM MF63 robustly induced cell death as measured by LDH release. Conclusions: These data show that inhibition of mPGES1 in vitro with the inhibitor MF63 results in decreases in PGE2 levels and reduced cellular proliferation, likely due in part to cell death induction. mPGES1 inhibitors are expected to have improved safety profiles and given our results, may have therapeutic potential in BCa. Citation Format: Benjamin Leeland Woolbright, Jordan Barney, Van Schloegel Schloegel, Erika Abbott, John Arthur Taylor. Microsomal prostaglandin E synthase-1: A therapeutic target in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3867.

Abstract 3209: BLZ945 and anti-PD-1 combination immunotherapy modulates the immune landscape in pancreatic ductal adenocarcinoma

Abstract Background: Immune therapies have shown great promise for some cancers. To date, pancreatic ductal adenocarcinomas (PDAC) have been largely resistant to immunotherapeutic approaches in part due to their exclusion of tumor infiltrating lymphocytes. The mechanisms by which this exclusion occurs are not well-characterized but are thought to involve both innate and adaptive immune responses. Methods: The primary objective of this study was to investigate how dual anti-PD-1/anti-CSF1R therapy changes the tumor immune cell niche and tumor growth in an allograft version of the KPC mouse model of PDAC (Pdx-1-Cre; LSL-KrasG12D; LSL-Trp53 R172H). Anti-PD1 therapy in the form of monoclonal antibody from BioXCell® was dosed twice weekly via intraperitoneal injections at 200µg/mouse. Anti-CSF1R in the form of the small-molecule inhibitor BLZ945 from Selleckchem® was dosed daily via oral gavage at 200 mg/kg. Human THP-1 cells differentiated and polarized to macrophages were used for viability and gene expression analyses. Results: In B6 recipient mice, the combination anti-PD-1 plus BLZ945 resulted in reduced percent tumor volume change (11% ±17) versus vehicle treated controls (121% ±174) (p=0.02). Flow cytometry of the spleens of tumor-bearing mice demonstrated an increase in conventional dendritic cells with combination treatment compared to controls (15.3 ±2.3% vs 8.3 ±0.6%, respectively; p=0.02). Mice lacking conventional dendritic cells (B6.BATF3-/-) had an increased percent tumor volume change (84% ±78) compared to B6 wild type mice (11% ±16) (p=0.01) when receiving combination treatment. IHC staining of allografted tumors revealed a trend towards increased infiltrating CD8+ T cells/hpf in B6 wild type mice treated with anti-PD-1 or combination therapy (21±24/hpf) compared to control treated mice (11±18/hpf). A similar trend was observed in B6.BATF3-/- mice (2.9±4.4/hpf vs 0.5±0.50/hpf); however, the magnitude was greatly reduced compared to B6 wild type mice. Interestingly, BLZ945 treated tumors did not show evidence of statistically significant reduced macrophage recruitment in vivo (268 vs 241, p=0.16). Macrophage viability in vitro was also unaffected by BLZ945 treatment (fold change in viability 0.03, p=0.6). Preferential changes in macrophage polarization in vitro were observed, with significant reductions in M2 polarization markers Arg-1, YM-1, and CD206 (p= 0.0005, 0.0029, and 0.012, respectively). Conclusions: The combination of an anti-PD-1 agent in combination with inhibition of the macrophage-predominant cytokine, anti-CSF1R, slows PDAC tumor growth in a conventional dendritic cell-dependent manner. Further characterization of the interplay between innate and adaptive immune cells upon immunotherapy treatment should be investigated to increase the efficacy of these therapeutics. Citation Format: Chelsie K. Sievers, Philip B. Emmerich, Hanna R. Rainiero, Connor Maloney, Rosabella Pitera, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Fotis Asimakopoulos, Dustin A. Deming. BLZ945 and anti-PD-1 combination immunotherapy modulates the immune landscape in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3209.

