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Abstract Abstract 756 Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferative neoplasms (MPNs) for which there is no approved therapy. Exaggerated JAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F) or high circulating levels of JAK1/2 activating cytokines (eg, interleukin [IL]-6), is believed to play a key role in MPN pathogenesis. INCB018424 (424), a selective oral inhibitor of JAK1/2, has demonstrated clinical benefits including reduction of splenomegaly and improvement of symptoms in a Phase I/II trial in MF patients. Thrombocytopenia was identified as the dose limiting toxicity occurring in 30% of patients at 25mg BID. Methods: Patients with primary, post-PV or post-ET MF were enrolled in the study. Following the characterization of multiple dosing regimens, an individually optimized dose regimen strategy was developed, based on available efficacy and safety data. In a subset of patients, spleen volume change was measured by MRI at 1, 3 and 6 months of treatment in order to establish an objective measure of spleen response. The impact of 424 on MF associated symptoms was assessed using a validated instrument, MFSAF (Mesa et al., Leukemia Research 2009). As a surrogate marker of functional benefit, exercise capacity was assessed with a standardized 6-minute walk test (6MWT) at baseline, 1, 3 and 6 months of therapy. Results: 155 patients were enrolled in the study, with median duration of treatment of 1+ years and the duration of drug exposure of >150 patient years (76 patients received >1 year of therapy). Clinical responses have been maintained over the entire duration of treatment and most patients remain on therapy (115 of 155 patients; 74%). Progression to AML occurred in 3 patients, which is below the expected frequency based on published data (Barosi et al., Blood 2007). SAEs related to 424 occurred in 12 patients, and are generally related to bone marrow suppression or return of or exacerbation of signs and symptoms of MF when therapy is discontinued. Further optimization of the dosing regimen utilized baseline platelet count to determine the starting dose (10 or 15mg BID) and allowed dose titration after 1 and 2 months of therapy; most patients were optimized to 15 or 20mg BID. This approach significantly reduced the incidence of thrombocytopenia (<5%, N=35), while providing equivalent efficacy to higher dose regimens. With an optimized dosing regimen, spleen volume reduction was evident as early as 1 month, and durable over 6 months, of therapy (33 % median decrease after 6 months, N=23). Eleven of 23 (48%) of patients achieved ≥ 35% reduction (equivalent to IWG clinical improvement criteria of 50% reduction by palpation) from baseline in spleen volume at month 6. MF patients have impaired exercise capacity at baseline (decreased 6MWT performance by 60-90 meters vs. age-matched controls). Treatment with 424 resulted in improved 6MWT performance, with median increase from baseline of 33, 58 and 70 meters after 1,3 or 6 months of therapy, respectively. Rapid and durable reduction of a total symptom score based on key symptoms (fatigue, abdominal discomfort/pain, bone/muscle pain, night sweats and pruritus) was noted (51 % and 58% of patients achieving 50% reduction in the total score following 1 and 6 months of treatment, respectively). Improvement in symptoms coincided with a rapid and sustained reduction in pro-inflammatory cytokines, including IL-1b, IL-1ra, IL-6 and TNFa, without tachyphylaxis to therapy. Finally, spleen response was associated with greater improvements in total symptom score, exercise capacity, and reduced fatigue (see Table). Conclusion: An optimized dosing regimen of INCB018424 resulted in sustained clinical, symptomatic and functional benefits in MF patients with an improved hematological safety profile compared to a 25 mg BID regimen. Safety and efficacy of 424 in MF patients is further supported by the follow-up data of >1 yr of 424 therapy. Disclosures: Verstovsek: Incyte: Research Funding. Bradley:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership.

Background: Distal femoral replacement (DFR) is a salvage option for complex primary and revision total knee arthroplasty (TKA). Although excellent immediate fixation and weight-bearing are achieved, there is a paucity of data on long-term outcomes of TKA with DFR. The purpose of the present study was to determine implant survivorship, clinical outcomes, and radiographic results of TKAs with contemporary DFR components in a large series. Methods: We identified 144 consecutive TKAs performed with DFR for non-oncologic indications from 2000 to 2015 at a single academic institution. Indications for the index DFR included 66 (46%) for native (n = 11) or periprosthetic (n = 55) femoral fracture, 40 (28%) for staged treatment of periprosthetic joint infection, 28 (19%) for aseptic TKA loosening, and 10 (7%) for other indications. Porous metal cones were used to augment femoral fixation in 28 patients (19%) and tibial fixation in 38 patients (26%). Outcomes included cumulative incidence of revision and reoperation (utilizing a competing risk model), Knee Society scores, and radiographic results. The mean age at the time of index DFR was 72 years, and 65% of patients were female. The mean follow-up was 5 years (range, 2 to 13 years) for the 111 patients who did not undergo revision, had not died, and were not lost to follow-up. Results: The 10-year cumulative incidences of revision for aseptic loosening, all-cause revision, and any reoperation were 17.0%, 27.5%, and 46.3%, respectively. There was an increased risk of reoperation in patients who underwent index DFR for aseptic TKA loosening (hazard ratio [HR], 2.30; p = 0.026) or periprosthetic joint infection (HR, 2.18; p = 0.022) compared with periprosthetic or native femoral fractures. However, there was no difference in risk of revision for aseptic loosening or all-cause revision based on the original operative indication. The mean Knee Society score increased from 45 preoperatively to 71 at the time of the latest follow-up (p < 0.001). Radiographic loosening was observed in 8 unrevised DFRs (7%). There were 7 above-the-knee amputations performed at the time of the final follow-up, all for intractable periprosthetic joint infection. Conclusions: TKAs with contemporary DFR had high 10-year cumulative incidences of both revision and reoperation, underscoring the salvage nature of this procedure as a final reconstructive option. Most patients experienced substantial clinical improvements with this end-stage revision procedure. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

INTRODUCTION: Due to the rising incidence and mortality of colorectal cancer (CRC) in individuals < 55 years (Siegel R, et al, JNCI, 2017), American Cancer Society (ACS) guidelines now recommend average-risk CRC screening beginning at age 45 years. The multi-target stool DNA (mt-sDNA) test, an FDA-approved screening test for average-risk individuals ≥50 years, is one ACS-recommended option for this age group. To minimize invasive testing in the younger age group, a screening test with high specificity is necessary to triage patients for diagnostic colonoscopy. To date, most endorsed CRC screening tests have not been rigorously studied in younger age groups. The objective of this study (the Act Now study [NCT03728348]) is to quantify the specificity of the mt-sDNA test in average risk individuals ages 45-49. METHODS: Act Now is an ongoing prospective, cross-sectional, multi-center study in subjects ages 45-49 at average risk for CRC. 942 subjects are targeted for enrollment and will complete a mt-sDNA test prior to undergoing a screening colonoscopy (blinded to mt-sDNA test results). Specificity for advanced colorectal neoplasia will be determined by comparing mt-sDNA test results to the most advanced finding on colonoscopy, based on procedure report and histopathological findings. Due to the low prevalence of CRC in this age group, mt-sDNA test sensitivity will be a secondary measure. RESULTS: To date, 480 subjects have completed a mt-sDNA test and screening colonoscopy. A total of 468 subjects (97.5%) have no first-degree relative (FDR) with CRC and 12 subjects (2.5%) have an FDR diagnosed at age ≥60 years. No subject has had a previous screening colonoscopy. The study population has a mean age of 47.4 years and is 48.8% female. Self-reported race includes 84.2% white, 11.5% black/African American, 3.3% Asian, and 1.0% other. Self-reported ethnicity includes 95.2% not Hispanic or Latino, 4.6% Hispanic or Latino, and 0.2% other. The mean BMI of subjects is 29.6 kg/m 2 . Most subjects (67.1%) have never smoked cigarettes, while 21.9% are former smokers and 11.0% are current smokers. CONCLUSION: The ongoing Act Now study will quantify the specificity of the mt-sDNA test in average risk individuals ages 45-49. Given concerns regarding the resources required to screen this age group for CRC, a noninvasive screening test with high specificity and sensitivity will help to optimize use of colonoscopy resources.