Abstract: Most common incidentally detected sellar-suprasellar region (SSR) masses are pituitary adenomas, followed by craniopharyngioma, rathke’s cleft cyst, hypophysitis, and meningioma. Besides these, certain unusual SSR lesions can sometimes present as diagnostic challenges, where diagnosis is often made post-operatively on histopathology, the pre-operative suspicion of which might have influenced the management strategies. Series describing such masses are few. Objective To present clinical, biochemical, and radiological characteristics and management outcomes of rare SSR lesions other than pituitary adenomas, craniopharyngioma, rathke’s cleft cyst, hypophysitis, and meningioma. Design, setting, patients Retrospective case record analysis of patients with uncommon SSR masses (from January 2006 to December 2016). Results Our series consisted of ten patients, five with neoplastic and five with non-neoplastic lesions. Neoplastic masses included granular cell tumor ( n  = 2), astrocytoma ( n  = 1), malignant peripheral nerve sheath tumor (MPNST, n  = 1), and metastasis from occult papillary carcinoma of thyroid ( n  = 1), while non-neoplastic masses were aspergillus abscess ( n  = 1), sterile abscess ( n  = 1), and tubercular abscess ( n  = 1), aneurysm of left internal carotid artery ( n  = 1), and ruptured dermoid cyst ( n  = 1). All patients (except one) presented with headache and/or visual disturbance. Only one patient had acromegaly while most others had hypopituitarism. We describe detailed MRI characteristics of each of the lesion. Seven patients underwent trans-sphenoidal surgery. Post-operatively, five patients had permanent diabetes insipidus, while two patients died in early post-operative period. Conclusion Our series expand the differential diagnostic considerations of SSR lesions. Most of the rare SSR masses present with symptoms of mass effects and hypopituitarism. Except for some non-neoplastic lesions like sellar abscesses, aneurysms, and dermoid cysts which can have some specific imaging characteristics that can provide clue to pre-operative diagnosis, most of the other neoplastic masses have overlapping radiological features, and pre-operative suspicion remains difficult.

Abstract: Transsphenoidal surgery (TSS) is the primary treatment modality for Cushing’s disease (CD). However, the predictors of post-operative remission and recurrence remain debatable. Thus, we studied the post-operative remission and long-term recurrence rates, as well as their respective predictive factors. Methods A retrospective analysis of case records of 230 CD patients who underwent primary microscopic TSS at our tertiary care referral centre between 1987 and 2015 was undertaken. Demographic features, pre- and post-operative hormonal values, MRI findings, histopathological features and follow-up data were recorded. Remission and recurrence rates as well as their respective predictive factors were studied. Results Overall, the post-operative remission rate was 65.6% (early remission 46%; delayed remission 19.6%), while the recurrence rate was 41% at mean follow-up of 74 ± 61.1 months (12–270 months). Significantly higher early remission rates were observed in patients with microadenoma vs macroadenoma (51.7% vs 30.6%, P  = 0.005) and those with unequivocal vs equivocal MRI for microadenoma (55.8% vs 38.5%, P  = 0.007). Patients with invasive macroadenoma had poorer (4.5% vs 45%, P  = 0.001) remission rates. Recurrence rates were higher in patients with delayed remission than those with early remission (61.5% vs 30.8%, P  = 0.001). Duration of post-operative hypocortisolemia ≥13 months predicted sustained remission with 100% specificity and 46.4% sensitivity. Recurrence could be detected significantly earlier (27.7 vs 69.2 months, P   〈  0.001) in patients with available serial follow-up biochemistry as compared to those with infrequent follow-up after remission. Conclusion In our study, remission and recurrence rates were similar to that of reported literature, but proportion of delayed remission was relatively higher. Negative/equivocal MRI findings and presence of macroadenoma, especially those with cavernous sinus invasion were predictors of poor remission rates. In addition to early remission, longer duration of post-operative hypocortisolism is an important predictor of sustained remission. Regular biochemical surveillance may help in identifying recurrence early.

Abstract: Introduction Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive disease caused by human T cell lymphotropic virus type 1 (HTLV1) that predominantly affects Japanese and Caribbean populations. (Goncalves, Proietti et al. 2010) Most studies have focused on Japanese cohorts. A recent whole genome/exome sequencing of 81 Japanese ATL cases identified alterations that overlap with the HTLV1 Tax interactome and are highly enriched for T cell receptor-NF-kB signaling, and T cell trafficking (Kataoka, Nagata et al. 2015). We recently showed that ATL in Caribbean patients has a poor prognosis and may have distinctive clinical features when compared to the Japanese cohort (Zell, Assal et al. 2016). In order to determine whether there are genomic differences between the two cohorts, we sequenced 15 ATL samples from the Caribbean cohort. Methods In this prospective study we perform comprehensive Next Generation Sequencing to assess the mutational spectrum of ATL in Caribbean patients. Samples were analyzed by complete genetic profiling with the Genoptix Nexcourse complete assay that contains 173 cancer related genes. Patient genomic DNA was utilized to identify relevant single nucleotide variants, insertion/deletions, copy number variations, and translocation fusion genomic alterations in a panel of up to 173 reportable genes at an average mean sequencing depth of 500X coverage. Results In the 15 patients, a total of 49 genes were found to be mutated ranging from 3 to 7 mutated genes in each patient. The percent of mutated genes amongst the total analyzed ranged from 1.7-4% for each patient and the percent of mutated genes known to be pathogenic ranged from 0-2.3% for each patient. There were 18 known pathogenic mutations in a total of 70 genetic mutations identified in this cohort (25.7%). The mean number of mutations in the acute and lymphomatous subtype was approximately 0.9%. Genes most commonly mutated in out cohort were TP53 (26.7%), FAT1 (26.7%), NOTCH1 (20%) and APC (20%). Novel mutations not reported by the Japanese cohort but present in our cohort are - NRAS, KRAS, EZH2, RICTOR, XPO1, VHL (known to be pathogenic), FAT1, APC, DDX3X, KIT, NOTCH2, MYC, TSC1, PLCG2, FGFR2, FGFR4, PDGFRA, EGFR, KEAP1, MCL1, ALK, BCL6, RIPK1, IGF1R, DDR2, KDR, AKT1, ERBB2, NKX2-1, BRCA2, PBRM1, CD79A, STAG2, PTCH1, KMT2A, HIST1HE, SPEN, ASXL1 (not known to be pathogenic). Mutations common to both the Japanese and our Caribbean cohort are - CARD11, TNFAIP3, TRAF3 (TCR signaling/NFkB pathway), NOTCH1 (signaling pathway), GATA3, CEBPA, TBL1XR1 (transcriptional regulation), EP300 (epigenetic regulation), TP53, POT1 (Telomere regulation and DNA repair). Serial analysis of a patient revealed increase in the size of the pathogenic clone with XPO1 mutation. XPO1 has been involved in nuclear transport of p53 and the increase in its clone size occurred with relapse after cytotoxic chemotherapy. The overall survival (OS) was shorter for TP53 mutated patients (99.3 days) versus non TP53 mutated patients (307.8 days). Discussion We report on mutational profiling in the largest cohort of Caribbean ATL and an additional 8 patients will be included in the analysis to be presented at ASH. A significant number of genes found to be mutated affected known pathways in the pathogenesis of ATL. There are known genes which are common between the Japanese and Caribbean cohorts but there are some notable differences. Previously we showed that the Caribbean cohort has a poorer OS than the Japanese cohort. TP53 mutations are more frequent and associated with decreased OS in this cohort. Genes involved in Wnt pathway - FAT1, APC, NOTCH1 were more frequently mutated in our cohort. FAT1 mutations have not been described in ATL. However, they have been implicated in oncogenesis in solid tumors, chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia. FAT1 acts as a tumor suppressor gene and encodes a cadherin-like protein, which potently suppresses cancer cell growth. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival (Morris, Kaufman et al. 2013). In in-vitro models of ATL, Wnt pathway dysregulation has been shown to promote ATL tumorigenesis (Bellon, Ko et al. 2013, Ma, Yasunaga et al. 2013). Based on this study the driver mutations of the Caribbean cohort appear to be the Wnt signaling pathway which is different from the TCR- NF-kB signaling pathway seen in the Japanese cohort. Figure Figure. Disclosures Hall: Genoptix, a Novartis Company: Employment.

Abstract: Background: Despite the demonstrated efficacy of ruxolitinib (potent and selective Janus kinase [JAK] 1 and JAK2 inhibitor) in patients with MF, inadequate responses or loss of response to ruxolitinib may occur, possibly due to persistent activation of the phosphatidylinositol 3-kinase (PI3K) pathway with chronic ruxolitinib therapy. Parsaclisib (INCB050465) is a potent and highly selective next-generation PI3Kδ inhibitor. We previously demonstrated preliminary efficacy in a phase 2 trial (INCB 50465-201, NCT02718300) of parsaclisib added to stable doses of ruxolitinib for patients with MF who experienced a suboptimal response to ruxolitinib. JAK inhibitors, including ruxolitinib, are associated with thrombocytopenia; therefore, patients with low platelet counts (PC) are traditionally more difficult to treat. We present the efficacy and safety subgroup analysis of this ongoing study in patients grouped by baseline PC. Methods: Eligible adults had primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF with suboptimal response (palpable spleen & gt;10 cm below left subcostal margin, or palpable splenomegaly 5-10 cm below left subcostal margin and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of ruxolitinib monotherapy (5-25 mg twice daily, stable dose for ≥8 weeks). Patients remained on their last stable ruxolitinib dose and received add-on parsaclisib 10 mg or 20 mg once-daily (QD) for 8 weeks and the same dose once-weekly thereafter (daily to weekly group), or