Non-Hodgkin Lymphoma Causing Hypopituitarism Can Imaging Help Diagnosis and Management?

Non-Hodgkin lymphomas of the hypothalamus and pituitary are rare. They usually remain clinically silent until onset of compressive features affecting surrounding structures. When symptomatic, patients most commonly present with diabetes insipidus, headaches, ophthalmoplegia and/or bilateral hemianopia. We report a case of a 67-year-old Caucasian female with a history of B-cell lymphoma in complete remission. She presented with left oculomotor nerve palsy and was subsequently found to have a sellar/suprasellar mass lesion on MRI. Alongside hypocortisolism and hypogonadotropic hypogonadism, she developed transient diabetes insipidus during her illness. Her clinical course was characterized by rapid intracranial progression of the sellar mass. MR spectroscopy suggested a diagnosis of lymphoma. Diagnostic biopsy confirmed high-grade diffuse large B-cell CNS lymphoma; this changed the definitive management from surgical excision to chemotherapy. Despite treatment, she succumbed to her illness within 7 months of initial presentation. This case highlights the aggressive nature of CNS lymphomas and the need for a high index of suspicion in an unusual presentation of sellar/suprasellar mass lesions.

Circulating miRNAs as Potential Biomarkers for Celiac Disease Development

Background & AimsCeliac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD.MethodsUsing next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort.Results53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken <1 year before TGA positivity: miR-21-3p, miR-374a-5p, 144-3p, miR-500a-3p, miR-486-3p let-7d-3p, let-7e-5p and miR-3605-3p. 6/26 downregulated miRNAs reconstituted upon GFD, including miR-150-5p/-3p, whereas no upregulated miRNAs were downregulated upon GFD. 15/53 biomarker candidates also differed between CeD biopsies and controls, with a concordant direction, indicating that these circulating miRNAs might originate from the intestine.ConclusionsWe identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.

Development of a hoRizontal data intEgration classifier for NOn-invasive early diAgnosis of breasT cancEr: the RENOVATE study protocol

IntroductionStandard procedures aimed at the early diagnosis of breast cancer (BC) present suboptimal accuracy and imply the execution of invasive and sometimes unnecessary tissue biopsies. The assessment of circulating biomarkers for diagnostic purposes, together with radiomics, is of great potential in BC management.Methods and analysisThis is a prospective translational study investigating the accuracy of the combined assessment of multiple circulating analytes together with radiomic variables for early BC diagnosis. Up to 750 patients will be recruited at their presentation at the Diagnostic Senology Unit of Ospedale Policlinico San Martino (Genoa, IT) for the execution of a diagnostic biopsy after the detection of a suspect breast lesion (t0). Each recruited patient will be asked to donate peripheral blood and urine before undergoing breast biopsy. Blood and urine samples will also be collected from a cohort of 100 patients with negative mammography. For cases with histological diagnosis of invasive BC, a second sample of blood and urine will be collected after breast surgery. Circulating tumour DNA, cell-free methylated DNA and circulating proteins will be assessed in samples collected at t0 from patients with stage I–IIA BC at surgery together with those collected from patients with histologically confirmed benign lesions of similar size and from healthy controls with negative mammography. These analyses will be combined with radiomic variables extracted with freeware algorithms applied to cases and matched controls for which digital mammography is available. The overall goal of the present study is to develop a horizontal data integration classifier for the early diagnosis of BC.Ethics and disseminationThis research protocol has been approved by Regione Liguria Ethics Committee (reference number: 2019/75, study ID: 4452). Patients will be required to provide written informed consent. Results will be published in international peer-reviewed scientific journals.Trial registration numberNCT04781062.

