Circulating MicroRNA Profiles as Potential Biomarkers for differentiated thyroid cancer recurrence

Context Circulating microRNAs (miRNAs) are emerging biomarkers of thyroid cancer. Objective This study sought to identify the profile of circulating miRNAs and its response to human recombinant TSH (rhTSH) in thyroid cancer patients with recurrent/persistent disease. Methods We obtained serum samples from 30 patients with differentiated thyroid cancer, 14 with recurrent/persistent disease and 16 with complete remission. We used next generation sequencing to define the miRnomes along with a comprehensive qPCR validation using two different platforms. We made a transversal study by comparing serum miRNA profiles of patients with or without recurrent/persistent disease and a longitudinal study looking at differences before and after rhTSH stimulation. Selected miRNAs were then studied in human thyroid cancer cell lines TPC-1, FTC-133 and OCUT-2 in response to TSH stimulation. Results We could not demonstrate any consistent differences in serum profiles of known miRNAs between patients with and without recurrent/persistent disease or before and after rhTSH stimulation. However, our sequencing data revealed two putative novel miRNAs that rise with rhTSH stimulation in the serums of patients with recurrent/persistent disease. We further confirmed by qPCR the upregulation of these putative miRNAs both in serums and in TSH-stimulated cells. We also show miRNAs that are good candidates for housekeeping genes in the serum of patients independently of the levels of TSH. Conclusions The present study does not provide evidence that known miRNAs can be used as circulating markers for recurrence of thyroid cancer. However, we suggest that novel miRNA molecules may be related to thyroid cancer pathogenesis.

Clonal Dynamics of IDH1 Mutations in Acute Myeloid Leukemia

Introduction: Isocitrate dehydrogenase 1 (IDH1) gene is mutated in 7-14% of acute myeloid leukemia (AML) patients. IDH1 encodes for an enzyme that catalyzes the conversion of isocitrate to α- ketoglutarate. IDH1 mutation leads to accumulation of the oncometabolite 2-hydroxyglutarate. Clonal evolutionary dynamics of IDH1 mutations in AML have not been clearly characterized. The introduction of targeted small-molecule therapy, Ivosidenib, in AML treatment underscores the significance of understanding the topography of clonal dynamics in IDH1-mutated AML to optimize precision medicine. Methods: We analyzed ~6000 patients with next-generation sequencing (NGS) data and identified 107 patients with IDH1 mutated AML. Disease status was determined for each NGS test date by manual chart review. IDH1 mutation status was characterized during course of AML at diagnosis, remission, relapse, and with persistent disease. Cytogenic risk category was determined using ELN 2017 guidelines. Kaplan Meier survival analysis and log-rank test were used to determine significant differences in overall survival among patient groups. Results: Of the 107 total patients, 39 patients (36%) had AML with myelodysplastic-related changes (AML-MRC) and 39 patients (36%) had AML-NOS. The most frequently co-mutated genes were SRSF2, DNMT3A, ASXL1, RUNX1, NRAS, BCOR, STAG2, NPM1, JAK2, and FLT-3 in order of frequency. Of the total patients, 74 patients (69%) had good cytogenetics, 17 patients (16%) had intermediate cytogenetics, and 16 patients (15%) had poor/very poor cytogenetics. Among the patients with IDH1-mutated AML, 85 patients (79%) were IDH1-positive at initial diagnosis, while 22 patients (21%) were IDH1- negative at diagnosis and acquired the mutation later in disease course. Of those 22 patients, 18 patients gained the mutation in the setting of persistent disease, 3 patients at remission, and 1 patient at relapse. In those with persistent AML (n=42), 30 patients (71%) remained IDH1-positive while 12 patients (29%) lost the mutation. In those achieving remission (n=66), 12 patients (18%) who were IDH1-positive remained IDH1-positive while 51 patients (77%) cleared the mutation. In those with relapsed disease (n= 21), 17 patients (81%) with IDH1-positive AML remained IDH1-positive while 4 patients (19%) lost the mutation at relapse. There were no significant differences in median overall survival in patients who were positive or negative for IDH1 mutations at diagnosis, positive or negative with disease persistence, or among patients who remained IDH1-positive or lost the IDH1 mutation at disease relapse. Patients that were IDH1-positive at diagnosis were more likely to have poorer cytogenetics than patients who were IDH1-negative at diagnosis (p=0.0016). Conclusion: In summary, this study found that IDH1 mutations are unstable throughout the course of AML and periodic genetic testing of AML patients is necessary for optimizing precision medicine approaches. In disease remission, most patients (77%) cleared the IDH1 mutation. In the relapse setting, 81% of patients retained IDH1-positive status. Our study, the largest of its kind to our knowledge, shows that serial genomic profiling for the IDH1 mutation across disease course may be beneficial in helping to tailor targeted therapy for IDH1+ AML. Disclosures Sweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy.