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety and efficacy were demonstrated in patients (pts) with moderate to severe UC in 3 Phase 3 studies, 1 and are being evaluated in an ongoing, open-label, long-term extension (OLE) study. 2 METHODS: We present updated safety and efficacy data from the OCTAVE Open OLE study (NCT01470612; Sep 2018; database not locked) 2 in completers/treatment failures in OCTAVE Sustain (NCT01458574) or non-responders in OCTAVE Induction 1/2 (NCT01465763/NCT01458951). Week (Wk) 8 data (OCTAVE Induction 1/2) and Wk 52 (completers) or early-termination data (OCTAVE Sustain) determined eligibility. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0) at Wk 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID) in the OLE study; all others received 10 mg BID. At Month 2, all pts had endoscopy, and induction non-responders with no clinical response were withdrawn. Incidence rates (IRs; unique pts with events per 100 pt-years [PY]) for adverse events (AEs) of special interest were calculated. Efficacy endpoints were derived from Mayo score (local read). RESULTS: Of 944 pts receiving ≥1 tofacitinib dose (for up to 5.5 years), 175 (18.5%) and 769 (81.5%) received 5 and 10 mg BID, respectively (454 and 1550 PY, respectively). 337 (35.7%) pts discontinued due to insufficient clinical response and 78 (8.3%) due to AEs excl. worsening UC. The most frequent AE class was infections and infestations (52.1%). The most frequent AEs were nasopharyngitis (20.3%) and worsening UC (19.5%). IRs (95% CI) for “Tofacitinib All” were: serious infections 1.61 (1.10, 2.27); herpes zoster (all) 3.35 (2.58, 4.27); major adverse cardiovascular events 0.15 (0.03, 0.44); malignancies excl. non-melanoma skin cancer (NMSC) 0.85 (0.50, 1.36); and NMSC 0.81 (0.46, 1.32), with no clustering of malignancy type. Table 1 shows AEs and IRs by dose. No new safety risks were identified. Table 2 shows efficacy data at Month 36. CONCLUSION: In pts with UC in the OLE study, no new safety risks emerged at 5.5 years vs earlier OLE analyses 2 or with tofacitinib in rheumatoid arthritis. Efficacy data continue to support long-term efficacy of tofacitinib 5 or 10 mg BID up to 36 months beyond OCTAVE Sustain.

The efficacy of radiosurgery for neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) remains debatable. We retrospectively analyzed radiosurgical outcomes for NF2-associated VS compared to sporadic VS using our database of 422 consecutive VS patients. Twenty-five patients with 30 NF2-associated VSs with a mean follow-up of 121 months were identified. NF2-associated VSs exhibited excellent tumor control (10-year cumulative rate, 92% vs. 92% in sporadic VSs; p = 0.945) and worse overall survival (73% vs. 97%; p = 0.005), mainly due to tumor progression other than the treated VSs. The presence of NF2 was not associated with failed tumor control via multivariate Cox proportional hazard analyses. No difference in radiation-induced adverse events (RAEs) was confirmed between cohorts, and prescription dose (hazard ratio 8.30, 95% confidence interval 3.19–21.62, p < 0.001) was confirmed as a risk for cranial nerve injuries via multivariate analysis. Further analysis after propensity score matching using age, volume, and sex as covariates showed that NF2-associated VSs exhibited excellent local control (100% vs. 93%; p = 0.240) and worse overall survival (67% vs. 100%; p = 0.002) with no significant difference in RAEs. Excellent long-term tumor control and minimal invasiveness may make radiosurgery a favorable therapeutic option for NF2 patients with small to medium VS, preferably with non-functional hearing or deafness in combination with postoperative tumor growth or progressive non-operated tumors, or with functional hearing by patients’ wish.

Executive Summary The risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-term risk of cervical neoplasia and cancer and the need for more intense screening, surveillance, and management. Although guidance for CC screening among HIV-infected women (see Table 1) has been supported by evidence from retrospective and prospective studies, recommendations for CC screening among non-HIV immunosuppressed women remains limited because quality evidence is lacking. Moreover, CC screening guidelines for HIV-infected women have changed because better treatments evolved and resulted in longer life expectancy. The objective of this report was to summarize current knowledge of CC, squamous intraepithelial lesions, and human papillomavirus (HPV) infection in non-HIV immunocompromised women to determine best practices for CC surveillance in this population and provide recommendations for screening. We evaluated those with solid organ transplant, hematopoietic stem cell transplant, and a number of autoimmune diseases. A panel of health care professionals involved in CC research and care was assembled to review and discuss existing literature on the subject and come to conclusions about screening based on available evidence and expert opinion. Literature searches were performed using key words such as CC, cervical dysplasia/squamous intraepithelial lesion, HPV, and type of immunosuppression resulting in an initial group of 346 articles. Additional publications were identified from review of citations in these articles. All generated abstracts were reviewed to identify relevant articles. Articles published within 10 years were considered priority for review. Reviews of the literature were summarized with relevant statistical comparisons. Recommendations for screening generated from each group were largely based on expert opinion. Adherence to screening, health benefits and risks, and available clinical expertise were all considered in formulating the recommendations to the degree that information was available. Results Solid Organ Transplant: Evidence specific for renal, heart/lung, liver, and pancreas transplants show a consistent increase in risk of cervical neoplasia and invasive CC, demonstrating the importance of long-term surveillance and treatment. Reports demonstrate continued risk long after transplantation, emphasizing the need for screening throughout a woman's lifetime. Hematopoietic Stem Cell Transplant: Although there is some evidence for an increase in CC in large cohort studies of these patients, conflicting results may reflect that many patients did not survive long enough to evaluate the incidence of slow-growing or delayed-onset cancers. Furthermore, history of cervical screening or previous hysterectomy was not included in registry study analysis, possibly leading to underestimation of CC incidence rates. Genital or chronic graft versus host disease is associated with an increase in high-grade cervical neoplasia and posttransplant HPV positivity. Inflammatory Bowel Disease: There is no strong evidence to support that inflammatory bowel disease alone increases cervical neoplasia or cancer risk. In contrast, immunosuppressant therapy does seem to increase the risk, although results of observational studies are conflicting regarding which type of immunosuppressant medication increases risk. Moreover, misclassification of cases may underestimate CC risk in this population. Recently published preventive care guidelines for women with inflammatory bowel disease taking immunosuppressive therapy recommend a need for continued long-term CC screening. Systemic Lupus Erythematosus and Rheumatoid Arthritis: The risk of cervical high-grade neoplasia and cancer was higher among women with systemic lupus erythematosus than those with rheumatoid arthritis (RA), although studies were limited by size, inclusion of women with low-grade neoplasia in main outcomes, and variability of disease severity or exposure to immunosuppressants. In studies designed to look specifically at immunosuppressant use, however, there did seem to be an increase in risk, identified mostly in women with RA. Although the strength of the evidence is limited, the increase in risk is consistent across studies. Type 1 DM: There is a paucity of evidence-based reports associating type 1 DM with an increased risk of cervical neoplasia and cancer. Recommendations The panel proposed that CC screening guidelines for non-HIV immunocompromised women follow either the (1) guidelines for the general population or (2) current center for disease control guidelines for HIV-infected women. The following are the summaries for each group reviewed, and more details are noted in accompanying table: Solid Organ Transplant: The transplant population reflects a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Hematopoietic Stem Cell Transplant: These women have a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening. A new diagnosis of genital or chronic graft versus host disease in a woman post–stem cell transplant results in a greater risk of CC than in the general population and should result in more intensive screening and surveillance. Inflammatory Bowel Disease: Women with inflammatory bowel disease being treated with immunosuppressive drugs are at greater risk of cervical neoplasia and cancer than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Those women with inflammatory bowel disease not on immunosuppressive therapy are not at an increased risk and should follow screening guidelines for the general population. Systemic Lupus Erythematosus and Rheumatoid Arthritis: All women with systemic lupus erythematosus, whether on immunosuppressant therapy or not and those women with RA on immunosuppressant therapy have a greater risk of cervical neoplasia and cancer than the general population and should follow CC screening guidelines for HIV-infected women. Women with RA not on immunosuppressant therapy should follow CC screening guidelines for the general population. Type 1 Diabetes Mellitus: Because of a lack of evidence of increased risk of cervical neoplasia and cancer among women with type 1 DM, these women should follow the screening guidelines for the general population.