Clinicohistopathological implications of phosphoserine 9 glycogen synthase kinase-3β/ β-catenin in urinary bladder cancer patients.

BACKGROUNDAberrant activation of phosphorylated form of glycogen synthase kinase-3β [pS9GSK-3β (Serine 9 phosphorylation)] is known to trigger Wnt/β-catenin signal cascade but its clinicohistopathological implications in bladder carcinogenesis remain unknown.AIMTo investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3β, β-catenin and its target genes in the pathobiology of bladder cancer.METHODSBladder tumor tissues from ninety patients were analyzed for quantitative expression and cellular localization of pS9GSK-3β by immunohistochemical (IHC) staining. Real time-quantitative polymerase chain reaction and IHC were done to check the expression of β-catenin, Cyclin D1, Snail and Slug at transcriptome and protein level respectively. Clinicohistopathological variables were obtained from histology reports, follow up and OPD visits of patients. Expressions of the markers were statistically correlated with these variables to determine their significance in clinical setting. Results were analysed using SPSS 20.0 software.RESULTSAberrant (low or no membranous/high nuclear/high cytoplasmic) expression of pS9GSK-3β was noted in 51% patients and found to be significantly associated with tumor stage and tumor grade (P = 0.01 and 0.04; Mann Whitney U test). Thirty one percent tumors exhibited aberrant co-expression of pS9GSK-3β and β–catenin proteins and showed strong statistical association with tumor stage, tumor type, smoking/tobacco chewing status (P = 0.01, 0.02 and 0.04, Mann-Whitney U test) and shorter overall survival probabilities of patients (P = 0.02; Kaplan Meier test). Nuclear immunostaining of Cyclin D1 in tumors with altered pS9GSK-3β/β–catenin showed relevance with tumor stage, grade and type.CONCLUSIONβ–catenin and pS9GSK-3β proteins are identified as markers of diagnostic/prognostic significance in disease pathogenesis. Observed histopathological association of Cyclin D1 identifies it as marker of potential relevance in tumors with altered pS9GSK-3β/β-catenin.

Early depth of tumor shrinkage and treatment outcomes in non-small cell lung cancer treated using Nivolumab.

Background It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated associations between early depth of response and survival outcomes among patients receiving nivolumab for NSCLC. Methods Using records from prospective observational cohorts, we identified 83 previously treated advanced patients with NSCLC who received nivolumab during 2016-2017. Thirty-one patients who achieved disease control were analyzed. Tumor assessments followed the Response Evaluation Criteria in Solid Tumors (RECIST). Using Kaplan-Meier and receiver operating characteristic (ROC) curve analyses, treatment outcomes were compared with percent tumor reductions from baseline to the first evaluation (8-12weeks after starting nivolumab). Results Early depth of response was predictive of 6-month progression-free survival (area under the ROC curve, 0.848). Based on ROC results, early tumor shrinkage was defined as a > 10% reduction by the first evaluation. Early tumor shrinkage was associated with significantly longer median progression-free survival (early tumor shrinkage: 16.6months, 95% confidence interval [CI] 8.5months-not reached; no early shrinkage: 5.1months, 95% CI 3.9-6.8months; P < 0.001) and significantly longer median overall survival (P = 0.046). Conclusions Early depth of tumor shrinkage was associated with outcomes after ICI treatment. Because of its simplicity and predictive ability, early tumor shrinkage may be a promising factor for use in clinical settings. However, confirmation of our results is needed.

