Citations

Background: The periacetabular region is a common location for metastatic disease. Although large lytic acetabular defects are commonly treated with a hip arthroplasty with a cemented component according to a Harrington-style reconstruction, the use of highly porous uncemented tantalum acetabular components has been described. Currently, there are no direct comparisons of these reconstructive techniques. The purpose of this study was to compare the outcomes of the Harrington technique and tantalum acetabular component reconstruction for periacetabular metastases. Methods: From 2 tertiary sarcoma centers, we retrospectively reviewed 115 patients (70 female and 45 male) with an acetabular metastatic defect who had been treated between 2002 and 2015 with a total hip arthroplasty using either the cemented Harrington technique (78 patients) or a tantalum acetabular reconstruction (37 patients). The mean patient age was 61 years, and the most common Eastern Cooperative Oncology Group status was 3 (39 patients). The mean follow-up for surviving patients was 4 years. Results: An additional surgical procedure was performed in 24 patients (21%). Harrington-style reconstructions were more likely to require a reoperation compared with tantalum reconstructions (hazard ratio [HR], 4.59; p = 0.003). The acetabular component was revised in 13 patients (11%); 5 patients (4%) underwent revisions that were due to loosening of the acetabular component. The 10-year cumulative incidence of revision of the acetabular component for loosening was 9.6% in the Harrington group and 0% in the tantalum group (p = 0.09). The mean Harris hip score significantly improved following reconstruction (31 to 67 points; p < 0.001), with no significant difference (p = 0.29) between groups. Conclusions: In patients with periacetabular metastatic disease treated with total hip arthroplasty, an acetabular reconstruction strategy utilizing highly porous tantalum acetabular components and augments successfully provided patients with a more durable construct with fewer complications compared with the cemented Harrington-style technique. Levels of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Objective To examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer. Methods We used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date. Results Of the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only ( n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test ( n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test. Conclusions Our results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

Abstract Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists. Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study. Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents &lt;10% involvement, score=1 represents 10–90% involvement, and score=2 represents &gt;90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ. Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis. In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year). Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year). Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO. Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.

Abstract Proteasome inhibitors are used in the treatment of myeloma and are under evaluation for the treatment of other malignancies including acute myeloid leukemia (AML). Via high throughput screening for inhibitors of cyclin D2 transactivation, we identified the off-patent antimicrobial, Clioquinol (CQ) that we subsequently determined acted by inhibiting the proteasome. CQ is a copper-binding halogenated 8-hydroxyquinoline that was used in the 1950’s-1970’s as an oral anti-parasitic agent. We determined that CQ decreased expression of cyclin D2, arrested cells in the G1 phase, and increased expression of p21, p27 and the abundance of ubiquitinated proteins. This constellation of changes can be associated with inhibition of the proteasome, so we evaluated the effects of CQ on proteasomal function. AML and myeloma cell lines as well as primary AML and normal hematopoietic cells were incubated with increasing concentrations of CQ. After a 24 hour incubation, cell lysates were prepared and the chymotrypsin-like activity of the proteasome was measured by monitoring the rate of cleavage of the fluorescent substrate Suc-LLVY-AMC. In cell lines and primary AML samples, CQ inhibited chymotrypsin-like activity at low micromolar concentrations and at concentrations associated with reductions in cyclin D2, G1 arrest, and increased p21 and p27 expression. Conversely, CQ did not inhibit the proteasome in normal hematopoietic cells up to 100 μM. As CQ is a copper-binding molecule, we tested the requirement of copper for its effects on the proteasome. Supplementing CQ with copper increased CQ’s potency as a proteasome inhibitor, but also negated its preferential inhibition of the proteasome in malignant cells over normal hematopoietic cells. Of note, copper alone had no effect on proteasomal function when added to intact cells. Since inhibiting the proteasome induces cell death, we tested the effects of CQ on the viability of AML (n=6), myeloma (n=14), and solid tumor (n=5) cell lines as well as primary AML samples (n=6) and primary normal hematopoietic cells (n=3). Forty-eight hours after incubation, CQ induced cell death in 6/6 AML, 12/14 myeloma, 0/5 solid tumor, 6/7 primary AML patient samples and 0/3 normal hematopoietic cells with an IC50 &lt;20 μM. Of note, after oral administration of CQ, trough serum concentrations of 20 μM can be achieved in patients. CQ-mediated reductions in cell viability were associated with its ability to inhibit the proteosome, as no proteasomal inhibition was detected in CQ-resistant cell lines. CQ-induced cell death was copper-dependent as supplementing copper in the medium enhanced the toxicity of CQ, while adding the strong copper chelator, tetrathiomoylbdate, abrogated CQ-induced cell death. Given the effects of CQ on AML cell lines and primary patient samples, we evaluated CQ in a mouse model of leukemia. Twice daily oral gavage with CQ prevented the growth of MDAY-D2 leukemia cells in DBA2 mice without evidence of toxicity. Thus, we have identified the off-patent anti-microbial agent CQ that inhibits the proteasome and induces apoptosis preferentially in malignant cells at clinically achievable concentrations. It acts through a copper-dependent mechanism and leverages the higher copper levels present in malignant cell. As such, CQ could be rapidly advanced into clinical trial as an oral proteasome inhibitor for the treatment of AML and myeloma.