FISH-Guided Evaluation of Hyperdiploidy and Other Cytogenetic Abnormalities in Childhood Burkitt Lymphoma

Background: Burkitt lymphoma (BL) is the most common lymphoma in childhood. Apart from MYC rearrangement, considered the hallmark of the disease, BL often presents with additional chromosome aberrations, the biological and clinical significance of which is not fully understood. Materials and methods: The study included 72 children (55 boys, 17 girls), aged 2-16 years (median 9), with BL diagnosed on the basis of histopathology and a demonstrable MYC rearrangement. Touch imprints from the diagnostic biopsy samples were investigated with i-FISH for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements genes and copy number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Deviations from the diploid status were further investigated for aneusomies of the carrier chromosome with the use of appropriate chromosome enumeration probes. Results: MYC gene was demonstrated in all cases with MYC/IGH fusion in 83.3% (60/72). 47 cases (65.3%) were found with least one additional aberration, most commonly with 1q gain (29.2%), 7q gain (19.4%), 13q deletion (19.4%), hemizygous 9p loss (8.3%) and hyperdiploidy (8.3%). Advanced clinical stage (IV), 7q gain (but not trisomy 7) and -9/9p- were significantly associated with shorter overall survival. There was no instance of relapse or death among the hyperdiploid cases. Conclusions: This extensive FISH investigation on imprints of affected tissue provides clinically meaningful information on the genetic profile of BL and may prove valuable in the management of patients with no karyotype available. In particular, the demonstration of hyperdiploidy through the use of chromosome enumeration probes could offer the means for the delineation of clonal evolution pathways and the recognition of a subgroup of children with excellent prognosis who could be cured with low-intensity chemotherapy regimens. Disclosures Kattamis: VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy.

Integration of Targeted Gene Expression Profiling and FDG-PET Radiomics Uncovers Radiometabolic Signatures Associated with Outcome in Diffuse Large B-Cell Lymphoma

Metabolic rewiring is a hallmark of cancer and a predominant feature of aggressive lymphoproliferative disorders such as diffuse large B-cell lymphomas (DLBCL), which need a reshaped metabolism in order to meet the increased demands related to rapid cell proliferation. Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. However, the relationship between metabolic rewiring and chemoresistance in lymphoma is yet to be elucidated. Radiomic analysis applied to functional imaging with fluoroedoxyglucose positron emission tomography (FDG-PET) provides a unique opportunity to explore DLBCL metabolism. In this study we hypothesized that distinct gene expression (GEP) signatures might be correlated with specific FDG-PET radiomics signatures, which in turn could be associated with resistance to standard chemoimmunotherapy and DLBCL outcome. First, we retrospectively analyzed a discovery cohort of 48 consecutive DLBCL patients (pts) treated at our center with standard first line R-CHOP/R-CHOP-like chemoimmunotherapy from 2010 to 2018, with available formalin-fixed paraffin embedded (FFPE) tissue from the initial diagnostic biopsy and FDG-PET radiomics data extracted from the same target lesion. Median follow-up was 55 months (range 18-110). We profiled this cohort with targeted-GEP (T-GEP) (NanoString platform), using a custom panel to define the cell of origin (COO) and MYC/BCL-2 levels, and a dedicated panel comprising 180 genes encompassing the most relevant cancer metabolism pathways. By applying the maxstat package we found that a 6-gene metabolic signature was strongly associated with outcome and outperformed the COO, the MYC/BCL-2 status and the International Prognostic Index (IPI) score for progression free survival (PFS) and overall survival (OS) in multivariate analysis. The 6-gene metabolic signature included genes regulating oxidative metabolism and fatty acid oxidation (SCL25A1, PDK4, PDPR) which were upregulated, and was inversely associated with genes involved in glycolytic pathways (MAP2K1, HIF1A, GBE1) which were downregulated. Notably 5-year PFS and OS were 100% and 95% in metabolic signature (met-Sig) low pts vs 24% and 45% in met-Sig high pts respectively (p<0.0001 for PFS and OS). There was no significant association between the COO, MYC/BCL-2 levels, standardized uptake value (SUV), and the 6-gene signature. The prognostic value of the 6-gene signature for OS was validated in 2 large publicly available cohorts of 469 (Sha et al. J Clin Oncol 2019) and 233 (Lenz et al. N Eng J Med 2005) pts. Next, we integrated PET radiomics and T-GEP data. Radiomics analysis (LifeX package) was performed by applying regions of interest semi-automatically, using a 25% SUV max threshold for segmentation. Fifty-five radiomic features (RFs) were extracted and 10 RFs significantly correlated either positively or negatively with the T-GEP metabolic signature (Spearman). After stability evaluation, applying a stepwise feature selection procedure, 4 RFs (Histo Curtosis, Histo Energy, Shape Sphericity, NGLDM Contrast) were used to generate a radiomic signature (hereafter called radiometabolic signature) characterized by the most significant correlation with both the metabolic T-GEP signature (r=0.43, p=0.0027) and PFS (p=0.004). These results (obtained analyzing the lesion of the initial diagnostic biopsy), were confirmed using different target lesions (i.e. the most FDG-avid and the largest lesion), and were validated in a second independent cohort of 64 patients (validation cohort) treated at our center in the same period of time (with no FFPE tissue available). A multivariate analysis performed in the whole cohort of 112 pts (discovery + validation) indicated that the radiometabolic signature retained independent prognostic value in relation to the IPI score and metabolic tumor volume. The robustness of the radiometabolic signature was further confirmed by using a second segmentation method (fixed 2.5 SUV max threshold). These data indicate that oxidative metabolic rewiring could be a powerful adverse prognostic predictor, suggesting the possibility of targeting oxidative metabolism to overcome chemorefractoriness in DLBCL. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for non-invasive assessment of cancer metabolism, and for predicting metabolic vulnerabilities in DLBCL. Figure 1 Figure 1. Disclosures Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Pileri: CELGENE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD; NANOSTRING: Other: ADVISORY BOARD. Derenzini: TAKEDA: Research Funding; BEIGENE: Other: ADVISORY BOARD; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; TG-THERAPEUTICS: Research Funding; ADC-THERAPEUTICS: Research Funding.