Clinical Outcomes of Patients with Newly Diagnosed Myelodysplastic Syndrome with MLL Aberrations

Introduction Mixed lineage leukemias (MLL) are an extremely aggressive subset of leukemias that are inherently resistant to several therapies. MLL aberrations (deletion KMT2A and MLL rearrangements) are extremely rare in myelodysplastic syndrome (MDS) and little is known regarding their clinical course or outcomes. The aim of the study is to determine the natural course of the disease in our patient population. Methods A retrospective cytogenetic database search of patients presenting to a tertiary cancer center from January 2005 to February 2021 with the diagnosis of MDS and CMML with presence of MLL aberrations was conducted. Deletion KMT2A was defined as deletion of 11q23 on cytogenetic studies. Patients who had received prior therapy with hypomethylating agents (HMAs), cytarabine-based regimens, or intensive chemotherapy were excluded. The International Working Group 2006 criteria was used for response assessment. Progression-free survival (PFS) was calculated from date of diagnosis to date of progression from MDS to AML. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up visit. Results Between January 2005 to February 2021, 3369 patients (pts) with the diagnosis of MDS (n=2761) and CMML (n=608) were identified. Of these, 30 pts had MLL aberrations with 18 pts with MLL rearrangements (MLL r) and 12 pts with deletion 11q23 (del-KMT2A). Baseline characteristics are present in Table 1. Among 18 pts with MLL r MDS, 6 pts did not undergo any therapy at our institution. Of the remaining 12, 9 (75%) pts received HMA based therapy, 1 (8%) patient (pt) proceeded to allogeneic stem cell transplant(allo-HSCT) and 2 (17%) pts received intensive chemotherapy (idarubicin, fludarabine and cytarabine). Of the 9 pts who received HMA therapy, 5 (56%) pts had transformation to AML, 2 (22%) pts achieved CR and underwent allo-HSCT, 1 (11%) pt had persistent disease and 1 (11%) developed concurrent metastatic sarcoma and stopped treatment. Out of the 2 (22%) pts who underwent allo-HSCT, 1 pt received maintenance HMA post-transplant but relapsed with transformation to AML after 9 months, and the other was lost to follow up. 1 (11%) pt who had persistent disease received intensive chemotherapy and went into CR and subsequently underwent double umbilical cord transplant and continues to remain in CR. The 2 (17%) pts who received intensive chemotherapy frontline both went into CR, but one developed concurrent malignancy and stopped treatment. The other pt was transitioned to HMA therapy but relapsed with transformation to AML. The 1 patient who received frontline allo-HSCT relapsed with transformation to AML after 5 months. The overall median follow-up duration was 24 months with a median OS of 10 months (Figure 1) and a median PFS of 3.5 months(Figure 2). 12 pts with del-KMT2A were identified, out of which 2 pts did not receive treatment. Of the remaining 10 pts, 8 (80%) received HMA based therapy and 2 (20%) pts received investigational treatments. Of the 8 pts who received HMA therapy, 1 (12.5%) achieved CR and remains in CR, 4 (50%) pts had no response, 2 (25%) had hematological improvement (HI) but one died of other causes and the other elected to stop treatment, 1 (12.5%) pt had transformation to AML. Of the 4 pts with no response, 2 pts elected to stop treatment, with 1 developing concurrent malignancy. Of the remaining 2 pts, 1 pt was placed on an investigational agent and had progression to AML and the other was placed on lenalidomide and then an investigational agent, but ultimately pursued hospice. Of the 2 pts on investigational agents both had persistent disease and one patient died and the other elected to stop treatment due to concurrent illness. The overall median follow-up duration was 154 months with a median OS of 16 months (Figure 1) and median PFS of 8 months (Figure 2). Clinical course is presented in Table 2. Conclusion Prognosis of patients with MLL alterations and MDS is very poor. MLL r MDS had worse outcomes with rapid transformation to AML compared to del-KMT2A. New therapies are needed for this group of patients. Figure 1 Figure 1. Disclosures Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

470. Relapsing COVID-19 Pneumonia in Patients Receiving Rituximab Therapy

Background Rituximab is a monoclonal antibody against the CD20 antigen on B-lymphocytes leading to B-cell death and depletion. Patients who receive rituximab and are infected with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) causing coronavirus disease (COVID-19) may have increased difficultly clearing the virus and be at risk for persistent disease. While the limited literature available is mixed regarding the severity of COVID-19 in patients receiving rituximab, there is minimal literature regarding persistent and relapsing COVID-19 in this patient population. This is a case series of patients with persistent COVID-19 who previously received rituximab. Methods This is a retrospective review of 5 patients admitted between 1/1/2021 and 5/1/2021 to our institution with confirmed COVID-19 and receipt of rituximab for any indication within the previous 12 months. Information regarding hospital readmissions, time course of positive infection, medical management, disease severity, and discharge disposition were collected. Results Five patients, median age of 46, currently or recently on rituximab therapy were admitted a median of 2 times due to persistent, severe COVID-19 (Table 1). Patients received their initial COVID-19 diagnosis a median of 34 days (8-102 days) since their last rituximab administration and had documented SARS-CoV-2 infection a median of 66 days (19-195 days; Figure 1). All 5 patients received remdesivir and corticosteroids over the course of their COVID-19 disease and 2 patients received convalescent plasma therapy 1 and 5 days prior to a positive SARS-CoV-2 antibody IgG. Figure 1. Patient SARS-CoV-2 Infection Course Table 1. Patient Clinical and Therapeutic Data Conclusion Rituximab therapy may be associated with persistent or relapsing COVID-19 disease. Controlled investigations are necessary to evaluate the exact impact anti-CD20 agents have on the course of COVID-19 and whether convalescent plasma or other therapies can prevent relapsing disease. Disclosures All Authors: No reported disclosures

Prognostic factors in children and adolescents with differentiated thyroid carcinoma treated with total thyroidectomy and RAI: a real-life multicentric study

Purpose This multicentric study aimed to investigate the main prognostic factors associated with treatment response at 1 year after radioactive iodine therapy (RAIT) and the last disease status in pediatric patients affected by differentiated thyroid carcinoma (DTC). Materials and methods In the period 1990–2020, all consecutive patients ≤ 18 years from six different centers were retrospectively included. Patients were classified as low, intermediate, and high risk for persistence/recurrence. The response to RAIT was evaluated and scored 1 year later according to 2015 ATA guidelines. Moreover, at the last follow-up, the disease status was evaluated and dichotomized as no evidence of disease (NED) or persistent disease. Results Two hundred and eighty-five patients (197 female, 88 male; mean age 14.4 years) were recruited. All, except nine, underwent near-total thyroidectomy followed by RAIT. One-year after first RAIT, 146/276 (53%) patients had excellent response, 37/276 (14%) indeterminate response, and 91/276 (33%) incomplete response. One-year after RAIT, children with excellent response had significantly lower stimulated thyroglobulin (sTg) compared to not excellent group (median sTg 4.4 ng/ml vs 52.5 ng/ml, p < 0.001). ROC curve showed sTg higher than 27.2 ng/ml as the most accurate to predict 1-year treatment response. After a median follow-up of 133 months, NED was present in 241 cases (87%) while persistent disease in 35 (13%). At multivariate analysis, sTg and 1-year treatment response categories were both significantly associated with the last disease status (p value 0.023 and < 0.001). Conclusions In pediatric DTC, sTg is significantly associated with 1-year treatment response and final outcome. However, 1-year response is the principal prognostic factor able to predict pediatric DTCs outcome.

