Citations

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (>5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

Background Follicular lymphoma (FL) is the second most common lymphoma accounting for approximately 15% of all non-Hodgkin's lymphoma (NHL). Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. This study analyzed patients with previously untreated (UFL) or relapsed/refractory low-grade FL (RFL) treated at our institution with (90)Y-IT. It represents the largest reported cohort for therapeutic use of (90)Y-IT in low-grade FL. Methods Medical records of patients with low-grade FL (WHO grade 1-2) who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2003 and December 2018 were analyzed. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Our cohort consists of 137 patients - 29% (40/137) with UFL and 71% (97/137) with RFL. The median age at diagnosis was 60 years (range, 18-86) with 54% (74/137) males. The median number of previous treatments in RFL patients was 1 (range, 1-5). ECOG performance status at the time of treatment was 0 in 90% and 1 in 10% of patients. 87% (119/137) had stage III/IV disease at the time of (90)Y-IT therapy. The median follow up from the time of (90)Y-IT therapy was 10.2 years (95% CI; 8.8, 11.6); 69% (95/137) of patients are alive. The ORR was 100% in UFL with 93% (37/40) CR while ORR in UFL was 93% (90/97) with 73% (71/97) CR. 45% (48/108) of the CR patients remain in continuous CR (CCR) with a median follow-up of 7 years (95% CI; 5.2, 9.9). CCR was observed in 55% (22/40) of UFL patients compared to 27% (26/97) of RFL patients. 63% (86/137) of patients had relapsed. More relapses occurred in the RFL group (69/97; 71%) compared to the UFL group (17/40; 43%), (p=0.002). In the entire cohort, the median PFS was 2.5 years (95% CI; 2.1, 3.5) and TTNT was 3.6 years (95% CI; 2.5, 4.7). Median PFS was significantly higher in UFL group compared to RFL group- 4.1 years (95% CI; 2.3, NR) vs 2.2 years (95% CI; 1.6, 3.1), respectively (Figure 1-A). Median TTNT was higher in UFL group compared to RFL group- NR (95% CI; 4.1 years, NR) vs 2.4 years (95% CI; 2, 3.6), respectively (Figure 1-B). Median OS (entire cohort) was 18 years (95% CI; 15.8, NR) with no statistically significant difference between UFL group and RFL group; NR (95% CI; NR, NR) vs 18 years (95% CI; 12.3, 20.5), respectively (Figure 1-C). Transformation to high grade lymphoma was seen in 19% (18/97) in RFL group compared to 2.5% (1/40) in UFL group, (p=0.005). Median time to transformation was 4.3 years (range, 1-11). More patients developed therapy-related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in the RFL group 14% (14/97) compared to 2.5% (1/40) in the UFL group (p= 0.02). Median time to develop MDS/AML was 3.3 years (range, 0-9.7). Grade ³3 neutropenia was observed in 46% of patients with median time to recovery of 21 days (range, 2-706). Grade ³3 thrombocytopenia was observed in 47% of patients with median time to recovery of 23 days (range, 7-548). Eighteen patients required growth factors support and 14 required transfusions. Non-hematologic AEs included mild to severe fatigue in 35 patients. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is an effective single-agent regimen for low-grade FL. The response and survival data in this large real-world cohort is superior to the pivotal trials of this agent conducted nearly 20 years ago. The data in untreated FL is also of interest and provides the rationale for our current randomized phase 2 trial in untreated FL (https://clinicaltrials.gov/show/NCT02320292). Long-term complete remission (>7 years) was seen in 35% of the study population. Based on these promising results, clinical trials combining RIC with novel agents that could potentiate its effects are warranted. Figure 1 (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UFL) and patients with relapsed/refractory FL (RFL), (B) Time to next therapy; comparing time to starting next line of treatment after (90)Y-IT treatment between UFL and RFL, (C) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UFL and RFL. Figure 1 Disclosures Tun: DTRM Biopharma: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; Curis: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. We are discussing its use as a frontline therapy in low grade FL.

