ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Carcinoma, Pancreatic Ductal , Lymphocyte Activation , Pancreatic Neoplasms , T-Lymphocytes , Humans , Adjuvants, Immunologic/therapeutic use , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/therapy , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy , Lymphocyte Activation/immunology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , T-Lymphocytes/cytology , T-Lymphocytes/immunology , mRNA VaccinesABSTRACT
The objective of this study is to compare aneuploidy rates between three distinct areas of the human trophectoderm: mural, polar and a region in between these two locations termed the 'mid' trophectoderm. This is a cohort study on in vitro fertilization (IVF) patients undergoing comprehensive chromosome screening at the blastocyst stage at a private IVF clinic. All embryos underwent assisted hatching on day 3 with blastocyst biopsy and comprehensive chromosome screening. Biopsied blastocysts were divided into three groups depending on which area (polar, mid, or mural) of the trophectoderm was protruding from the zona pellucida and biopsied. Aneuploidy rates were significantly higher with cells from the polar region of the trophectoderm (56.2%) compared with cells removed from the mural region of the trophectoderm (30.0%; P = 0.0243). A comparison of all three areas combined also showed a decreasing trend, but this did not reach clinical significance, polar (56.2%), mid (47.4%) and mural trophectoderm (30.0%; P = 0.1859). The non-concordance demonstrated between polar and mural trophectoderm can be attributed to biological occurrences including chromosomal mosaicism or procedural differences between embryologists.
Subject(s)
Preimplantation Diagnosis , Aneuploidy , Biopsy , Blastocyst , Cohort Studies , Female , Fertilization in Vitro , Humans , PregnancyABSTRACT
PURPOSE: Based largely on reports that predate modern reporting standards, mitotane has been considered a systemic treatment option for both hormone control and antitumor control of metastatic adrenocortical cancer (ACC), although the therapeutic window is narrow. METHODS: We searched electronic medical records to identify patients with metastatic ACC treated and prescribed single-agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989-September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors 1.1. Patient demographics, toxicities, and treatment outcomes were reviewed. Next-generation sequencing was performed in selected cases. RESULTS: Thirty-six patients were identified. The mean age was 54 and 50% had functional tumors. Grade 3 or greater toxicities were documented in 16 out of 36 patients (44%) and 17% had documented long term adrenal insufficiency. Progression of the disease as the best response occurred in 30 out of 36 patients (83%) and one patient (3%) experienced clinical progression. Three patients achieved a complete response (CR) (8%), one patient achieved a partial response (3%), and one patient (3%) had stable disease after slow disease progression prior to initiation of therapy (durable for 6 months). All responders had nonfunctional tumors. Next-generation sequencing in two of the three CR patients was performed and failed to identify any novel alterations. CONCLUSION: In this retrospective series, mitotane had a low response rate and low tumor control rate; however, a disproportionately high complete response rate suggested it should be used in selected individuals. Adrenal insufficiency is common with mitotane use and aggressive treatment with steroid supplementation should be considered when appropriate to avoid excess toxicities. Biomarkers are desperately needed to further define this disease. IMPLICATIONS FOR PRACTICE: This is the first objective report of single-agent mitotane using modern objective criteria. Although the vast majority of patients did not respond (and toxicity was high), we identified a remarkable 8% complete response rate (i.e. cure) in biopsy proven stage IV adrenocortical cancer patients. Biomarkers are desperately needed for this rare disease.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Mitotane/therapeutic use , Adrenal Cortex Neoplasms/pathology , Adrenal Insufficiency/chemically induced , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/drug therapy , Adrenal Insufficiency/epidemiology , Adrenocortical Carcinoma/pathology , Adult , Aged , Aged, 80 and over , Biomarkers/analysis , Biopsy , Disease Progression , Electronic Health Records/statistics & numerical data , Female , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Palliative Care/methods , Remission Induction/methods , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
The purpose of this study was to identify a technique that allows for comprehensive chromosome screening (CCS) of individual cells within human blastocysts along with the approximation of their location in the trophectoderm relative to the inner cell mass (ICM). This proof-of-concept study will allow for a greater understanding of chromosomal mosaicism at the blastocyst stage and the mechanisms by which mosaicism arises. One blastocyst was held by a holding pipette and the ICM was removed. While still being held, the blastocyst was further biopsied into quadrants. To separate the individual cells from the biopsied sections, the sections were placed in calcium/magnesium-free medium with serum for 20 min. A holding pipette was used to aspirate the sections until individual cells were isolated. Individual cells from each section were placed into PCR tubes and prepped for aCGH. A total of 18 cells were used for analysis, of which 15 (83.3%) amplified and provided a result and 3 (16.7%) did not. Fifteen cells were isolated from the trophectoderm; 13 (86.7%) provided an aCGH result, while 2 (13.3%) did not amplify. Twelve cells were euploid (46,XY), while 1 was complex abnormal (44,XY), presenting with monosomy 7, 10, 11, 13, and 19, and trisomy 14, 15, and 21. A total of 3 cells were isolated from the ICM; 2 were euploid (46,XY) and 1 did not amplify. Here, we expand on a previously published technique which disassociates biopsied sections of the blastocyst into individual cells. Since the blastocyst sections were biopsied in regard to the position of the ICM, it was possible to reconstruct a virtual image of the blastocyst while presenting each cell's individual CCS results.
Subject(s)
Blastocyst/metabolism , Comparative Genomic Hybridization/methods , Mosaicism , Aneuploidy , Blastocyst/cytology , Ectoderm/cytology , Ectoderm/metabolism , Female , Humans , Single-Cell Analysis , Trophoblasts/cytology , Trophoblasts/metabolismABSTRACT
PURPOSE: The aim of this study was to assess the diagnostic performance of computed tomography (CT) for initial staging of non-endometrioid carcinomas of the uterine corpus. MATERIALS AND METHODS: Waiving informed consent, the Institutional Review Board approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study of 193 women with uterine papillary serous carcinomas, clear cell carcinomas, and carcinosarcomas, who underwent surgical staging between May 1998 and December 2011 and had preoperative CT within 6 weeks before surgery. Two radiologists (R1, R2) independently reviewed all CT images. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and area under the curve were calculated using operative notes and surgical pathology as the reference standard. RESULTS: The respective sensitivities and specificities achieved by R1/R2 were 0.79/0.64 and 0.87/0.75 for detecting deep myometrial invasion (MI) on CT; 0.56/0.63 and 0.93/0.79 for detecting cervical stromal invasion; 0.52/0.45 and 0.95/0.93 for detecting pelvic nodal metastases; and 0.45/0.30 and 0.98/0.98 for detecting para-aortic nodal metastases. Although CT had suboptimal sensitivity for the detection of omental disease, it had high PPV for omental seeding at surgical exploration (1.00 for R1 and 0.92 for R2). Inter-observer agreement ranged from moderate in the detection of deep MI (κ = 0.42 ± 0.06) to almost perfect in the detection of para-aortic nodal metastases (κ = 0.88 ± 0.08). CONCLUSION: In patients with uterine non-endometrioid carcinomas, CT is only moderately accurate for initial staging but may provide clinically valuable information by 'ruling-in' isolated para-aortic lymph node metastases and omental dissemination.
Subject(s)
Adenocarcinoma, Clear Cell/pathology , Carcinoma, Papillary/pathology , Carcinosarcoma/pathology , Cystadenocarcinoma, Serous/pathology , Tomography, X-Ray Computed/methods , Uterine Neoplasms/pathology , Adenocarcinoma, Clear Cell/diagnostic imaging , Adenocarcinoma, Clear Cell/surgery , Aged , Aged, 80 and over , Carcinoma, Papillary/diagnostic imaging , Carcinoma, Papillary/surgery , Carcinosarcoma/diagnostic imaging , Carcinosarcoma/surgery , Cystadenocarcinoma, Serous/diagnostic imaging , Cystadenocarcinoma, Serous/surgery , Female , Follow-Up Studies , Humans , Image Processing, Computer-Assisted/methods , Male , Middle Aged , Neoplasm Staging , Preoperative Care , Prognosis , Retrospective Studies , Uterine Neoplasms/diagnostic imaging , Uterine Neoplasms/surgeryABSTRACT
PURPOSE: To evaluate interreader and inter-test agreement in applying size- and necrosis-based response assessment criteria after transarterial embolization (TAE) for hepatocellular carcinoma (HCC), applying two different methods of European Association for the Study of the Liver (EASL) criteria. METHODS: Seventy-four patients (median age, 67 years) from a prospectively accrued study population were included in this retrospective study. Four radiologists independently evaluated CT data at 2-3 (1st follow-up, FU) and 10-12 (2nd FU) weeks after TAE and assessed treatment response using size-based (WHO, RECIST) and necrosis-based (mRECIST, EASL) criteria. Enhancing tissue was bidimensionally measured (EASLmeas) and also visually estimated (EASLest). Interreader and inter-test agreements were assessed using intraclass correlation coefficient (ICC) and κ statistics. RESULTS: Interreader agreement for all response assessment methods ranged from moderate to substantial (κ = 0.578-0.700) at 1st FU and was substantial (κ = 0.716-0.780) at 2nd FU. Inter-test agreement was substantial between WHO and RECIST (κ = 0.610-0.799, 1st FU; κ = 0.655-0.782, 2nd FU) and excellent between EASLmeas and EASLest (κ = 0.899-0.918, 1st FU; κ = 0.843-0.877, 2nd FU). CONCLUSION: Size- and necrosis-based criteria both show moderate to excellent interreader agreement in evaluating treatment response after TAE for HCC. Inter-test agreement regarding EASLmeas and EASLest was excellent, suggesting that either may be used. KEY POINTS: ⢠Applying EASL criteria, visual estimation and bidimensional measurements show comparable interreader agreement. ⢠EASL meas and EASL est show substantial interreader agreement for treatment response in HCC. ⢠Agreement was excellent for EASL meas and EASL est after TAE of HCC. ⢠Visual estimation of enhancement is adequate to assess treatment response of HCC.
Subject(s)
Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Chemoembolization, Therapeutic , Female , Humans , Liver/diagnostic imaging , Male , Middle Aged , Observer Variation , Reproducibility of Results , Retrospective Studies , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
OBJECTIVE: The purpose of this article is to review imaging workup of perihilar cholangiocarcinoma, including MDCT and MRI protocols, imaging findings, differential diagnosis, and staging. A reporting template is included. CONCLUSION: Imaging plays a central role in the detection, differential diagnosis, and staging of perihilar cholangiocarcinoma.
Subject(s)
Bile Duct Neoplasms/diagnosis , Bile Ducts, Intrahepatic , Cholangiocarcinoma/diagnosis , Diagnostic Imaging , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/pathology , Humans , Neoplasm StagingABSTRACT
Intraductal papillary mucinous neoplasms (IPMN) are being diagnosed with increasing frequency, necessitating an algorithm to help stratify patients into low- and high-risk groups, for follow-up versus more invasive evaluation. New evidence concerning their natural history and overall risk of malignancy has emerged since the 2006 International Association of Pancreatology consensus guidelines, prompting an update in 2012, that distinguishes radiologic 'worrisome features' from 'high-risk stigmata'. The aim of this article is to illustrate, with case examples, the variable imaging patterns of IPMN and how their radiologic features, such as cyst size and mural nodules, are interpreted in the context of the new 2012 guidelines. The 2012 and 2006 guidelines will be compared and discussed with reference to additional studies that have since been published. Despite these guidelines, lingering uncertainty remains about the natural history of IPMN, a source of unease to both radiologists and referring clinicians alike, mandating further refinement of clinical and radiologic parameters predictive of malignancy. Emerging data regarding the risk of extrapancreatic malignancy, as well as synchronous or metachronous pancreatic ductal adenocarcinoma remote in location from a branch duct IPMN are also reviewed. With the expanding research and evolving understanding of this clinicopathologic entity across the globe, radiologists will continue to play an important role in the management of patients with IPMN.
Subject(s)
Carcinoma, Pancreatic Ductal/diagnosis , Guidelines as Topic , Pancreatic Neoplasms/diagnosis , Adenocarcinoma/pathology , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/therapy , Dilatation, Pathologic , Endosonography , Humans , Neoplasm Invasiveness , Pancreatic Ducts/pathology , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Radiography, InterventionalABSTRACT
PURPOSE: To develop a preoperative CT-based nomogram for predicting overall survival (OS) in patients with non-endometrioid carcinomas of the uterine corpus. METHODS: Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 193 women with histopathologically proven uterine papillary serous carcinomas (UPSC), uterine clear cell carcinomas (UCCC), and uterine carcinosarcomas (UCS) who underwent primary surgical resection between May 1998 and December 2011, and had a preoperative CT ≤ 6 weeks before surgery. All CT scans were reviewed for local or/and regional tumor extent, presence of pelvic or/and para-aortic adenopathy, and presence of distant metastases. Univariate survival analysis was performed using log-rank test and Cox regression. Variables shown significant by the univariate analysis were evaluated with the multivariable Cox regression analysis and the results were used to create a nomogram for predicting OS. The predictive accuracy of the nomogram was assessed with the concordance probability index (c-index) and a 3-year calibration plot. RESULTS: Mean patient age was 67.2 years (range 49.0-85.9); histologies included UPSC (n = 116), UCCC (n = 27), and UCS (n = 50). Median follow-up was 38.1 months (0.9-168.5 months). At multivariate analysis, patient age, ascites, and omental implants on CT were significant adverse predictors of OS and were used to build the nomogram. Concordance index for the nomogram was 0.640 ± 0.028. CONCLUSION: We developed a nomogram with a good concordance probability at predicting OS based on readily available pretreatment clinical and imaging characteristics. This preoperative nomogram has the potential to improve initial treatment planning and patient counseling.
Subject(s)
Nomograms , Tomography, X-Ray Computed , Uterine Neoplasms/diagnostic imaging , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Prognosis , Retrospective Studies , Survival Analysis , Uterine Neoplasms/mortality , Uterine Neoplasms/pathologyABSTRACT
BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. METHODS: Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. RESULTS: As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5 years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8 months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003). CONCLUSIONS: Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/pathology , Female , Humans , Insulin-Like Growth Factor Binding Protein 1/blood , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/metabolism , Kaplan-Meier Estimate , Liver Neoplasms/blood , Liver Neoplasms/pathology , Male , Middle Aged , Receptor, IGF Type 1/metabolismABSTRACT
OBJECTIVE: The purpose of this retrospective study was to measure interobserver agreement in the assessment of malignant imaging features of intraductal papillary mucinous neoplasms (IPMNs) on MDCT. MATERIALS AND METHODS: Pancreatic protocol CT studies were reviewed for 84 patients with resected IPMNs. Maximal diameter of the dominant cyst, presence of a mural nodule, presence of a solid component, and diameters of the main pancreatic duct (MPD) and common bile duct (CBD) were measured by four radiologists independently. In each patient, the IPMN was classified into one of three types: main duct, branch duct, or mixed IPMN. Interobserver agreement of lesion features was examined using the intraclass correlation coefficient (ICC) for continuous features and Fleiss kappa for categorical features. RESULTS: The final dataset included 55 branch duct IPMNs, nine main duct IPMNs, and 20 mixed IPMNs. Moderate agreement (ĸ = 0.458; 95% CI, 0.345-0.564) was observed in assigning branch duct, main duct, or mixed IPMN subtypes. Measurement agreement was substantial to excellent for dominant cyst (ICC = 0.852; 95% CI, 0.777-0.907), MPD (0.753, 0.655-0.837), and CBD (0.608, 0.463-0.724) but only fair to moderate for the detection of the presence of mural nodule (ĸ = 0.284, 0.125-0.432) or solid component (ĸ = 0.405, 0211-0.577). CONCLUSION: Substantial to excellent interobserver agreement in the measurement of cyst diameter, MPD, and CBD support their use for characterizing malignant features of IPMN on MDCT. However, the subjective interpretation of the presence of solid components and mural nodules by individual radiologists was more variable.