Tubotympanic cholesteatoma

Chronic suppurative otitis media is defined as a chronic inflammation of the mucoperiosteal lining of the middle ear cleft. It is described as a persistent disease that is insidious in onset, often capable of causing severe destruction with irreversible sequelae, and clinically present with hearing loss and discharge. It has been classified into tubotympanic (safe) and atticoantral (unsafe) perforation. Cholesteatoma always occur in the atticoantral type and in marginal perforation. We report a case of cholesteatoma that occurred as a tubotympanic type of perforation.

Running Behind “POPO”—Impact of Predictors of Poor Outcome for Treatment Stratification in Pediatric Crohn's Disease

Background and Aims: Intensifying therapy for Paediatric Crohn's Disease (CD) by early use of immunomodulators and biologics has been proposed for cases in which predictors of poor outcome (POPO) were present. We investigated therapy stratifying potential comparing POPO-positive and -negative CD patients from CEDATA-GPGE®, a German-Austrian Registry for Paediatric Inflammatory Bowel disease.Methods: CD patients (1–18 years) registered in CEDATA-GPGE® (2004–2018) within 3 months of diagnosis and at least two follow-up visits were included. Disease course and treatments over time were analysed regarding positivity of POPO criteria and test statistical properties.Results: 709/1084 patients included had at least one POPO criterion (65.4%): 177 patients (16.3%) had persistent disease (POPO2), 581 (53.6%) extensive disease (POPO3), 21 (1.9%) severe growth retardation POPO4, 47 (4.3%) stricturing/penetrating disease (POPO6) and 122 (11.3%) perianal disease (POPO7). Patients with persistent disease differed significantly in lack of sustained remission &gt;1 year (Odd Ratio (OR) 1.49 [1.07–2.07], p = 0.02), patients with initial growth failure in growth failure at end of observation (OR 51.16 [19.89–131.62], p &lt; 0.0001), patients with stricturing and penetrating disease as well as perianal disease in need for surgery (OR 17.76 [9.39–33.58], p &lt; 0.001; OR 2.56 [1.58–4.15], p &lt; 0.001, respectively). Positive Predictive Value for lack of sustained remission was &gt;60% for patients with initial growth failure, persistent or stricturing/penetrating disease.Conclusion: Predictors of poor outcome with complicated courses of disease were common in CEDATA-GPGE®. An early intensified approach for paediatric CD patients with POPO-positivity (POPO2-4, 6-7) should be considered, because they have an increased risk to fare poorly.

Transsphenoidal Surgery of Invasive Corticotroph Adenomas: Results in A Series of 86 Consecutive Patients