Background: The development of novel treatment strategies has extended the median survival of MM to nearly a decade but the disease remains incurable and relapse is inevitable. The Bcl-2 pathway is highly relevant to MM cell survival and can be mitigated therapeutically. AT-101 is a novel, orally available pan Bcl-2 inhibitor (Bcl-2, Bcl-xl, Mcl-1, and Bcl-w). Preclinical in vitro and in vivo studies showed that AT-101 enhanced cytotoxicity of lenalidomide-dexamethasone (Rd). We conducted a phase I study in RRMM patients to establish the effective dose of AT-101 with Ld as well as record safety and preliminary efficacy of this combination (NCT02697344). Methods: Key eligibility criteria included: RRMM with measurable disease (serum monoclonal protein ≥1.0 g/dL or urine monoclonal protein >200mg/24 hour or serum immunoglobulin free light chain >10mg/dL AND abnormal serum free light chain ratio). Patients must have received 1-3 prior treatment regimens and have an absolute neutrophil count ≥1.0 x 109, platelets 75 x 109, creatinine clearance ≥50 mL/min, and ECOG performance status ≤2. AT-101 dosing was designed to reach a maximum daily target of 20mg (Cohort 1; 10 mg PO QD, Cohort 2; 20 mg PO QD) utilizing a standard 3 +3 dose escalation design in combination with standard doses of Rd. Treatment was given as outpatient for a maximum of 12, 28-day cycles. For pharmacodynamic studies, AT-101 alone was given in cycle 1, with R (25 mg on days 1-21) and d (40 mg weekly) added cycle 2 onwards. Results: Enrolled patients (n=10) included 60% males with median age 68.5 years (range 55-75) and median time since MM diagnosis 4.5 years (range 0.6-8.3). MM ISS stage was II/III in 7 patients and 8/10 had high-risk cytogenetics with 4 each having del17p and 1q+. Only 1 patient had t(11;14).Patients had received median 2 prior lines of therapy (range 1-3), with 7 having had prior autologous stem cell transplant (ASCT) and the initial induction regimen being bortezomib (V), R and dexamethasone (d) (VRd) in 8, Rd in 1 and cyclophosphamide (C) with Vd (VCd) in 1 patient. At the time of study entry, 3 patients were R refractory while 2 were refractory to both, V and daratumumab (Dara). Median duration of treatment was 7.5 cycles (range 2-12) and 3 patients completed all planned 12 cycles of treatment. Among the evaluable patients, dose limiting toxicities (DLTs) at 20 mg daily dose of AT-101 with 25 mg of R and 40 mg weekly included one patient with grade 4 febrile neutropenia and grade 4 neutropenia lasting 9 days and one patient with grade 4 thrombocytopenia lasting 8 days. G3/4 adverse events (AEs) included atrial flutter (n=1), white blood cell count decrease (n=3), neutropenia (n=5), febrile neutropenia (n=1) and thrombocytopenia (n=2), and back pain (n=1) . No G3/4 non-hematological AEs were noted. Any grade non-hematologic AEs seen in at least 20% (n=2) patients included fatigue (n=9), neuropathy (n=6), nausea (n=3), diarrhea (n=5), constipation (n=3), and creatinine increased (n=2). No patients experienced tumor lysis syndrome. Overall response rate (ORR) was 44% (2 each with very good partial response, VGPR and PR) and clinical benefit rate (CBR) was 89% with 2 additional patients showing minor response (MR) and 2 experiencing stable disease (SD) (Fig 1). Patients with high-risk disease had an ORR of 43% and a CBR of 100%. Median progression-free survival (PFS) for all patients was 8.1 months. Correlative analysis from patients who showed an objective response to treatment revealed a significant increase in bone marrow Th-effector cells, NK cells and cytotoxic CD8+ T-cells along with a significant decrease in immunosuppressive T-regulatory and B-regulatory cells was noted after 1 complete cycle of the combination therapy (p<0.05, Fig 2). Conclusions: This is the first reported clinical trial combining a Bcl-2 inhibitor with immunomodulatory drugs (IMiDs) in MM. AT-101-Rd is a clinically active regimen with an ORR of 40% in predominantly high-risk RRMM patients with an acceptable toxicity profile. Additional patients with MM experienced clinical benefit despite refractory status to prior therapy in this early phase clinical trial. These early findings support the further investigation of AT-101 specifically, and Bcl-2 inhibitors in general, with IMiDs in patients with MM. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: AT-101 is not currently FDA-approved for treatment of any condition.

Abstract Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular disease (ASCVD) score is a risk stratification tool used by cardiologists to classify patients with a score ≥7.5% as high risk for the incidence of ASCVD events. To date, there are no clinically relevant models that predict the likelihood of ACVE in MM patients treated with K nor are we aware of any protective factors against ACVE. Our study aims to identify factors which can predict and mitigate the incidence of ACVE. Methods: A retrospective chart review of 372 MM patients who were treated with K between 2011 and 2018 at our institution was performed.Data were summarized using descriptive statistics; Chi-square tests of association and Kruskal-Wallis tests were employed to test for differences across groups, where appropriate. Logistic regression was performed to examine the risk factors associated with ACVE. Results: Of the 372 patients, 243 (65%) were Durie-Salmon Stage (DSS) III, 70 (19%) were International Staging System (ISS) III; 186 (50%) were men. There were a total of 102 (27%) ACVE and 33 (9%) ≥grade 3 events. The most common ACVE were congestive heart failure (29%), asymptomatic elevations in pulmonary arterial systolic pressure (PASP) (27%), and hypertension (HTN) (16%). Sixty-eight (66%) Caucasians, 14 (14%) African Americans and 17 (17%) Hispanics developed ACVE. Aspirin (ASA) (64%), beta blockers (BB) (51%), calcium channel blockers (CCB) (43%) and statins (37%) were the most common cardiac medications patients were taking at the time of K initiation. Regardless of cardiac history, patients who were taking a CCB had higher odds of experiencing an ACVE compared to patients who were not taking a CCB (CCB + Cardiac history: OR=1.9; CI=1.0-3.7; CCB, no Cardiac history: OR=6.3; CI= 2.1-18.4) (Table 1). Patients with an ASCVD score ≥7.5% did not have an increased incidence of ACVE but did have an increased incidence of ≥grade 3 vs. grade 1-2 ACVE (100% vs. 78%, p=0.092). Prior cardiac history, including history of HTN, was common (59%) but not associated with incidence or severity of ACVE. Those with type 2 diabetes had a higher rate of ≥grade 3 vs. grade 1-2 ACVE (33% vs. 10%, p=0.004). Patients on certain CV medications while receiving K-based treatment had a higher incidence of ACVE compared to those not on these medications, including BB (51% vs. 34%, p=0.002), CCB (43% vs. 26%, p=0.002), aldosterone antagonists (AA) (8% vs. 3%, p=0.024) and statins (37% vs. 25%, p=0.022). Patients on ASA were more likely to experience ≥grade 3 compared to grade 1-2 ACVE (78% vs. 53%, p=0.016). ACE inhibitors or angiotensin receptor blockers (ACE/ARB) were not associated with increased incidence or severity of ACVE. The use of K in relapsed, as opposed to induction setting, was associated with a higher incidence of ACVE (31% vs. 20%, p=0.035). Maximum dose and number of K doses were not associated with ACVE. There was no relationship between PASP elevation and age >75, use of BB, CCB, AA, ACE/ARB, number of K treatments or maximum dose of K. Factors that were associated with increased odds of ACVE in multivariate analysis included patients who received K in the relapsed setting (OR= 1.7; CI=0.94-3.0) and use of an AA (OR= 4.5; CI=1.4-14.1) (Table 1). Conclusion: In line with prior studies, 28% of MM patients treated with K at our institution developed an ACVE, with 9% grade 3 or above. Use of CCB and AA were particularly associated with increased risk of ACVE, while use of ACE/ARB were not. ASCVD score ≥7.5% was associated with an increased incidence of ≥grade 3 ACVE in K-treated patients and should perhaps be evaluated as a predictive tool in prospective studies. Disclosures Siegel: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Biran:Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding.

Abstract We describe the features of 24 cases of atypical CD5+ small B-cell leukaemia unclassifiable by current methods. The male/female ratio was 3 (18M/6F), with a median age at diagnosis of 58 years (range 39–84 years). All cases were CD5 positive, but with an immunophenotype and morphology atypical for CLL. All cases were negative for t(11;14) and other B cell malignancies were excluded. FISH analysis was carried out using probes for IGH break apart, t(14;19) involving BCL3, trisomy 12, 13q14, 11q22–23 (ATM) and 17p13 (p53 locus). IgVH somatic mutations were analysed using direct sequencing (2% cut off). FISH using IgH break apart probe showed 8 (32%) cases with a split at 14q32. These 8 cases were further investigated using a FISH probe for t(14;19). Four cases (16%) exhibited t(14;19) ie. showed the IgH/BCL3 rearrangement in >70% of cells. Further characterisation of the 24 cases, at additional loci showed that 4 (16%) patients had 17p deletion, 3 (12%) 11q deletion, 3 (12%) 13q deletion, and 14 cases (56%) trisomy 12. The 8 cases showing a split IgH signal did not show deletions of 17p, 11q, or 13q but trisomy 12 was present in 7/8 (88%) patients. Sixteen out of 24 (67%) cases had unmutated IgVH genes with VH3 and VH4 families being used in 91% (22/24). Interestingly, unlike in chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL), the VH1 family was not used in this group of patients. All 4 cases with t(14;19) showed unmutated IgVH genes. Of the sixteen patients without involvement of 14q32, only 2 patients have died with a median follow up of 5.5 years. Of the 4 cases with the t(14;19) (IgH/BCL3 rearrangement), 3 required treatment within 2.5 years of diagnosis and two out of four patients died 5 years after diagnosis, following Richter’s transformation suggesting that this rearrangement is a poor prognostic factor and defines a group with a distinct clinical outcome. Our findings show a high frequency of 14q abnormalities in atypical CD5+ small B-cell leukaemia. BCL3 rearrangement is seen in a significant subset of these cases. The BCL3 gene encodes a nuclear protein that belongs to the IkB family of inhibitors of NFkB. It is involved in the regulation of a variety of transcription factors and it is able to stimulate the expression of cyclin D1. The dysregulation of BCL3 via its juxtaposition to the regulatory element of the IgH locus in our cases suggests a pathogenic role for BCL3 in these B cell disorders and may define a group of patients with a more aggressive clinical course. Further, we have examined these cases for signatures, defined in myeloma, characteristic of NFkB deregulation. We suggest that in cases of CD5 positive B-cell disorders with an immunophenotype and morphology atypical for CLL, and negative for t(11;14), rearrangements involving the IgH locus are frequent and have allowed us to identify cases with poor prognosis and with a pathogenesis that involves deregulation of NFkB.

Intracerebral haemorrhage (ICH) describes haemorrhage into the brain parenchyma that may result in a decline of the patient’s neurological function. ICH is a common cause of morbidity and mortality worldwide. Aggressive surgical treatment for ICH has remained controversial as clinical trials have failed to demonstrate substantial improvement in patient outcome and mortality. Recently, promising mechanical and pharmacological minimally invasive surgery (MIS) techniques for the treatment of ICH have been described. MIS was designed with the objective of reducing morbidity due to complications of surgical manipulation. Mechanical MIS includes the use of tubular retractors and small diameter instruments for ICH removal. Pharmacological methods consist of catheter placement inside the haematoma cavity for the passive drainage of the haematoma over the course of several days. One of the most favourable approaches for MIS is the use of natural corridors for reaching the lesion, such as the transsulcal parafascicular approach. This approach provides an anatomical dissection of the subjacent white matter tracts, causing the least amount of damage while evacuating the haematoma. A detailed description of the currently known MIS techniques and devices is presented in this review. Special attention is given to the transsulcal parafascicular approach, which has particular benefits to provide a less traumatic MIS with promising overall patient outcome.

Abstract Background: Immune checkpoint inhibitors (ICPIs) have led to dramatic improvement in outcome of several cancers. Program death ligand1 (PD-L1) staining and tumor mutational burden (TMB) have emerged as independent predictive biomarkers of ICPIs in lung cancer. Here we examine the landscape of TMB and PD-L1 expression in breast cancer and present a case of patient with high TMB and PD-L1 negative breast cancer with exceptional response to ICPIs. Methods: Hybrid-capture based comprehensive genomic profiling of 395 cancer related genes using the FoundationOne assay was performed on 14,867 breast carcinomas sequenced in the course of routine clinical care. Ventana (SP-263) PD-L1 status (n=1425) and hormone receptor status was available for a subset of patients. Subgroup analyses were performed based on histological type [invasive lobular carcinoma (ILC, n=740)], molecular subtypes [ER-positive (ER+; n= 1371), HER2-amplified (HER2+; n=1522), and TNBC (n=917)], patient age (≤45, 46-60, ≥61), and local vs. metastatic disease (n=5241 and 6710). Results: Consistent with previous reports, the rates of positive PD-L1 staining are highest in TNBC (14%) and lowest in HER2+, ILC, and ER+ disease (6.0%, 5.1%, 2.3%). Interestingly, the rate of PD-L1 positivity, defined as ≥1% tumor staining, was significantly lower in metastatic disease vs. local disease (6.3% vs. 11.1%; p = 0.005). The frequency of high TMB, defined as &gt;10 mutations/mb, was greatest in ILC and HER2+ disease (13.6% and 9.9%) and lowest in TNBC and ER+ disease (7.0% and 6.9%). Rates of high TMB were associated with increased patient age (3.7%, 9.3%, and 12.8% frequency in patients ≤45, 46-60, and ≥61) and were significantly higher in metastatic vs. local disease (11.1% vs 5.3%; p&lt;2E-23). PD-L1 positive and TMB high populations were not significantly co-occurrent (OR = 1.02, p = 0.87). Similar percentages of PD-L1 positivity were observed in both TMB low (9.3%) and TMB high (9.5%). However, among patients with very high TMB (&gt;20 mut/mb), there was a significant association between TMB and PD-L1 positivity (OR = 2.6, p = 0.023). Nevertheless, even with high cutoff, 79% of the TMB high samples were PD-L1 negative. We also report on a stage IIIb (T4, N2, M0) ER+ HER2- breast cancer patient with high TMB (40muts/mb) and negative PD-L1 IHC who previously progressed on aromatase inhibitor with CDK4/6 inhibitor and chemotherapy but achieved durable complete response of &gt; 1 year with nivolumab in combination with capecitabine. Conclusions: Predictive biomarkers for ICPIs are critical to identify a subset of breast cancer patients who may respond to immunotherapy. TMB high and PD-L1 positivity do not significantly co-occur and the majority of TMB high cases were PD-L1 negative. Nevertheless, this group of patients may still benefit with ICPIs. Further studies are needed to evaluate this subset of patients. Citation Format: Ethan Sokol, Lee Albacker, Aixa Soyano, Ricardo Parrondo, Brenda Ernst, Emmanuel Gabriel, Garrett Frampton, Jeffrey Ross, Siraj Ali, Jon Chung, Saranya Chumsri. Incidence of high tumor mutation burden (TMB) and PD-L1 positivity in breast cancers and potential response to immune checkpoint inhibitors (ICPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4894.

Background Endoscopic skull‐base surgery (ESBS) is employed in the management of diverse skull‐base pathologies. Paralleling the increased utilization of ESBS, the literature in this field has expanded rapidly. However, the rarity of these diseases, the inherent challenges of surgical studies, and the continued learning curve in ESBS have resulted in significant variability in the quality of the literature. To consolidate and critically appraise the available literature, experts in skull‐base surgery have produced the International Consensus Statement on Endoscopic Skull‐Base Surgery (ICAR:ESBS). Methods Using previously described methodology, topics spanning the breadth of ESBS were identified and assigned a literature review, evidence‐based review or evidence‐based review with recommendations format. Subsequently, each topic was written and then reviewed by skull‐base surgeons in both neurosurgery and otolaryngology. Following this iterative review process, the ICAR:ESBS document was synthesized and reviewed by all authors for consensus. Results The ICAR:ESBS document addresses the role of ESBS in primary cerebrospinal fluid (CSF) rhinorrhea, intradural tumors, benign skull‐base and orbital pathology, sinonasal malignancies, and clival lesions. Additionally, specific challenges in ESBS including endoscopic reconstruction and complication management were evaluated. Conclusion A critical review of the literature in ESBS demonstrates at least the equivalency of ESBS with alternative approaches in pathologies such as CSF rhinorrhea and pituitary adenoma as well as improved reconstructive techniques in reducing CSF leaks. Evidence‐based recommendations are limited in other pathologies and these significant knowledge gaps call upon the skull‐base community to embrace these opportunities and collaboratively address these shortcomings.

Background Preliminary clinical studies on the safety and efficacy of the pipeline embolization device (PED) for the treatment of small/medium aneurysms have demonstrated high occlusion rates with low complications. Objective To evaluate the safety and effectiveness of the PED for treatment of wide necked small and medium intracranial aneurysms. Methods PREMIER is a prospective, multicenter, single arm trial. Patients were treated with the PED for unruptured wide necked aneurysms, measuring ≤12 mm along the internal carotid artery or vertebral artery, between July 2014 and November 2015. At 1 year post-procedure, the primary effectiveness endpoint was complete occlusion (Raymond grade 1) without major parent vessel stenosis (≤50%) or retreatment, and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurologic death. Results A total of 141 patients were treated with PEDs (mean age 54.6±11.3 years, 87.9% (124/141) women). Mean aneurysm size was 5.0±1.92 mm, and 84.4% (119/141) measured <7 mm. PED placement was successful in 99.3% (140/141) of patients. Mean number of PEDs implanted per patient was 1.1±0.26; a single PED was used in 92.9% (131/141) of patients. At 1 year, 97.9% (138/141) of patients underwent follow-up angiography with 76.8% (106/138) of patients having met the study’s primary effectiveness endpoint. The combined major morbidity and mortality rate was 2.1% (3/140). Conclusions Treatment of wide necked small/medium aneurysms with the PED results in high rates of complete occlusion without significant parent vessel stenosis and low rates of permanent neurologic complications. Trial registration NCT02186561 .