Subject(s)
Adenocarcinoma, Mucinous/diagnostic imaging , Carcinoma, Pancreatic Ductal/diagnostic imaging , Multidetector Computed Tomography/methods , Pancreatic Neoplasms/diagnostic imaging , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Observer Variation , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: The LI-RADS Treatment Response (LR-TR) algorithm was introduced in 2017 to assist radiologists in assessing hepatocellular carcinoma (HCC) response following locoregional therapy. The objective of this study was to evaluate the associations between pre-treatment LI-RADS diagnostic categories, post-treatment LR-TR categories, and mRECIST response categories with overall survival (OS) of patients with HCC. METHODS: This retrospective study included untreated patients with one or two lesions who underwent transarterial embolization with or without concomitant ablation from December 2003 to December 2017. Two radiologists (R1 and R2) reviewed pre- and post-treatment CT imaging. Associations between pre- and post-treatment variables, including post-treatment LR-TR categories (Viable, Equivocal, Nonviable), with OS were assessed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Eighty-five patients were included (median age = 71 years, range 50-87; 17 women). The median OS from first embolization was 43.92 months. Pre- and post-treatment tumor size, pre-treatment LR-TIV (compared with LR-5), and post-treatment LR-TR Viable (compared with LR-TR Nonviable) were associated with OS (p < 0.05 for all). Median OS was shorter for LR-TR Viable patients (R1, 25.64 months, 95% CI 18.58-35.70; R2, 26.43 months 95% CI 20.68-43.92) than for LR-TR Nonviable patients (64.21 months R1 and R2, 95% CI 42.71-92.45 and 36.30-94.09, respectively). mRECIST categories showed similar associations with OS. Inter-reader agreement was moderate for LI-RADS categories (κ = 0.57, 95% CI 0.35-0.78) and substantial for LR-TR categories (κ = 0.68, 95% CI 0.55-0.81). CONCLUSIONS: LR-TR categories show a strong association with OS in HCC patients treated with transarterial embolization.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/therapy , Female , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Magnetic Resonance Imaging , Middle Aged , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
PURPOSE: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adrenal Cortex Neoplasms/diagnostic imaging , Adrenal Cortex Neoplasms/immunology , Adrenocortical Carcinoma/diagnostic imaging , Adrenocortical Carcinoma/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Programmed Cell Death 1 Receptor/immunology , Survival Rate , Young AdultABSTRACT
PURPOSE: Clinical applications of dual energy computed tomography (DECT) have been widely reported; however, the importance of the different image reconstructions and radiation organ dose remains a relevant area of investigation, particularly considering the different commercially available DECT equipment. Therefore, the purpose of this study was to assess the image reliability and compare the information content between several image reconstructions in a rapid-switching DECT (rsDECT), and assess radiation organ dose between rsDECT and conventional single-energy computed tomography (SECT) exams. MATERIALS AND METHODS: This Institutional Review Board-approved retrospective study included 98 consecutive patients who had a history of liver cancer and underwent multiphasic liver CT exams with rsDECT applied during the late arterial phase between June 2015 and December 2015. Virtual monochromatic 70 keV, material density images (MDI) iodine (-water) and virtual unenhanced (VUE) images were generated. Radiation dose analysis was performed in a subset of 44 patients who had also undergone a multiphasic SECT examination within 6 months of the rsDECT. Four board-certified abdominal radiologists reviewed 24-25 patients each, and a fifth radiologist re-evaluated all the scans to reach a consensus. The following imaging aspects were assessed by the radiologists: (a) attenuation measurements were made in the liver and spleen in VUE and true unenhanced (TUE) images; (b) subjective evaluation for lesion detection and conspicuity on MDI iodine (-water)/VUE images compared with the virtual monochromatic images/TUE images; and (c) overall image quality using a five-point Likert scale. The radiation dose analyses were evaluated in the subset of 44 patients regarding the following parameters: CTDIvol, dose length product, patient's effective diameter and organ dose using a Monte Carlo-based software, VirtualDose™ (Virtual Phantoms, Inc.) to 21 organs. RESULTS: On average, image noise on the TUE