Therapeutic Efficacy and Dosimetry of Targeted Alpha Therapy using 225Ac-PSMA-617 in a Murine Model of Prostate Cancer

Targeted alpha therapy shows promise as a treatment in metastatic castration-resistant prostate cancer (mCRPC), owing to the high dose deposition and short range characteristics of alpha particle radiation. Ac-225 decays via multiple alpha particles – each capable of inducing irreparable DNA double-strand breaks in cell nuclei. PSMA-617 is a targeting ligand with specific affinity for prostate-specific membrane antigen (PSMA), a protein that is overexpressed in mCRPC but has low expression in normal tissues. Coupled with the lethal effects of alpha radiation, 225Ac-PSMA-617 is potentially highly cytotoxic to mCRPC while sparing normal tissues. The objective of this study was to evaluate the efficacy of alpha-particle radioligand therapy in a mouse model of mCRPC. Radiation dosimetry analysis was carried out to determine tumor dose as well as dose-limiting organs. NSG mice bearing subcutaneous PSMA-expressing C4-2 tumors were injected with escalating activities of 225Ac-PSMA-617: 20, 40, and 100 kBq/mouse (n=8/group). The tumor volumes were assessed over time by weekly low-dose microCT and compared with an untreated control group. In parallel, twenty-five NSG mice were used in a biodistribution study at five time points – 1, 4, 24, 48, and 168 hours post-administration of 40 kBq of the radiopharmaceutical. After sacrifice, percent tumor and organ radioactivity uptake was measured using gamma spectroscopy. Biexponential curve-fitting was used to fit the time-activity curves for the tumor and each organ, and integrated according to standard medical internal radiation dose methods to estimate the tumor and organ doses. Significant tumor growth retardation was observed in all treatment groups compared with the untreated group. Mice treated with 100 kBq exhibited some weight loss, while the mice treated with lower activities experienced only transient weight loss. There was a significant survival benefit conferred on tumor-bearing mice treated with 225Ac-PSMA617. The biodistribution over five time points showed high uptake and slow tumor activity clearance, and low uptake with fast clearance in non-target organs. The salivary glands, a dose-limiting organ in humans, did not show high uptake in mice, possibly due to lower PSMA expression. Estimates of the absorbed dose to the tumor and organs are reported. An administered activity of 40 kBq per mouse of the peptidomimetic 225AcPSMA-617 is well-tolerated and results in significant tumor growth retardation and improved survival. This work provides a preclinical foundation for further studies towards a more effective treatment option for advanced castration-resistant prostate cancer.

Angiogenic and immunomodulatory biomarkers in axitinib-treated patients (pts) with advanced renal cell carcinoma (aRCC).

614 Background: Axitinib (axi) is approved for 2nd-line treatment of aRCC. In AXIS trial, median progression-free survival (PFS) was significantly longer in axi- vs sorafenib (sor)-treated pts (hazard ratio [HR] 0.67, 95% CI 0.54–0.81, P&lt;0.0001). Association between mRNA/miRNA expression and clinical outcomes in a subset of axi- or sor-treated pts from AXIS was assessed. Methods: mRNA/miRNA analyses were performed on archival tumor samples. Expression was summarized for responders (complete and partial response) vs non-responders (stable and progressive disease), and for maximum percent tumor change. PFS and overall survival (OS) were analyzed by Kaplan-Meier. Results: Pt characteristics were similar between axi (n=34) and sor (n=33) arms. Association with outcomes is shown in the Table. A correlation was observed for CD68 protein and mRNA expression in axi-treated pts (R=0.4774 P=0.0043 and R=0.3985 P=0.0196, respectively). Both CXCR4 and TLR3 showed differences between treatment arms and association with PFS. TNFSF10 &lt;median, and CD163, CSF1R and miR-221-5p ≥median were associated with shorter OS with axi vs sor ( P&lt;0.05). Clinical trial information: NCT00678392. Conclusions: Immune-related biomarkers were associated with clinical outcomes in axi/sor-treated aRCC pts. Lower CCR7 expression was associated with better response and OS in axi-treated pts. CXCR4 and TLR3 may be predictive of response to axi. Analysis in a larger cohort is warranted.[Table: see text]

PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma.

Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE). Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots. Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03). Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.