AbstractObjectiveTo characterize the molecular and phenotypic basis of a severe slow‐channel congenital myasthenic syndrome (SCCMS).MethodsIntracellular and single‐channel recordings from patient endplates; alpha‐bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure.ResultsAmong 24 variants reported to cause SCCMS only two appear in the AChR δ‐subunit. We here report a 16‐year‐old patient harboring a novel δL273F mutation (δL294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR δ subunit. Kinetic analyses with ACh and the weak agonist choline indicate that δL273F prolongs the channel opening bursts 9.4‐fold due to a 75‐fold increase in channel gating efficiency, whereas a previously identified εL269F mutation (εL289F in HGVS nomenclature) at an equivalent location in the AChR ε‐subunit prolongs channel opening bursts 4.4‐fold due to a 30‐fold increase in gating efficiency. Structural modeling of AChR predicts that inter‐helical hydrophobic interactions between the mutant residue in the δ and ε subunit and nearby M2 domain residues in neighboring α subunits contribute to structural stability of the open relative to the closed channel states.InterpretationThe greater increase in gating efficiency by δL273F than by εL269F explains why δL273F has more severe clinical effects. Both δL273F and εL269F impair channel gating by disrupting hydrophobic interactions with neighboring α‐subunits. Differences in the extent of impairment of channel gating in δ and ε mutant receptors suggest unequal contributions of ε/α and δ/α subunit pairs to gating efficiency.

Background: There is no consensus on managing severe patellar bone loss after total knee arthroplasty. We previously described an initial series involving a novel technique of patellar bone-grafting with a short follow-up. The purpose of this study was to determine long-term survivorship and the radiographic and clinical results of patellar bone-grafting during revision total knee arthroplasty in a larger series with an extended follow-up. Methods: We identified 90 patients from a single institution who underwent 93 patellar bone-grafting procedures for severe patellar bone loss from 1997 to 2014. The mean age of the patients was 70 years, and 46% of patients were female. Forty-five knees (48%) underwent first-time revisions, and 19 knees (20%) had undergone a failed attempt at patellar resurfacings. Intraoperative patellar caliper thickness increased from a mean of 7 to 25 mm after patellar bone-grafting (p < 0.01). Radiographic review determined changes in patellar height, tracking, and remodeling. Knee Society scores (KSSs) were calculated. The mean follow-up was 8 years (range, 2 to 18 years). Kaplan-Meier methods determined survivorship free of any revision and any reoperation. Cox proportional hazards analysis determined predictive factors for failure. Results: Survivorship free of patellar revision was 96% at 10 years. Survivorship free of any revision was 84% at 10 years. Survivorship free of any reoperation was 78% at 10 years. Increasing patient age was the only protective factor against further patellar revision (hazard ratio, 0.95; p < 0.01). When comparing initial radiographs with final radiographs, patellar height decreased from 22 to 19 mm (p < 0.01), 80% compared with 59% of patellae articulated centrally in the trochlea (p = 0.01), and 32% compared with 77% had remodeling over the lateral femoral condyle (p < 0.01). Anterior knee pain decreased from 51% to 27% postoperatively (p = 0.01). The mean knee flexion improved from 101° to 108° (p = 0.03). The mean KSS improved from 50 to 85 points (p < 0.01). Conclusions: Reliable long-term clinical results can be expected with patellar bone-grafting for severe patellar bone loss during revision total knee arthroplasty. Pain, range of motion, and other reported outcomes improve despite radiographic changes to patellar height, tracking, and remodeling. This technique is a durable and reliable option when standard patellar resurfacing is not possible. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract The purpose of this study was to evaluate a single center's experience with adult patients who had cleft lip, cleft palate, or both. The authors aimed to identify common long-term needs in this patient population and evaluated the relationship of team-based care in meeting those needs. To do so, the authors retrospectively reviewed chart records from a single private practice and tertiary referral cleft center for all patients who were ≥15 years of age and who had a history of clefts of the lip or palate, or both, from January 1, 2013, to June 30, 2014. The authors compared the concerns of the patients who received cleft-team–based care by a single, multidisciplinary cleft team; multiple multidisciplinary cleft teams; or no formal cleft team. The authors analyzed data for 142 patients. The most common patient concerns were lip aesthetics (64%), nose aesthetics (61%), septal deviations (47%), nasal obstruction (44%), malocclusion (32%), oronasal fistulas (29%), and speech (21%). Oronasal fistulas were more commonly reported in the group of patients who had care by multiple teams (42.9%; P < .001). Malocclusion was more commonly reported in the group of patients who had care by multiple teams (50%; P = .001). The authors found that adult patients who have undergone rehabilitation for cleft lip and palate appear to have a common set of long-term needs. Multidisciplinary cleft-team–based care appears to be the most effective way to address these needs.

Background: Osteonecrosis of the hip is the underlying etiology for 3% to 12% of total hip arthroplasties (THAs). Compared with patients who undergo THA because of osteoarthritis, those who do so because of osteonecrosis typically are younger, have a greater number of underlying diagnoses, and have inferior clinical outcomes and implant survivorship. The purpose of this study was to compare the long-term implant survivorship (median follow-up, 10 years), functional outcomes, and radiographic results of contemporary THAs with a highly cross-linked polyethylene (HXLPE) liner between patients with osteonecrosis and those with osteoarthritis. Methods: All patients who underwent primary THA with an HXLPE liner from 1999 to 2007 were identified from our institutional total joint registry. Patients with a primary diagnosis of osteonecrosis were matched 1:1, on the basis of age, sex, and body mass index (BMI), to patients with a diagnosis of osteoarthritis. This resulted in 461 hips in 413 patients with osteonecrosis matched to 461 hips in 427 patients with osteoarthritis (mean age, 59 years; 47% female; and mean BMI, 29 kg/m 2 ). Long-term implant survivorship, patient-reported outcomes, and radiographic findings were compared. In addition, a subgroup analysis of the osteonecrosis group was performed to see whether certain underlying etiologies portended poor outcomes. The median follow-up was 10 years. Results: The 15-year cumulative rates of revision were 6.6% and 4.5% in the osteonecrosis and osteoarthritis groups, respectively (hazard ratio [HR] = 1.8, p = 0.09). The 15-year cumulative rates of any reoperation were 10.5% and 6.4% in the osteonecrosis and osteoarthritis groups, respectively (HR = 2.2, p = 0.008). There were no radiographic signs of component loosening or osteolysis in the entire cohort. Despite a lower median preoperative Harris hip score (HHS) for patients with osteonecrosis, both groups had marked improvements in their scores, which were similar at all time points after surgery. The cumulative rate of reoperations at 15 years was 0% for hips with radiation-induced osteonecrosis, 6.3% for those with alcohol-induced osteonecrosis, 9.0% for those with posttraumatic osteonecrosis, 12.1% for those with steroid-induced osteonecrosis, and 25% for those with idiopathic osteonecrosis. Conclusions: Contemporary THA with an HXLPE liner offers excellent long-term implant survivorship and functional outcomes for patients with osteonecrosis; however, the risk of a reoperation is higher when compared with patients with osteoarthritis. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.