images was 49% higher within the liver (pâ¯<â¯0.0001) and 48% higher within the spleen (pâ¯<â¯0.0001). CT numbers for the spleen were significantly higher on VUE images (pâ¯<â¯0.0001). Twenty-eight lesions in 24/98 (24.5%) patients were not observed on the VUE images. The conspicuity of vascular anatomy was considered better on MDI iodine (-water) Images 26.5% of patients. Using the Likert scale, the rsDECT image quality was considered to be satisfactory. Considering the subset of 44 patients with recent SECT, the organ dose was, on average, 37.4% less with rsDECT. As the patient's effective diameter decreased, the differences in dose between the rsDECT and SECT increased, with the total average organ dose being less by 65.1% when rsDECT was used. CONCLUSION: VUE images in the population had lower image noise than TUE images; however, a few small and hyperdense findings were not characterized on VUE images. Delineation of vascular anatomy was considered better in around a quarter of patients on MDI iodine (-water) images. Finally, radiation dose, particularly organ dose, was found to be lower with rsDECT, especially in smaller patients.
Subject(s)
Image Processing, Computer-Assisted/methods , Liver Neoplasms/diagnostic imaging , Radiation Dosage , Tomography, X-Ray Computed/methods , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Iodine , Liver/diagnostic imaging , Male , Middle Aged , Radiography, Dual-Energy Scanned Projection/methods , Reproducibility of Results , Retrospective Studies , Young AdultABSTRACT
PURPOSE: The purpose of the study was to assess the inter-observer agreement on the qualitative and quantitative evaluation of relative signal intensity of liver lesions on delayed hepatobiliary phase (HBP) MRI with gadoxetate (Gd-EOB-DTPA). METHODS: 105 patients with liver lesions, who had delayed HPB MRI using gadoxetate were reviewed retrospectively. For each patient, four readers (two fellows in training and two attending radiologists) qualitatively assessed the relative SI of the largest representative lesion on a five point scale, and quantitatively measured the relative SI of the lesion to adjacent liver parenchyma using region of interests (ROI). Intra-class correlation (ICC) and kappa statistics with quadratic weights (k) analysis, and maximally selected rank statistic were performed. RESULTS: Substantial agreement between fellows (k = 0.719; ICC = 0.705) and almost perfect agreement between attending radiologists (k = 0.853; ICC = 0.849) were found for both qualitative and quantitative assessments of relative SI on delayed HPB imaging. A cut-off ratio to differentiate between hypointense and iso- to hyperintense lesions by ROI was calculated to be 0.90. CONCLUSION: Inter-observer agreement of liver lesion relative SI on delayed HBP imaging is high and may improve with radiologist experience. A cut-off ratio of relative SI at 0.90 may be useful to quantitatively distinguish hypointense from iso- to hyperintense liver lesions.
Subject(s)
Contrast Media/administration & dosage , Gadolinium DTPA/administration & dosage , Liver Neoplasms/diagnosis , Magnetic Resonance Imaging/methods , Biopsy , Female , Humans , Image Enhancement/methods , Liver Neoplasms/pathology , Male , Middle Aged , Observer Variation , Reproducibility of Results , Retrospective StudiesABSTRACT
Hepatocellular carcinoma (HCC) is often diagnosed on the basis of high quality imaging without a biopsy in the cirrhotic liver. This is a case of a 64-year-old Caucasian man with no history of liver disease or cirrhosis that presented with fatigue, weight loss, and abdominal distension and was found to have a large, isolated liver mass with arterial enhancement and portal venous washout on triple-phase computed tomography (CT) suspicious for HCC. The patient was initially referred for a surgical evaluation. Meanwhile, he developed fevers, pancytopenia, and worsening back pain, and a subsequent spinal MRI revealed a heterogeneous bone marrow signal suspicious for metastatic disease. A bone marrow biopsy that followed was diffusely necrotic. A core biopsy of the patient's liver mass was then performed and was diagnostic of acute monocytic-monoblastic leukemia. Findings from peripheral flow cytometry and a repeat bone marrow biopsy were also consistent with this diagnosis, and induction chemotherapy with cytarabine and idarubicin was initiated. This case describes a rare presentation of myeloid sarcoma (MS) as an isolated, hypervascular liver mass that mimics HCC in its radiographic appearance. Due to the broad differential for a liver mass, a confirmatory biopsy should routinely be considered prior to surgical intervention.