Abstract Cyclin Ds are key regulators of the cell cycle that are frequently over-expressed in multiple myeloma and leukemia and act to promote the phosphorylation of Rb, thereby facilitating the transition from G1 to S phase. Over-expression of cyclin Ds increases cell proliferation and chemoresistance. In contrast, reducing cyclin Ds levels directly or indirectly through G1 arrest can decrease cellular proliferation and induce apoptosis. To identify novel pharmaceutical inhibitors of cyclin D transactivation, we screened the LOPAC and Prestwick libraries of drugs and natural compounds (n = 2400) using NIH 3T3 cells stably expressing the Cyclin D2 promoter-driving a luciferase reporter gene. From this library screen and subsequent validation experiments we identified Cyproheptadine as a novel inhibitor of Cyclin D2 transactivation. Cyproheptadine has been used previously for the treatment of atopic dermatitis and anorexia, but its ability to inhibit cyclin D expression has not previously been reported. By immunoblotting, Cyproheptadine decreased expression of cyclin D1, D2 and D3 proteins in human myeloma and leukemia cell lines at low micromolar concentrations. Consistent with effects on the cyclin Ds, Cyproheptadine arrested cells in the G1 phase at concentrations associated with reduction in cyclin D expression. Decreased cyclin D expression and G1 arrest can induce apoptosis, so we tested the effects of Cyproheptadine on cell viability. Myeloma and leukemia cell lines were treated with increasing concentrations of Cyproheptadine and viability was measured by the MTS assay. Cyproheptadine reduced the viability of 7/10 myeloma and 7/8 AML cells lines with an IC50 ranging from 10–25μM. In contrast, it was less toxic to HeLa or NIH3T3 cells with IC20 &gt; 50 μM. Cyproheptadine also reduced the viability of primary myeloma (8/8) and AML patient samples (7/9) with an IC50 &lt;25 μM, but was less toxic to normal hematopoietic cells (IC20 &gt; 50 μM). In a MDAY-D2 mouse model of leukemia, treatment with Cyproheptadine (50mg/kg/d) abolished formation of malignant leukemic ascites without untoward toxicity. Cyproheptadine-induced cell death was associated with reductions in mitochondrial membrane potential. Furthermore, reductions of pro-caspases -3 and -9 were observed prior to the reduction in pro-caspase-8, indicating that Cyproheptadine activates the mitochondrial pathway of caspase activation. Cyproheptadine is a known H1 histamine and serotonin receptor inhibitor, but pre-incubation with histamine, serotonin, or a combination of histamine and serotonin did not abrogate Cyproheptadine-induced cell death. Moreover, the structurally related H1 receptor inhibitor loratadine did not decrease cyclin D expression or reduce cell viability. Therefore, the pro-apoptotic activity of Cyproheptadine is not due to a competitive inhibition of the H1 and/or serotonin receptors, suggesting that Cyproheptadine has additional targets. In summary, Cyproheptadine arrests cells in G1, reduces cyclin D expression, and induces apoptosis via the mitochondrial pathway of caspase activation. Given the prior safety and toxicity record of Cyproheptadine, this drug could be rapidly advanced into clinical trial for the treatment of hematologic malignancies.

Objective To assess real‐world effectiveness of initial treatment with newer compared to injectable disease‐modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). Methods This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon‐β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS‐quintile. Time to new/enlarging T2‐hyperintense and gadolinium‐enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS‐quintile. Results A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS‐quintile–adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29–0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14–0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person‐years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36–0.72, p < 0.001) and gadolinium‐enhancing lesions (HR = 0.38, 95% CI = 0.23–0.63, p < 0.001) than those on injectables. Interpretation Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long‐term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42–55

8060 Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p<0.0001), respectively). For all stages, treatment with CMT compared with CT or RT alone was also associated with better PFS and OS, 18.0 vs 3.9 months (p<0.0001), and 41.5 vs 10.2 months (p=0.002) respectively. Non-anthracycline-based regimens were associated with better PFS (p=0.001) and OS (p=0.045). No survival differences were seen between Asian and non-Asian pts. Conclusions: This series represents one of the largest experiences of ENKL in NA. Our data are consistent with Asian studies in: 1) majority of pts present with early stage disease; 2) overall poor outcome; 3) superiority of CMT and non-anthracycline regimens. Advances in understanding biology and international collaborative efforts are required to improve outcome in this rare entity.