Objective: Surgery is first-line treatment for corticotroph adenomas. Although most of corticotroph adenomas are noninvasive microadenomas that show expansive growth to surrounding tissues, a small subset of them is locally invasive and difficult to manage. The aim of this study was to evaluate surgical outcome of invasive corticotroph adenomas from a single-center. Patients and Methods: The clinical features and outcomes of CD patients who underwent transsphenoidal surgery (TSS) between January 2000 and September 2019 at Peking Union Medical College Hospital were collected from medical records. The clinical, endocrinological, radiological, histopathological, surgical outcomes and a minimum 12-month follow-up of 86 consecutive CD patients with invasive corticotroph adenomas were retrospectively reviewed. Results: Eighty-six patients with invasive corticotroph adenomas were included in the study. The average age at TSS was 37.7 years (range, 12 to 67 years), with a female-to-male ratio of 3.1:1 (65/21). The median duration of symptoms was 52.6 months (range, 1.0 to 264 months). The average of maximum diameter of tumor was 17.6 mm (range, 4.5–70 mm). All 86 patients with invasive corticotroph adenomas were performed TSS by microscopic or endoscopic approach. Gross-total resection was achieved in 63 patients (73.3%), subtotal resection in 18 (20.9%), and partial resection in 5 (5.8%). After surgery, the overall postoperative immediate remission rate was 48.8% (42/86), 51.2 % (44/86) of patients maintained persistent hypercortisolism. In 42 patients with initial remission, 16.7 % (7/42) of them experienced a recurrence. In these patients with persistent disease and recurrent CD, data about further treatment was available for 30 patients. The radiotherapy was used for 15 patients, and 4 (26.7%) of them achieved biochemical remission. Repeat TSS was performed in 5 patients, and none achieved remission. Medication was administrated in 4 patients, and one of them obtained disease control. Adrenalectomy was performed in 6 patients, and 5 (83.3 %) achieved biochemical remission. At last follow-up, (33.3%) 10 of 30 patients were in remission, and 20 patients still had persistent disease. The remission rate in patients with invasive corticotroph adenomas who underwent gross-total resection and first TSS were significantly higher than that in patients undergoing subtotal resection, partial resection, and a second TSS (all P＜0.05). However, there was no significant difference in the remission rate between patient with different tumor size, Knosp Grade and surgical approaches (P＞0.05).Conclusion: The management of invasive corticotroph adenomas remain a therapeutic challenge due to incomplete resection of invasive and/or a large adenoma. With application of multiple techniques assistance, approximately half of the patients could achieve gross-total resection and biochemical remission via TSS by experienced neurosurgeons. The extent of tumor resection and number of operations were associated with surgical remission rate in invasive corticotroph adenomas. If the remission was not achieved by surgery, other treatments including radiotherapy, medical therapy, and even bilateral adrenalectomy are required.

ISTHMUS TOPOGRAPHY IS A RISK FACTOR FOR PERSISTENT DISEASE IN PATIENTS WITH DIFFERENTIATED THYROID CANCER

Aim: The risk of differentiated thyroid cancer (DTC) recurrence is widely evaluated according to the 2015 ATA Risk Stratification System. Topography of malignant nodules has been previously reported as an additional risk factor but is not included in the ATA system. Thus, our study aimed to evaluate the relationship between DTC topography and response to initial therapy. Patients and Methods: We enrolled 401 low- to intermediate-risk patients with DTC who had undergone thyroidectomy and radioiodine therapy. DTC topography was recorded and compared with the response to therapy as assessed 12 months after end of therapy. Results: Overall, 366/401 (91.3%) patients had an excellent response to initial therapy while 22/401 (5.5%) and 13/401 (3.2%) had incomplete biochemical or structural response, respectively. Incomplete response occurred in 10/36 (27.8%), 5/125 (4.0%), and 4/111 (3.6%) patients whose unifocal malignant nodules were located in the isthmus, right lobe, or left lobe. Incomplete response was also observed in 4/54 (7.4%) and 12/75 (16%) patients carrying multifocal cancers in one or both lobes, respectively. Patients with isthmic cancer more frequently demonstrated incomplete response compared with those who had cancer in other locations (p=0.00). No significant relationship was found with age, gender, maximum size of malignant nodule, Hashimoto’s thyroiditis, vascular invasion, and extrathyroidal extension (p=0.78, p=0.77, p=0.52, p=0.19, p=0.73, and p=0.26, respectively). The risk of incomplete response was about 65% higher in patients with isthmic lesions compared with other patients (odds ratio=6.725). A log-rank test demonstrated that disease-free survival (DFS) of patients with isthmic lesions was significantly shorter than that of other patients (p=0.02). Conclusion: Our data show that isthmus topography of malignant thyroid nodules is a risk factor for having both persistent disease 12 months after primary treatment and reduced DFS.