Diffusion-weighted MRI for preoperative prediction of histologic response in patients with borderline resectable pancreatic cancer; A prospective phase II study (DIFFERENT study)

Introduction: Preoperative prediction of histological response to neoadjuvant therapy is a remarkable findings for making decision of surgical resection in borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). No prospective study reported investigating surrogate marker to predict their histological response to neoadjuvant therapy. Method: Twenty-eight patients with BRPC and LAPC who underwent diffusion-weighted magnetic resonance imaging (DW-MRI) prior to expected neoadjuvant chemotherapy and surgery were reviewed prospectively. Analyses for correlation between percent tumor cell destruction and the following was performed to investigate the parameter and cut off value: tumor size, whole tumor or vascular abutment site apparent diffusion coefficient (ADC) value of DW-MRI, maximum standardized uptake value of 18F-fluorodeoxyglucose positron emission tomography, carbohydrate antigen 19-9, and their change ratios or differences. The strong parameters were assessed for prediction ability of the therapeutic histological response and R0 curability. Result: Pre/post-treatment ADC value was correlated with tumor cell destruction rate among all parameters (R=0.630/0.714, P<0.001/<0.0001). The pre/post-treatment ADC cut-off value for discriminating between grade I and grade IIa and more after treatment was determined as 1.17/1.36x10-3 mm2/s and the sensitivity, 83/100%; specificity, 73/77%; accuracy, 75/82% for response, and the sensitivity, 63/75%; specificity, 75/80%; accuracy, 71/79% for R0 curability. The pre/post-treatment ADC cut-off value for discriminating between grade -3 mm2/s and the sensitivity, 92/100%; specificity, 63/81%; accuracy, 75/89% for response, and the sensitivity, 63/88%; specificity, 70/70%; accuracy, 68/75% for R0 curability. Conclusion: Post-treatment ADC value were confirmed to be a predictor of R0 curability in patients with BRPC and LAPC, and there was a significant correlation between the pre/post-treatment ADC value and histological tumor cell destruction rate.

Hearing preservation after cyberknife stereotactic radiosurgery for vestibular schwannomas

Background: The aim of this study is to evaluate retrospectively prognosis and auditory function after CyberKnife (CK) stereotactic radiosurgery (SRS) for vestibular schwannomas (VS) and to determine the radiation effects on hearing loss/preservation. Materials and Methods: The records of forty-one41 patients (24 males, 17 females) with VS who had received CK-SRS treatment were enrolled and retrospectively analyzsed. All patients underwent SRS (18 Gy in 3 sessions) between 2007 and 2012 at Tri-Service General Hospital, Taipei, Taiwan. Audiograms had been obtained before and after radiosurgery, and magnetic resonance imagingMRI and computed tomographyCT had been repeated to evaluate the tumour control rate. Age, percent tumour coverage, conformality index, new conformality index, cochlear dose, and audiometric test results were collected and analyzsed for all patients. Results: There were 41 patients enrolled in this study. The mean follow-up period of imaging studies was 56.6 ± 15.5 mo. At the postoperative assessment, there are 13 patients (76%) of Gardner–Robertson (GR) hearing maintained in Grade I and four4 patients (23%) of GR hearing changed to Grade II within those levels after treatment. There are 15 patients (62%) of GR hearing had been maintained in Grade II, and 9 patients (37%) of GR hearing changed to Ggrade I within those levels after treatment. After CK-SRS radiotherapy, 22 patients (22/41, 53%) had GR Ggrade I hearing, and 19 patients (19/41, 46%) had GR Ggrade II hearing. The patients with hearing deterioration had larger tumour volumes, lower cochlear volumes, higher cochlear radiation doses, and poorer hearing beforeprior to radiosurgery. Conclusions: Excellent tumour control and hearing preservation rates were observed for VS patients treated by CK SRS, with rates consistent with those reported in the literature. Compared with therapeutic alternatives, CK SRS is an effective tool for VS treatment and preserves hearing well.

Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies

Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies