Histologic Follow-up Research Articles

The utility of the Milan System as a risk stratification tool for salivary gland fine needle aspiration cytology specimens.

To perform a retrospective investigation of our institutional experience with salivary gland fine needle aspirations (FNA) through the framework of The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and assess the risks of neoplasm and malignancy for each diagnostic category. All salivary gland FNAs performed from January 2009 to December 2016 were retrospectively categorised according to the MSRSGC. When available, pre-operative cytological results were correlated with subsequent histological follow-up. In total, 893 FNAs were reviewed. The specimens were retrospectively classified as nondiagnostic (ND: 13.5%), non-neoplastic (NN: 16.1%), atypia of undetermined significance (AUS: 10.8%), benign neoplasm (BN: 34.9%), salivary gland neoplasm of uncertain malignant potential (SUMP: 8.2%), suspicious for malignancy (SM: 2.7%) and malignant (M: 13.8%). Histological follow-up was available for 429 cases (48%); the majority (68.1%) were benign. The risks of neoplasm and malignancy for each category were as follows: ND: 64.5%, 16.1%; NN: 42.9%, 17.9%; AUS: 79.6%, 30.6%; BN: 100%, 2.2%; SUMP: 100%, 46.6%; SM: 94.7%, 78.9%; and M: 100%, 98.5%. The MSRSGC is a useful classification scheme for stratifying salivary gland lesions according to their associated risk of malignancy and guiding clinicians toward appropriate management. Diagnostic pitfalls are seen in a small proportion of cases and a multidisciplinary approach for assessing salivary gland pathology is essential in their evaluation.

Subtyping salivary gland neoplasm of uncertain malignant potential based on cell type demonstrates differential risk of malignancy.

The newly unveiled Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has proposed salivary gland neoplasm of uncertain malignant potential (SUMP) as an indeterminate category. The category is reserved for fine-needle aspiration (FNA) cases that are diagnostic of a salivary gland neoplasm but cannot be further designated as a specific tumor type. The objective of the current study was to evaluate the clinical utility of subtyping SUMP cases based on different cell types. A retrospective search of cytology databases at 2 institutions for salivary gland FNAs from 2006 through 2017 was conducted. The cytologic diagnosis of each case was reclassified according to the MSRSGC. Histologic follow-up was retrieved for correlation. Cases reclassified as SUMP that had a follow-up pathologic diagnosis were subject to cytology review and subtyping into oncocytic/squamoid, basaloid, or myoepithelial subtypes based on cytomorphology. The risk of malignancy (ROM) for each subtype was analyzed. There were 92 SUMP cases, which comprised 5.9% of 1560 consecutive salivary gland FNAs within the 12-year study period. Histologic follow-up was available for 59 patients. After cytology review, there were 18 cases (30.5%) of oncocytic/squamoid subtype, 25 (42.4%) of basaloid subtype, and 16 (27.1%) of myoepithelial subtype. Pathologic correlation revealed an ROM of 61.1% (11 of 18 cases) for the oncocytic/squamoid subtype, 40.0% (10 of 25 cases) for the basaloid subtype, and 18.8% (3 of 16 cases) for the myoepithelial subtype. The differences in ROM among the 3 subtypes were statistically significant (P = .0476). Subtyping SUMP cases into categories based on cell type demonstrated differential ROMs for better clinical stratification. Future prospective studies are mandatory to confirm this finding.

Potential influence of p16 immunohistochemical staining on the diagnosis of squamous cell lesions in cervical biopsy specimens: observation from cytologic-histologic correlation.

The p16 immunohistochemical (IHC) marker has been used increasingly as an adjunct to morphologic assessment of cervical biopsies in which the differential diagnoses include high-grade squamous intraepithelial lesion (HSIL) and its mimics. The objective of this study was to assess the potential influence of p16 IHC staining on the evaluation of cervical biopsy as observed through cytologic-histologic correlation (CHC). Cervical biopsy samples that had cytologic diagnoses of either low-grade squamous intraepithelial lesion (LSIL) or HSIL and also had histologic follow-up were retrieved from the department database. CHC and the use of p16 IHC from 2 periods (group 1, 2008; group 2, 2014-2016) were compared and analyzed. Histology on 452 samples from patients who had prior LSIL cytology in group 1 yielded 126 benign (27.9%), 272 LSIL (60.2%), and 54 HSIL (11.9%) diagnoses. By comparison, 491 samples from the patients in group 2 yielded 106 benign (21.6%), 277 LSIL (56.4%), and 108 HSIL (22.0%) diagnoses. The difference in CHC discrepancies between the 2 groups was significant (P = .0001), mainly because of the increased diagnosis of HSIL in group 2. Although p16 IHC was not applied to any sample from group 1, it was performed on 141 of 491 samples (28.7%) from group 2. Further follow-up of patients who had histologic HSIL revealed that residual HSIL was identified significantly more often in those who did not have p16 IHC applied in the preceding cervical biopsy than in those did (P = .0004). A similar comparison was performed between 113 patients from group 1 and 152 patients from group 2 who had a prior diagnosis of HSIL cytology, and the difference was statistically insignificant. The use of p16 IHC on cervical biopsies in patients who had a prior cytologic diagnosis of LSIL may lead to greater detection and upgrading of HSIL, thereby compounding the discrepancy in CHC.

Histogram Analysis of Adrenal Lesions With a Single Measurement for 10th Percentile: Feasibility and Incremental Value for Diagnosing Adenomas.

Our purpose was to assess whether histogram analysis of adrenal lesions from a single measurement of mean attenuation and SD, using a threshold of 10% of negative voxels, can replace voxel counting while maintaining diagnostic accuracy. In a 4-year period, 325 adrenal lesions were detected on CT examinations of 308 consecutive patients. After exclusions, 91 patients with 108 lesions, including 20 malignant lesions and 88 adenomas (defined by histologic results or follow-up), were enrolled. Two observers retrospectively measured lesion size, mean attenuation value, and SD attenuation value and generated a pixel histogram. The 10th percentile (P10) was obtained from the conventional histogram analysis and was also calculated from the following formula: P10 = mean attenuation - (1.282 × SD). Diagnostic accuracies of the mean attenuation criterion, histogram analysis, and calculated 10th percentile were compared. The study group was composed of 74 patients with 88 adenomas and 17 patients with 20 malignant lesions, including seven adrenocortical carcinomas and 13 metastases; 93.1% of histograms showed normal distribution. The correlation between histogram analysis and calculated 10th percentile was 0.9827 and 0.9843 for reader 1 and 2 (p < 0.00001 for both). For both readers, sensitivity and specificity of the mean attenuation analysis were 65.9% (95% CI, 55.0-75.7%) and 100.0% (95% CI, 83.2-100%). The sensitivity and specificity of histogram analysis and calculated 10th percentile were the same, 87.5% (95% CI, 78.7-93.6%) and 95.0% (95% CI, 75.1-99.8%), for both readers. The increment increase in sensitivity was significant (p < 0.001), whereas the decrease in specificity was not (p = 0.15). For most adrenal lesions, the pixel attenuation has a gaussian distribution, allowing estimation of 10th percentile with a single measurement. The accuracy of histogram analysis and calculated 10th percentile outperformed the mean attenuation as a diagnostic criterion for nonfunctioning adenomas.

Long-term clinical, radiological, and histological follow-up after complex ventral incisional hernia repair using urinary bladder matrix graft reinforcement: a retrospective cohort study

BackgroundComplex ventral incisional hernia repair represents a challenging clinical condition in which biologically derived graft reinforcement is often utilized, but little long-term data inform that decision. Urinary bladder matrix (UBM) has shown effectiveness in diverse clinical settings as durable reinforcement graft material, but it has not been studied over a long term in ventral incisional hernia repair. This study evaluates the clinical, radiographic, and histological outcome of complex incisional hernia repair using UBM reinforcement with 12–70 months of follow-up.MethodsA single-arm, retrospective observational study of all ventral incisional hernia repairs utilizing UBM reinforcement over a 6-year time frame by a single surgeon was performed. Patients were assessed in long-term follow-up clinically and with the Carolina Comfort Scale. A subset of patients was assessed with abdominal wall ultrasound or CT scan. Three patients had abdominal wall fascial biopsies years after the incisional hernia repair with UBM graft, and the histology is analyzed.Results64 patients underwent repair of complex incisional hernias with UBM graft reinforcement by a single surgeon. 42 patients had concomitant procedures including large or small bowel resection, excision of infected mesh, evacuation of abscess or hematoma, cholecystectomy, or panniculectomy with abdominoplasty. 16 patients had ostomies at the time of repair. Median follow-up time is 36 months, with a range of 12–70 months. Nine patients (14%) have required surgical repair of a recurrent hernia, and a tenth patient has a recurrence that is managed non-surgically, for a total recurrence rate of 15.6% over the entire time frame. Median time to recurrence was 32 months, and a Kaplan–Meier freedom from recurrence curve is depicted. 28 patients have undergone ultrasound or CT assessments of the abdominal wall which demonstrate radiographic fascial integrity 12–70 months after repair. Three patients have been re-explored for unrelated reasons in the years following ventral incisional hernia repair with UBM, and full thickness fascial biopsies demonstrate a robust remodeling response histologically similar to native myofascial tissue. No patients have developed graft infection, fistulization to the graft, or required graft explantation. Carolina Comfort Scale assessment of 45 patients 3 years after the repair averaged 16 out of a possible 115.ConclusionIn 64 patients undergoing complex ventral incisional hernia repair with UBM reinforcement, all have experienced successful resolution of complex clinical conditions and 15.6% of these repairs have recurred at a median follow-up of 3 years. Three full-thickness biopsies of the repaired fascia years later shed light on a promising remodeling response which may signal strength and durability comparable to native fascia.

Celiac Disease 30 Years After Diagnosis: Struggling With Gluten-free Adherence or Gaining Gluten Tolerance?

Studies investigating patients with coeliac disease (CD) on very long-term follow-up are limited. We aimed to evaluate the characteristics of patients with CD diagnosed more than 30 years ago. Clinical, histologic, genetic, and demographic data of patients with CD diagnosis made before 1985 were collected and their standardised mortality ratio calculated. According to the gluten-free diet (GFD) status, CD patients were divided into 3 groups and a specific questionnaire on GFD awareness and gluten-free products was administered to patients and caregivers. A total of 337 CD patients were included in the study. The standardised mortality ratio was 0.37 (confidence interval 0.10 to 0.94) compared with a matched population. A total of 197 patients were grouped according to GFD compliance, with 35 CD patients reporting chronic voluntary gluten ingestion. No significant differences were found between groups regarding family history of CD, symptoms and histology at diagnosis, autoimmune disorders. Follow-up histology was performed in 63 patients. Twenty patients had normal histology on gluten-containing diet (GCD). Questionnaire scores were lower in patients on GCD. Caregivers scores were not correlated with patients' gluten consumption. Although poor adherence to GFD is the major predictor of persistence of mucosal lesions at follow-up histology, a proportion of patients did not show a relapse of villous atrophy in spite chronic voluntary gluten ingestion, nor increase in mortality. Moreover, GFD knowledge and adherence could be partly lost during the transition between childhood and adulthood.

Prognostic Factors in Paranasal Sinus Squamous Cell Carcinoma and Adenocarcinoma: A SEER Database Analysis.

Background Outcome studies on sinonasal malignancy are limited to retrospective case series, often with inclusion of diverse histology and short follow-up. The objective of this study was to identify key predictive variables that independently impact survival for paranasal sinus squamous cell carcinoma (SCC) and adenocarcinoma (AC) and to compare these variables in the context of these two distinct clinicopathologic entities. Methods: Analysis was conducted using the Surveillance, Epidemiology, and End Results database from 1973 to 2012 to identify key variables that impact survival for SCC and AC. Results A total of 3,714 cases were included. There were 2,895 SCC cases and 819 AC cases. The mean age at diagnosis was 64.1 years. The male to female ratio for SCC and AC was 1.85 and 1.04, respectively. Patients with SCC and AC were most often diagnosed with stage IV disease in 61.8 and 63.4% of cases, respectively. The majority of patients received combined surgery and radiation (52% for SCC and 43.1% for AC). For SCC, increased age ( p < 0.001) and stage ( p < 0.001) were negative predictors, and surgery improved survival ( p < 0.001) on multivariate analysis. For AC, prognostic factors associated with worse survival include increased age ( p < 0.001) and grade ( p < 0.001) on multivariate analysis. Overall survival was significantly higher in AC compared with SCC at 5 years ( p = 0.001). Conclusion SCC and AC of the paranasal sinuses are both aggressive malignancies with poor survival. For both histological subtypes, increased age predicts worse survival and grade also closely links to survival in AC. These data have important potential implications for treatment planning and pretreatment counseling.

Histological Follow-up for Women with High-grade Squamous Intraepithelial Lesion Pap Results and Aptima High Risk-HPV Testing Results

Histological Follow-up for Women with High-grade Squamous Intraepithelial Lesion Pap Results and Aptima High Risk-HPV Testing Results

The new guidelines of Papanicolaou Society of Cytopathology for respiratory specimens: Assessment of risk of malignancy and diagnostic yield in different cytological modalities.

In 2016, the Papanicolaou Society of Cytopathology (PSC) issued a new classification scheme for respiratory cytology. We aim to evaluate our samples according to this classification and to assess risk of malignancy and diagnostic yield of different cytological modalities. Respiratory specimens (sputum, bronchial wash/brush, BAL and FNA) obtained between 2007 and 2016 were reclassified according to PSC guidelines. Risk of malignancy for each diagnostic category was determined. Diagnostic yield was evaluated based on three-categorical approach. One thousand, two hundred and ninety respiratory specimens were retrieved, of which 280 had histologic follow-up. Samples were reclassified as nondiagnostic 16%, negative for malignancy 53%, atypical 5.4%, neoplastic (benign neoplasm/low-grade carcinoma) 0.4%, suspicious for malignancy 2.1% and malignant 23.1%. Risk of malignancy for each category was 64.01% for ND, 48.27% for NM, 59.09% for A, 100% for N-B-LG; 90% for SM and 89.74% for M. When only malignant cases were considered positive tests, cytology sensitivity was 55% and specificity 88%. Our results were in line with PSC guidelines, but the use of multiple cytological techniques may cause some discrepancies in overall diagnostic yield and in estimated risks of malignancy, which is important due to the widespread utilization of different cytological procedures.

Utility of The Paris System for Reporting Urinary Cytology in upper urinary tract specimens

Diagnosing upper urinary tract (UUT) lesions using cytology has been historically difficult because of a lack of standardized terminology, cytomorphologic criteria, and the presence of instrumentation artifact. The goal of The Paris System for Reporting Urinary Cytology (TPSRUC) was to provide standardized terminology and cytomorphologic criteria. The aim of this study was to evaluate the utility of TPSRUC in UUT cytology specimens at our institution. Single ThinPrep archival slides from 30 UUT cytology cases with corresponding histological follow-up were reviewed using TPSRUC. Those results were compared with the original cytology diagnoses. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for high-grade urothelial carcinoma (HGUC) using TPSRUC were 71%, 100%, 100%, and 71%. The TPSRUC was reliable at identifying HGUC. These data showed that this system had a lower sensitivity (71% versus 100%) and NPV (71% versus 100%) for UUT specimens compared with original cytology diagnoses. TPSRUC had a sensitivity and specificity that were comparable to reported overall sensitivity and specificity of UUT cytology for detection of HGUC. A major cause of discrepancy with TPSRUC was the classification of urine samples (n = 8) from histologically proven HGUC cases as only atypical (n = 6) or negative (n = 2), mainly owing to nuclear hypochromasia rather than hyperchromasia. Thus, hyperchromasia, a criteria used in TPSRUC, may not be as relevant in UUT specimens.

Thyroid Nodules with Indeterminate Cytology: Utility of the American Thyroid Association Sonographic Patterns for Cancer Risk Stratification.

The 2015 American Thyroid Association (ATA) guidelines recommend using a classification based on sonographic patterns to set the size threshold for biopsies. Each pattern is associated with a distinct estimated rate of malignancy that it was hypothesized should stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs). Ultrasound images of 463 ITNs (38% atypia/follicular lesions of undetermined significance; 62% follicular neoplasms) with histological follow-up consecutively evaluated between October 2008 and June 2015 at the authors' academic cancer center were independently evaluated by three observers and classified into one of the five sonographic patterns proposed by the ATA. Nodules with sonographic patterns not defined in the classification were grouped into a non-ATA pattern category. Differences in clinical and histological findings between the sonographic patterns were assessed. The prevalence of malignancy and odds ratio for malignancy were calculated for each sonographic pattern (low and intermediate patterns were collapsed for the analysis). The distribution of size and cytological diagnosis was significantly different between sonographic patterns (p < 0.001). The overall rate of malignancy was 27%. The rate of malignancy for the very low, low/intermediate, high, and non-ATA patterns were 0%, 19%, 56%, and 36%, respectively, and were all significantly different. Compared to the low/intermediate suspicion patterns, the odds ratios for malignancy were 2.35 for the non-ATA and 5.18 for the high suspicion patterns (p < 0.001). The odds ratio of the non-ATA pattern was 0.45 over the high suspicion pattern (p = 0.04). Results were similar in both cytological categories and for each observer separately. Sonographic patterns were associated with distinct histopathological profiles (p < 0.001). ATA sonographic patterns are associated with distinct clinical features and pathological outcomes, and effectively stratify the cancer risk in ITNs. Thus, the ATA sonographic patterns should be used not only to set the size threshold for biopsy, but also to personalize management after the biopsy.

Added value of 18F-FDG PET-CT in staging of Ewing sarcoma in children and young adults

BackgroundEwing sarcoma (ES) is currently staged using Radiography, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and skeletal scintigraphy (bone scan). 18F- fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET-CT) is increasingly used for staging and follow-up, but its role is still under evaluation.ObjectiveTo evaluate the added information from 18F-FDG PET-CT studies compared to conventional imaging and to estimate radiation doses received from radiological and nuclear medicine imaging during staging of Ewing sarcoma.Material and methodsSixty-one patients under the age of 30 years (mean 16, range 5–26) were diagnosed with Ewing sarcoma in Norway during the period 2005–2012. Nineteen patients met the inclusion criteria for this population-based study: pre therapeutic 18F-FDG PET-CT and a minimum follow-up of 12 months. Imaging reports, medical records and pathology reports were collected and compared for all patients. Biopsy histology, supplementary imaging and long-term follow-up (median 27 months) were taken as composite gold standard.Results18F-FDG PET-CT detected more lesions than conventional imaging in four patients (21%) but this did not change planned treatment as they all had extensive metastatic disease. The 18F-FDG PET-CT study was false negative in one patient and showed false positive lesions in three patients (16%). The estimated mean (range) effective total radiation dose was from CT: 7 mSv (2–16), skeletal scintigraphy: 3 mSv (0–5) and 18F-FDG PET-CT: 5 mSv (4–6).Conclusion18F-FDG PET-CT is useful for staging of Ewing sarcoma and increase detection of metastases. False positive lesions are quite common, emphasizing the need for supplementary imaging or biopsy of suspected FDG positive metastases.

FDG-PET/MRI in patients with pelvic recurrence of rectal cancer: first clinical experiences.

To determine the value of 18F-FDG-PET/MRI in the diagnosis and management of patients with pelvic recurrence of rectal cancer. Forty-four patients (16 women, 28 men) with a history of rectal cancer who received FDG-PET/MRI between June 2011 and February 2017 at our institution were retrospectively enrolled. Three patients received two FDG-PET/MRIs; thus a total of 47 examinations were included. Pelvic recurrence was confirmed either with histology (n = 27) or imaging follow-up (n = 17) (> 4 months). Two readers (one radiologist, one nuclear medicine physician) interpreted the images in consensus. Pelvic lesions were assessed regarding FDG uptake and morphology. Sensitivity, specificity, positive and negative predictive values as well as accuracy of PET/MRI in detecting recurrence were determined. In 47 FDG-PET/MRIs 30 suspicious pelvic lesions were identified, 29 of which were malignant. Two patients underwent resection and had histologically proven pelvic recurrence without showing suspicious findings on FDG-PET/MRI. Changes in management due to FDG-PET/MRI findings had been implemented in eight patients. Eighty per cent (16/20) of resected patients had histologically negative resection margins (R0), one patient had uncertain resection margins. Sensitivity of FDG-PET/MRI in detecting recurrence was 94%, specificity 94%, positive/negative predictive value and accuracy were 97%, 90% and 94%, respectively. FDG-PET/MRI is a valuable tool in the diagnosis and staging of pelvic recurrence in patients with rectal cancer. • Metabolic information obtained from PET coupled with excellent soft tissue contrast from MRI could facilitate detection of rectal cancer recurrence and assist in treatment planning. • PET/MRI demonstrates high sensitivity and specificity for the diagnosis of local recurrence of rectal cancer • PET/MRI led to alterations in management in 18.2% of patients.

Results from a Long Term Histological Follow up of De Novo HBV-infection in Liver Transplant Patients Unrelated to HBV-Reinfection and HBV-Reactivation

Introduction The development of hepatitis-B is considered as a serious complication after liver transplantation. It may cause severe graft dysfunction and even lead to graft loss and to patient´s death. HBV-de novo infection is a rather rare phenomenon, however it deserves attention in the era of donor organ shortage. The aim of the present analysis was to examine the course of HBV-infection in liver transplant patients without HBV-associated liver disease pretransplant including long term histological follow-up. Patients and Methods Since 1988 3005 liver transplantations have been performed at Charité, Campus Virchow-Klinikum for various liver diseases. Prevalence of patients with de novo HBV-infection transplanted for other reasons than HBV-associated liver disease was determined in a local transplant data base. Recipients of antiHbc-positive organs were excluded from the analysis. The analysis focused on the moment of HBV-detection and on the long term follow-up in terms of biochemical and histological changes during almost 30 years in a high volume transplant center in Germany. Statistical analysis was performed using SPSS version 24. Results 39 patients were identified with the diagnosis of de novo hepatitis-B (1.3%). None of the patients was transplanted because of HBV-associated liver disease, so that HBV-reinfection was ruled out. Furthermore none of them received an antiHbc-positive organ. Median time from liver transplantation to the diagnosis was 366 (8-5497) days. No fibrosis progression could be detected. Furthermore, steatosis and the grade of inflammation did not significantly change between the time of HBV-infection and the end of histological follow-up for 2897 (106-8045) days in median. Patients with a poor virological control especially in the beginning of the 90ies era before NUCs or low genetic barrier NUCs demonstrated a significantly decreased survival and 1 HBV-associated graft loss. Conclusion Since the introduction of NUCs with high genetic barrier HBV-associated graft infection is a condition that can be controlled very well without significant fibrosis progression, graft loss or patient death if recognized on time within a regular transplant follow-up schedule.

Abstract 958: Anti-GD2 chimeric antigen receptor T cells as a potent immunotherapy regimen in xenograft models of histone 3 K27M mutant diffuse midline glioma

Abstract Histone 3 K27M mutated diffuse midline glioma (H3K27M DMG) is a universally fatal pediatric brain tumor. Despite improved understanding of the molecular origins of this disease, translations to improvement in clinical outcomes have yet to materialize. To date, there has been little target exploration for immunotherapy applications in H3K27M DMG. Here we report substantial preclinical efficacy of chimeric antigen receptor (CAR)-bearing T cells targeting the disialoganglioside GD2 in patient-derived orthotopic xenograft models of H3K27M DMG. GD2 is highly and uniformly expressed in patient-derived H3K27M DMG cultures, and in vitro assays demonstrate substantial target-dependent cytokine generation and target cell killing. Two H3 WT pediatric high-grade gliomas (HGG) cultures do not express significant levels of GD2, and the H3K27M mutation is associated with increased synthesis of ganglioside pathway synthesis enzymes, suggesting expression of the GD2 antigen is driven by H3K27M-induced transcriptional dysregulation. Single-dose systemic administration of GD2-4-1BBz-CAR T cells in multiple orthotopic xenograft models of H3K27M DMG achieves potent and lasting antitumor efficacy within a 4-week period of administration compared to a CD19-4-1BBz-CAR T cell control cohort. In brainstem xenografts, GD2-CAR T cell therapy cleared established tumor as measured by in vivo bioluminescence imaging and follow-up histology, and significantly prolonged survival. Using a fluorescently-labeled GD2-CAR, we demonstrate tumoricidal GD2-CAR T cells infiltrating the brain parenchyma and sparing of local neurons during tumor clearing. Treatment-associated neuroinflammation in brainstem xenografts is accompanied by transient ventriculomegaly due to swelling of the targeted tumors, which is accompanied by transient weight loss followed by full recovery. Similar swelling in thalamic xenograft models is lethal in a significant fraction of animals, presumably due to uncal herniation. These results demonstrate potent antitumor effects of GD2-directed CAR T cells in H3K27M DMG, and suggest an important role for neuroanatomic site in neurotoxicity associated with CAR T cell therapy. If these results are predictive of human response, GD2-directed CAR T cell therapy in the setting of careful clinical management could have a transformative impact upon H3K27M DMG outcomes. Citation Format: Christopher W. Mount, Robbie Majzner, Shree Sundaresh, Evan P. Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Pamelyn Woo, Skyler P. Rietberg, Hannes Vogel, Michelle Monje, Crystal L. Mackall. Anti-GD2 chimeric antigen receptor T cells as a potent immunotherapy regimen in xenograft models of histone 3 K27M mutant diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 958.

No diagnostic impact of routinely use of respiratory gating to characterize lung nodules with 18F-FDG PET/CT

PurposeTo evaluate diagnostic impact of routinely use of respiratory gated (RG) 18FDG PET/CT to distinguish benign and malignant lung nodules. MethodsWe analyzed retrospectively data of 76 patients referred for metabolic characterization of lung nodules who underwent whole body 18FDG PET/CT scan followed by RG PET/CT (deep-inspiration breath-hold, DIBH). RG was prospectively planned without knowledge of WB PET/CT results. Independent reading of PET/CT scans with or without respiratory gating was separately conducted by two nuclear medicine physicians. Uptake of lung nodules was evaluated visually (positive if nodule's uptake superior to pulmonary background uptake), and quantitatively (SUVmax, SUVmean, metabolic volume, tumor to background ratio). Reference standard was obtained for all patients by histology (n=37) or clinico-radiological follow-up (n=39). Sub-groups were also evaluated (nodule<15mm, lower lobe nodules). ResultsNodules were classified positives without RG scans in 43/76 (59.7%) patients and with RG scans in 41/75 (54.6%) patients. Results were discordant for 5/75 (6.7%) patients. According to the reference standard, 35/39 cancers were correctly identified by PET/CT without RG, and 34/38 by RG PET/CT. Without RG PET, sensitivity, specificity and accuracy were 89.7%, 78.4% and 84.2% respectively. With RG PET, sensitivity, specificity and accuracy were 89.5%, 81.1% and 85.3% respectively, not statistically different. Concerning quantitative analysis, results were not statistically better with RG than without RG and were not better than visual analysis. Sub-groups analysis showed no added value of RG scans in specific groups (lower lobes and smaller nodules). ConclusionRoutinely use of RG did not help in the diagnosis of neoplastic lung nodules. Others evaluations are needed to assess the contribution of RG for others selective indications (therapeutic evaluation, radiotherapy planning, characterization of liver lesions).

Treatment of HBV-Recurrence After Liver Transplantation – 30 Years of Experience

Introduction Hepatitis-B-(HBV)-associated end stage liver disease has been one of the main indication for liver transplantation (LT) for the last decades. After LT, a HBV-reinfection remains as a serious issue and preventing strategies range from the sole application of hepatitis-B immunoglobulins (HBIG) during the anhepatic phase, to modern nucleotide analogues in combination with HBIG and later HBIG-discontinuation. The aim of the analysis was to evaluate different prophylaxis strategies and to sum up the results of 30 years at a high volume transplant center. Patients and Methods We performed 372 liver transplantations due to a HBV-associated liver disease at our clinic sinca 1988. Demographic, clinical, biochemical and histological data was extracted from a prospectively organized data base. The median follow up was 13 years. We evaluated indication for transplantation, serological status and age at time of transplantation, type of prophylaxis, stage of fribosis at 1, 3, 5, 7, 10 and 13 years after LT. The incidence and time of HBV-reinfection were investigated and analyzed. Primary endpoint was the survival depending on the type of prophylaxis. Results Among 372 LTs we identified 109 (29.3%) HBV-reinfections. HBV-reinfections after LT were significantly more frequent in male patients (84.4% vs. 73.4% in the group of with no reinfections, p=0.022). Furthermore, patients with an acute liver failure due to HBV-infection (11.0% vs. 2.8%, p=0.028) were at a significantly lower risk for a reinfection after LT as well as patients with a HCV-coinfection (11.4% vs. 4.6%, p=0.047). No significant differences in the distribution of HBV-reinfection could be observed regarding the presence of HCC (24.7 vs. 30.1; p=0.388) and HDV-co-infection (23.3 vs. 29.8%; p=0.474). Re-transplantation was not a significant risk factor for a reinfection, but the HBV-associated graft loss was significantly higher in the group of patients with a HBV-reinfection (7.3% vs. 1.9%, p=0.000). Patients with HBV-reinfection demonstrated a significantly poorer survival than patients without reinfection (log rank; p=0.004). Controlled HBV-reinfection did not demonstrated any fibrosis progression during a median histological follow-up of 13 years. Reinfection did not significantly influence the survival in patients who received NUCs and HBIG (log rank; p=0.233) compared to patients who received HBIG or nothing at all as HBV-prophylaxis (log rank; p=0.004). HBIG-discontinuation was initiated in 67 patients with just 1 patient with HBV-recurrence. Conclusion Female gender, acute liver failure for transplant indication as well as a HCV-coinfection had a lower risk for HBV-reinfection. Hbs-Ag –positive grafts did not develop fibrosis during a long-term follow up. The most reliable mode to prevent HBV-recurrence is still the combination of NUCs with a high genetic barrier and HBIG. HBIG can safely be discontinued after a still undetermined period of time after liver transplantation.

Impact on clinical follow‐up of the Milan System for salivary gland cytology: A comparison with a traditional diagnostic classification

No universally accepted classification exists for salivary gland FNA. The proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) offers a uniform classification with management recommendations. We compared FNA diagnoses from a prior study with specific diagnoses with corresponding MSRSGC diagnoses. One-hundred and sixty-four cases from a prior cytological study with histological follow-up were re-reviewed by one of the authors and assigned to one of the MSRSGC categories. The original and MSRSCG diagnoses were compared, as were follow-up recommendations. The MSRSGC system classified 29 specimens as non-diagnostic (seven histologically shown to be benign salivary gland, two non-mucinous cysts, 14 sialadenitis, one pleomorphic adenoma, one haemangioma, one lymphoma, one adenoid cystic carcinoma, one squamous carcinoma and one benign lymphoid proliferation). The original study diagnosed these lesions as: seven benign cysts, 15 benign salivary gland tissue, one benign neoplasm and two insufficient for diagnosis. In seven cases, MSRSGC disagreed with original diagnoses and surgical resection showed lesions where optimal follow-up was more consistent with original cytological diagnosis. In 10 cases with disagreement, the MSRSGC was associated with a more appropriate follow-up based on the surgical diagnosis. Malignancy risks for the Milan categories were: non-diagnostic (12%), non-neoplastic (5%), atypia of undetermined significance (19%), neoplasm, benign (5%), neoplasm (40%), suspicious for malignancy (60%) and malignant (93%). MSRSGC was comparable with the original reported diagnoses in the majority of cases. Both systems had high accuracy for distinguishing benign from malignant lesions and both were associated with appropriate follow-up in most cases.

Differential immunohistochemical expression of type I collagen and matrix metalloproteinase 2 among major salivary glands of young and geriatric mice.

Objective This study aimed to demonstrate the immunohistochemical changes associated with MMP-2 and type 1 collagen separately for the first time in the major salivary glands (the parotid, submaxillary, and sublingual glands) that occur with aging in mice.Material and Methods Fourteen Balb/c white mice (50-80 g) were used in this study. The animals were divided into two equal groups. Group I consisted of young animals (2-month-old) (n=7) and Group II consisted of older animals (18-month-old) (n=7). After routine histological follow-ups, Hematoxylin-eosin (H&E), Masson’s Trichrome staining and immunohistochemical staining was performed for type I collagen and MMP-2.Results We observed that there were age-related decreases in the number of acinar cells, increase in eosinophilic zymogen granules in cells, collagen accumulation in fibrotic areas and dilatation in interlobular ducts. Also, while type I collagen and MMP-2 immunoreactivity were moderate in the salivary glands of the young mice, they were high in the salivary glands of the old mice (p=0.001). In the H-score assessment, MMP-2 immunoreactivity was lower at a significant level in young mice than in old mice (p=0.001).Conclusions This study showed that anatomical, physiological and morphological abnormalities occur in all three major salivary glands as a natural consequence of aging.

The Value of Negative Diagnosis in Thyroid Fine-Needle Aspiration: a Retrospective Study with Histologic Follow-Up.

The Bethesda System for reporting thyroid cytopathology (BSRTC) predicts an incidence of malignancy of less than 5% in thyroid nodules with a benign diagnosis on fine-needle aspiration (FNA). However, recent series have suggested that the true rate of malignancy might be significantly higher in this category of patients. We reviewed our experience by performing a retrospective analysis of patients with benign thyroid FNA results who underwent thyroidectomy between 2008 and 2013 at a large academic center. Information including demographics, ultrasound features, FNA diagnosis, and surgical follow-up information were recorded. Slides were reviewed on cytology-histology discrepant cases, and it was determined whether the discrepancy was due to sampling or interpretation error. A total of 802 FNA cases with a benign diagnosis and surgical follow-up were identified. FNA diagnoses included 738 cases of benign goiter and 64 cases of lymphocytic thyroiditis. On subsequent surgical resection, 144 cases were found to be neoplastic, including 117 malignant cases. False negative, defined as interpretation error and inadequate biopsy of the nodule harboring malignancy, was 6%. When cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were excluded from the analysis, false-negative rate was 5%. When microPTC cases were excluded, false-negative rate was 3% and was slightly less than 3% when both microPTC and NIFTP cases were excluded from the analysis. Retrospective review of neoplastic cases showed that 57% were due to sampling error and 43% were due to interpretation error. Interpretation error was more likely to occur in follicular patterned neoplasms (75%), while sampling error was more common in non-follicular variants of papillary thyroid carcinoma (non-FVPTC) (61%). With the exclusion of microPTC, interpretation errors were still more likely to occur in follicular neoplasms (79%) but there was no significant difference in sampling error between non-FVPTC (37%) and follicular patterned neoplasms (42%). Tumor size was larger in cases with interpretation error (mean = 2.3cm) compared to cases with sampling error (mean = 1.4cm). This study shows that the false-negative rate of thyroid FNA at our institution is not significantly above the rate suggested by the BSRTC. Interpretation errors were more likely to occur in follicular patterned neoplasms, while non-FVPTC was more frequently found in false negative cases due to inadequate sampling.