ABSTRACT
Radiological and nuclear incidents are low probability but very high risk events. Measures can be, and have been, implemented to limit or prevent the impact on the public. Preparedness, however, remains the key to minimizing morbidity and mortality. Incidents may be related to hospital-based mis-administration of radiation in interventional radiology or nuclear medicine, industrial or nuclear power plant accidents. Safety and security measures are in place to prevent or mitigate such events. Despite efforts to prevent them, terrorist-perpetrated incidents with, for example, a radiological dispersal device (RDD) are also possible. Due to a misunderstanding of, or lack of, formal education regarding things in this realm, there can be considerable anxiety, even fear, about radiation-related incidents. Multiple studies evaluating healthcare provider willingness to report to work rank radiation as the hazard that will keep the largest number of workers at home. Even incidents that do not constitute a disaster can spiral out of control quite rapidly, placing considerable demands on community resources. Our communities will face these threats in the future and it is the responsibility of physicians and allied healthcare personnel to be trained and ready to care for those affected. The scope of resources needed to prepare for and respond to such incidents is indeed vast. It encompasses the coordinated effort of first responders and physicians, the preparedness of national agencies involved in responding to such events, and individual community cooperation and solidarity. This article reviews the approach to the short- and long-term effects of a radiological or nuclear incident on an affected population, with a specific focus on the medical and public health issues. It also summarizes the strengths and weaknesses of our current ability to respond effectively and makes recommendations to improve these capabilities.
Subject(s)
Disaster Planning/organization & administration , Emergency Medical Services/organization & administration , Mass Casualty Incidents , Public Health , Radioactive Hazard Release , HumansABSTRACT
OBJECTIVES: To evaluate the hypothesis that infertility may result in a decrease in quality of life and an increase in marital discord and sexual dysfunction. The burden of infertility is physical, psychological, emotional, and financial. METHODS: Couples seeking treatment for infertility were asked to complete standardized validated questionnaires assessing quality of life (Quality of Well-Being Scale-Self Administered, version 1.04), marital adjustment (Locke-Wallace Marital Adjustment Test), and sexual function (Brief Index of Sexual Functioning for Women and International Index of Erectile Function for men). Couples seeking elective sterilization served as the control subjects. RESULTS: Eighteen infertile couples and 12 couples seeking elective sterilization participated in the study. The mean age, years together, and household income were comparable. Infertile couples had made a mean of 14.5 office visits for infertility, and 83% of couples reported feeling societal pressures to conceive. The Marital Adjustment Test scores for the women of the infertile couples were significantly lower than the scores of the controls (P = 0.01); however no difference was noted in the men. A trend toward lower quality-of-life scores was noted in women (P = 0.09) but not in the men of infertile couples. No statistically significant impact on sexual functioning in women was noted; however, the men in the infertile couples had lower total International Index of Erectile Function scores (P = 0.05) and intercourse satisfaction scores (P = 0.03). CONCLUSIONS: Women in infertile couples reported poor marital adjustment and quality of life compared with controls. Men may experience less intercourse satisfaction, perhaps because of the psychological pressure to try to conceive or because of the forced timing of intercourse around the woman's ovulatory cycle.
Subject(s)
Infertility/psychology , Adult , Cross-Sectional Studies , Family Characteristics , Female , Humans , Income/statistics & numerical data , Infertility/complications , Libido , Male , Marriage , Parity , Penile Erection , Personal Satisfaction , Prevalence , Quality of Life , Severity of Illness Index , Sexual Behavior , Sexual Dysfunction, Physiological/complications , Sexual Dysfunction, Physiological/epidemiology , Sexual Dysfunction, Physiological/psychology , Sterilization, Reproductive/psychology , Surveys and QuestionnairesABSTRACT
Members of the cathelicidin family are present in all mammals studied. Generally, these proteins contain a conserved N-terminal domain and a structurally and functionally divergent C-terminal region that expresses antibacterial or other activities when proteolytically released. Rabbit granulocytes produce CAP18, a cathelicidin that conforms to this structural and functional organization, and also 15-kDa protein isoforms (p15s) that share several key structural features with other cathelicidins but apparently do not undergo processing with release of an active peptide. To further define the importance of proteolysis in the antibacterial activities of these proteins, we have purified from granulocytes proCAP18, its C-terminal peptide (CAP18p), and two p15 isoforms to apparent homogeneity. Of these four polypeptides, only CAP18p was independently cytotoxic to encapsulated Escherichia coli (90% inhibitory concentration, approximately 600 nM) but it was approximately 50-fold less potent on a molar basis than the bactericidal/permeability-increasing protein (BPI). However, all four cathelicidin species, notably including proCAP18, exhibited antibacterial synergy with BPI, and the p15s also displayed synergy with CAP18p in the absence of BPI. Subnanomolar concentrations of proCAP18 blocked lipopolysaccharide-induced chemiluminescence of human leukocytes, showing a molar potency more than 100-fold greater than that of CAP18p ( approximately 20 nM) or BPI ( approximately 50 nM). Thus, while independent bactericidal activity of cathelicidins requires processing, other host-defense functions do not and are more potently expressed by the unprocessed protein than by the C-terminal peptide.
Subject(s)
Antimicrobial Cationic Peptides/pharmacology , Membrane Proteins , Neutrophils/metabolism , Protein Precursors/pharmacology , Protein Processing, Post-Translational , Animals , Antimicrobial Cationic Peptides/isolation & purification , Antimicrobial Cationic Peptides/metabolism , Blood Proteins/pharmacology , Cathelicidins , Culture Media , Drug Antagonism , Drug Synergism , Endopeptidases/metabolism , Escherichia coli/drug effects , Humans , Isotonic Solutions , Lipopolysaccharides/pharmacology , Protein Isoforms/isolation & purification , Protein Isoforms/metabolism , Protein Isoforms/pharmacology , Protein Precursors/isolation & purification , Protein Precursors/metabolism , RabbitsABSTRACT
PURPOSE: To prospectively compare thin-section low-dose multi-detector row computed tomographic (CT) colonography with conventional colonoscopy for the detection of colorectal neoplasms. MATERIALS AND METHODS: One hundred five patients underwent CT colonography immediately before colonoscopy. Supine and prone CT colonographic acquisitions to image the region during a 30-second breath hold were performed. CT colonographic images were prospectively interpreted for the presence, location, size, and morphologic features of polyps. The time of image interpretation was noted. Sensitivity, specificity, and positive and negative predictive values of CT colonography were calculated, with 95% CIs, by using colonoscopic findings as the reference standard. The weighted CT dose index was calculated on the basis of measurements in a standard body phantom. Effective dose was calculated by using commercially available software. RESULTS: Median CT data interpretation time was 12 minutes. One hundred thirty-two polyps in 59 patients were identified at colonoscopy; no polyps were detected in 46 patients. Sensitivities for detection of polyps smaller than 5 mm, 6-9 mm, and larger than 10 mm in diameter were 12% (11 of 91 polyps), 70% (19 of 27 polyps), and 93% (13 of 14 polyps), respectively. Estimated overall specificity was 97.7% (515 of 527 imaging results). The total weighted CT dose index for combined supine and prone CT colonography was 11.4 mGy. The effective doses for combined CT colonography were 5.0 mSv and 7.8 mSv for men and women, respectively. CONCLUSION: Low-dose multi-detector row CT colonography has excellent sensitivity and specificity for detection of colorectal neoplasms 10 mm and larger.