P.157 Frame-based stereotactic brain biopsy: A retrospective review of diagnostic yield and complications at a Canadian Center

Background: Historically, frame-based stereotactic brain biopsy (SBB) has played an important role in the diagnosis of intracranial lesions. We performed a single centre analysis of the outcomes and efficacy of SBB at the London Health Sciences Centre (LHSC). Methods: We performed a retrospective chart review of frame-based SBB from 2006 to 2017 at the LHSC. Intra-operative and final pathology reports were analyzed for biopsy diagnosis and the diagnosis was compared with pre-operative neuroimaging reports for correlation. SBB-associated morbidity and mortality were investigated using chart review and post-operative neuroimaging. Results: 173 consecutive patients were identified. The overall morbidity rate was 8.7% (15 cases) and mortality rate was 0.6% (1 case). Final biopsy diagnostic accuracy was 96%, intra-operative diagnostic accuracy was 94% and pre-operative imaging diagnostic accuracy was 65%. Elevated partial thromboplastin time and the presence of hemorrhage on post-operative CT were associated with neurological morbidity and mortality. The need to obtain three or greater samples the time of biopsy was associated with non-diagnostic biopsy. Conclusions: At the LHSC, SBB is a relatively safe and effective surgical procedure with high diagnostic yield and relatively low risk of complications. Intra-operative pathology has a high efficacy in determining diagnosis when compared to final pathology.

Delays in the referral and primary management of cutaneous malignant melanoma at Tygerberg Hospital

Background: Cutaneous malignant melanoma (CMM) is a significant cause of skin cancer-related mortality. The time between the diagnostic biopsy and primary surgical excision, the surgical interval (SI), is a modifiable factor that may impact melanoma outcomes. Delays in the SI are attributable to many factors.Aim: To determine the SI in patients with resectable CMM treated at Tygerberg Academic Hospital (TAH).Methods: A retrospective review of patients referred to the TAH multidisciplinary melanoma clinic with histologically confirmed CMM between January 2015 and December 2017 was done. Patients 18 years with resectable melanoma (T1b-T4b N0-3 M0-1a) who received definitive surgery were included.Results: The cohort (n = 40) comprised mostly Caucasians referred from the Cape metropolitan (metro) area, with a median age at diagnosis of 59 years. Thirty-one (77.5%) patients had T3 or T4 lesions on diagnostic biopsy. Twenty patients (50%) underwent a sentinel lymph node biopsy (SLNB) which led to an upstaging in 20% of cases. The median length of the SI was 13.5 weeks. Eighteen patients (45%) underwent primary excision within the recommended 12 weeks from diagnostic biopsy. There was a significant association between the SI and patients living in the Cape metro (p = 0.04) as well as the SI and p Stage (p = 0.01).Conclusion: Surgical interval guidelines for cutaneous melanoma are poorly defined. We used 12 weeks as an extrapolation of international guidelines. Even though this target was not met, the study is proposed to be of value in guiding future protocols and ultimately allowing for improved, timely service to patients.

A disease-based evaluation of lung cancer care quality in a community healthcare system.

251 Background: Lung cancer care is complex, but, for quality improvement, can be simplified into five ‘nodal points’: lesion detection, diagnostic biopsy, radiologic staging, invasive staging, and treatment. We previously demonstrated great heterogeneity in passage through these nodal points in patients who received surgical resection for lung cancer in our healthcare system. However, examining only surgical patients may underestimate the enormity of the opportunity for quality improvement. With the aim of identifying quality gaps in pre-treatment evaluation for lung cancer, we evaluated the flow of care through these nodal points within a community-based healthcare system. Methods: We classified lung cancer care procedures received by all suspected lung cancer patients treated within the Multidisciplinary Thoracic Oncology Program at Baptist Cancer Center, Memphis TN between 2014 and 2019, into five nodal points. We compared the frequency of, and time intervals between, nodal points among patients receiving surgical, nonsurgical (chemotherapy/radiation), or no definitive treatment, using Chi-square or Kruskal Wallis tests, where appropriate. Results: Of 1304 eligible patients: 11% had no pre-treatment diagnostic procedure, 20% no PET/CT, and 39% no invasive staging. 39% of patients underwent surgical resection, 51% received non-surgical treatment, and 10% received no treatment. Patients who had surgery were less likely than those who had non-surgical treatment to get a diagnostic test, radiologic staging, and invasive staging (Table). Patients who had non-surgical treatment were more likely to pass through all five nodal points (50% v 68%, p<0.0001). The median (IQR) duration from initial lesion identification to treatment (n=1126) was 77 days (45-190); 27 days (10-90) from lesion identification to diagnostic biopsy (n=1115); and 38 days (26-63) from diagnostic biopsy to treatment (n=1041). Patients who had surgery received less timely care than those who had non-surgical or no treatment: median 122 v 66 v 68 days from lesion identification to treatment; 40 v 21 v 29 days from lesion identification to diagnostic biopsy; 46 v 38 v 31 days from diagnostic biopsy to treatment (p<0.0001 all comparisons). Conclusions: Quality improvement initiatives within our healthcare system, such as the establishment of a coordinated multidisciplinary program, enhanced care quality over previous benchmarks. Despite improvements, lung cancer patients who had surgery received less frequent and less timely pre-treatment evaluation than those without surgery. Implementing a standardized cancer care pathway from diagnosis to surgery could help to reduce variations in optimal care delivery.[Table: see text]

Successful Treatment of a Keratoacanthoma in a Young Patient with the Application of Topical 5% Imiquimod Cream

Keratoacanthomas (KA) are epithelial tumors that present as rapidly evolving nodules with a central hyperkeratotic plug, and occasionally show signs of spontaneous regression. A 21-years-old patient strongly refused the diagnostic biopsy and insisted on a non surgical treatment. He was successfully treated with imiquimod 5% cream.