parsaclisib 5 mg or 20 mg QD for 8 weeks and 5 mg QD thereafter (all daily group). For the subgroup analysis, patients were grouped by baseline PC (≥100×10 9/L, higher PC or 50- & lt;100×10 9/L, low PC). Key objectives were to evaluate the impact of baseline PC on spleen volume (SV) and total symptom score (TSS) as assessed by Myelofibrosis-Symptoms Assessment Form (MFSAF) v3.0 daily diary at week 12 and week 24, and safety. Results: At data cutoff (Aug 27, 2020), 67 patients were enrolled, 21 with low PC and 46 with higher PC. Median age of both groups was 68 years, and median prior duration of ruxolitinib use was 34.7 months for low PC and 14.9 months for higher PC. Patients with low PC had higher baseline symptoms (MFSAF-TSS median [range], 21.4 [0.6-47] ) than patients with higher PC (MFSAF-TSS, 10 [0-43]). Responder analysis for SV reduction (SVR) is summarized in Table 1. At week 12, slightly more patients with low PC achieved ≥10% SVR compared with patients with higher PC, whereas, at week 24, responses were similar between the 2 groups. Of patients with at least 10% SVR at week 24, 4 of 6 with low PC and 9 of 13 with higher PC were receiving all daily dose regimens. Median (range) percentage change in MFSAF-TSS was −20.5 (−56.6 to +17.1) and −22.2 (−100 to +500) at week 12, and −26.1 (−54.7 to +2.4) and −23.1 (−91.3 to +222.5) at week 24, for patients with low PC and higher PC, respectively. Overall for both baseline platelet groups, nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Most common (≥20%) TEAEs were dyspnea (33%), falls (33%), peripheral edema (29%), and nasal congestion (24%) for patients in the low PC group, and diarrhea (28%), nausea (24%), abdominal pain (24%), cough (20%), and fatigue (20%) for patients with higher PC. Interruption of parsaclisib due to thrombocytopenia was observed in 9 of the 21 patients (43%) with low PC and 3 of the 46 patients (7%) with higher PC. One patient with low PC had thrombocytopenia leading to ruxolitinib interruption. Conclusion: Add-on parsaclisib demonstrated promising preliminary efficacy in patients with MF experiencing suboptimal response to ruxolitinib monotherapy. In a subgroup analysis by baseline PC, responses for SV and MFSAF-TSS reduction were similar in both groups, indicating that patients with low PC can also tolerate and benefit from this treatment combination. Phase 3 trials in ruxolitinib-experienced and ruxolitinib-naive patients are underway to further assess the combination of JAK and PI3K inhibitors. Figure 1 Figure 1. Disclosures Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Rampal: Blueprint: Consultancy; Jazz Pharmaceuticals: Consultancy; Disc Medicine: Consultancy; Constellation: Research Funding; Stemline: Consultancy, Research Funding; Kartos: Consultancy; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Memorial Sloan Kettering: Current Employment; Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy. Ali: CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Gerds: CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; PharmaEssentia Corporation: Consultancy; Novartis: Consultancy. Hobbs: Incyte Corporation: Research Funding; AbbVie.: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Bayer: Research Funding. Kremyanskaya: Chimerix: Research Funding; Constellation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Bristol Myers Squibb: Research Funding; Astellas: Research Funding; Astex: Research Funding. Winton: Samus Therapeutics: Research Funding; Incyte Corporation: Research Funding; Blueprint Medicines: Research Funding. O'Connell: Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Genentech: Research Funding; Astex Pharmaceuticals: Consultancy, Research Funding; Shionogi: Consultancy. Oh: Novartis: Consultancy; Kartos Therapeutics: Consultancy; Incyte Corporation: Consultancy; Geron: Consultancy; Disc Medicine: Consultancy; CTI BioPharma: Consultancy; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Abbvie: Consultancy; PharmaEssentia: Consultancy; Sierra Oncology: Consultancy. Schiller: Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Evidera: Consultancy; NCI: Consultancy; UCSD: Research Funding; Eli Lilly: Research Funding; Onyx: Research Funding; UC Davis: Research Funding; Ambit: Research Funding; MedImmune: Research Funding; Bluebird Bio: Research Funding; ASH foundation: Other: Chair-unpaid; Ono-UK: Consultancy, Research Funding; Takeda: Research Funding; Leukemia & Lymphoma Society: Research Funding; Kaiser Permanente: Consultancy; Samus: Research Funding; Boehringer-Ingleheim: Research Funding; Millennium: Research Funding; Ariad: Research Funding; Cellerant: Research Funding; Janssen: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Trovagene: Research Funding; Bio: Research Funding; National Marrow Donor Program: Research Funding; Sellas: Research Funding; Ono: Consultancy; Cyclacel: Research Funding; CTI Biopharma: Research Funding; Tolero: Research Funding; Pharma: Consultancy; AstraZeneca: Consultancy; NIH: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Sangamo: Research Funding; Biomed Valley Discoveries: Research Funding; Incyte: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; Pharmamar: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Mateon: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding; Novartis: Speakers Bureau. Assad: Incyte: Current Employment, Current equity holder in publicly-traded company. Erickson-Viitanen: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhou: Incyte: Current Employment, Current equity holder in publicly-traded company. Daver: Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Novartis: Consultancy; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Syndax: Consultancy; Agios: Consultancy; Dava Oncology (Arog): Consultancy; FATE Therapeutics: Research Funding; Novimmune: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Shattuck Labs: Consultancy; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.