AbstractBackgroundChronic headaches are the second most prevalent disease and second most common cause for years lived with disability worldwide. Occipital neuralgia can cause headaches or be present in addition to other more prevalent causes of headache. If these headaches fail to respond to conservative and pharmacological therapy, physicians proceed to more invasive treatments, starting with infiltration of the greater occipital nerve with local anesthetic with or without corticosteroids, followed by nerve ablation or stimulation. Occipital nerve stimulation gained more popularity as the technology improved and more pain physicians received training on interventional procedures.MethodsIn this manuscript, we are presenting our experience with ultrasound-guided implant of occipital nerve stimulators using peripheral nerve stimulator systems. After confirming appropriateness of treatment by a successful occipital nerve block (i.e., resulting in &gt;50% relief in patients’ pain intensity), we implanted five stimulator systems in three patients (two bilateral).ResultsWe followed these patients for an average of eight months, and the average pain reduction was ∼50%. We did not observe any adverse events during or immediately after surgery. One patient developed an adverse reaction to the adhesive of the battery transmitter, but it was not severe enough to stop her from using the stimulator.ConclusionsConsidering the ease of implant and minimal side effects, implant of peripheral nerve stimulators to stimulate the occipital nerve is a promising treatment modality for patients with chronic headache who present with features of occipital neuralgia. However, wider use of this treatment modality is subject to further studies.

5565 Background: The goal of this study was to determine the recurrence rates (R) of patients with grade 1 and 2 stage 1A and IB ovarian tumors treated with and without chemotherapy. Methods: We conducted a five-center retrospective study of patients with Stage 1A/B grade 1 and 2 ovarian carcinoma. All women underwent comprehensive staging including a minimum of unilateral salpingo-ophorectomy, unilateral pelvic and para-aortic lymphadenectomy, and omentectomy. Clear cell histologies were classified as grade 3 and excluded. The minimum cancer-free survivor follow-up was 3 years. Results: We identified 82 patients with Stage 1A/B grade 1 and 2 who met criteria for the study. The median age was 58 yrs (range 29 to 83) and the median follow-up was 5.3 yrs (range 3 to 11 yrs). The majority were of endometrioid histology (51), followed by mucinous (19), papillary serous (11), and mixed (1). Recurrences were of endometrioid (4), mucinous (1), or papillary serous (1) histology. For Stage 1A, overall recurrence rate was 9% (6/67). The overall recurrence rates for Stage 1A, grade1 tumors was 6% and among grade 2 tumors 12% (p=0.40). Among Stage 1A patients not treated with chemotherapy, there was a 7% (2/29) and 9.5% (2/21) recurrence rate for grade 1 and grade 2 tumors, respectively. For the grade 1 tumors, both patients are alive with disease at 3 and 5 yrs. For the grade 2 tumors, one is alive without evidence of disease at 7 yrs and the other died from disease at 4 yrs. Time to recurrence (TTR) was 2.3 yrs for grade 1 tumors and 2.6 yrs for grade 2 tumors. For Stage 1A patients treated with a platinum chemotherapy regimen, there were no recurrences (0/5) for grade 1 tumors and a 16% (2/12) recurrence rate for grade 2 tumors. Of the recurrences, one patient died from disease at 1.4 yrs and the other is alive with stable disease at 6 yrs. Time to recurrence was 2.85 yrs for grade 2 tumors. For grade 1 or 2, Stage 1A tumors, recurrence rates and time to recurrence were not effected by chemotherapy administration (R, p=0.55 and p=0.54, respectively; TTR, grade 2, p=0.85). No recurrences were observed in the 15 patients with Stage IB, grade 1 and 2 tumors. Conclusions: In comprehensively staged patients with Stage 1A/B, grade 1 and 2, low recurrence rates suggest adjuvant chemotherapy may not be indicated. No significant financial relationships to disclose.

Background Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF). Objectives The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF. Methods We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40–$59 999; $60–$74 999; $75–$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000). Results Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000. Conclusions We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF.