Search

Purpose To describe a patient with recurrent acute retinal necrosis (ARN), her treatment, and propose a possible pathophysiologic mechanism. Method Case report. Results A four-year-old girl presented elsewhere with bilateral ARN, was treated, but developed a retinal detachment in the left eye that failed vitrectomy surgery. She was referred 10 years later with recurrent ARN. The infection was difficult to get under control, but eventually responded to intravenous acyclovir and foscarnet. She was given laser photocoagulation. She was placed on oral valacyclovir prophylaxis and was disease free for 10 years at which point she decided to go to South America on vacation and stop her valacyclovir. Within a few days she developed a recurrence of ARN and flew back for treatment. She had discrete areas of retinal necrosis, vasculitis, and the laser photocoagulation lesions appeared to be ringed by a retinal change suggestive of retinitis. She responded to antiviral treatment, but developed a retinal detachment that was successfully treated. Her visual acuity was 20/20 six years later, and she was using antiviral prophylaxis. Conclusions Recurrent ARN can respond to aggressive treatment. Chorioretinal scars, such as from photocoagulation, may be potential sites of viral invasion during recurrences. Anti-viral prophylaxis may be indicated for at risk patients.

OBJECTIVE To determine whether long-term diet (D) and exercise (E) interventions, alone or in combination (D+E), have beneficial effects for older adults with knee osteoarthritis 3.5-years after the interventions end. METHODS This is a secondary analysis of a subset (N = 94) of the first 184 participants who had successfully completed the Intensive Diet and Exercise in Arthritis (IDEA) trial (N = 399) and who consented to follow-up testing. Participants were older (age ≥ 55 years), overweight and obese adults with radiographic and symptomatic knee osteoarthritis in at least one knee who completed 1.5-year D+E (N=27), D (N=35), or E (N=32) interventions and returned for 5-year follow-up testing an average of 3.5-years later. RESULTS During the 3.5-years following the interventions, weight regain in D+E and D was 5.9 kg (7%) and 3.1 kg (4%), respectively, with a 1 kg (1%) weight loss in E. Compared to baseline, weight (D+E, -3.7 kg, P=.0007; D, -5.8 kg, P

Epinephrine is a lifesaving medication to treat systemic allergic reactions including anaphylaxis. Epinephrine autoinjectors (EAIs) are expensive, not available everywhere in the world, and shortages can limit their access. Epinephrine prefilled syringes and epinephrine kits are lower-cost alternatives to EAIs. Advantages, disadvantages, and costs of available products are discussed and the socioeconomic factors impacting access to EAIs described. EAIs designed for infants also are discussed.

Delayed administration of epinephrine (adrenaline), the first-line and only effective treatment of a systemic allergic reaction (SAR) and anaphylaxis, is associated with increased mortality. However, epinephrine is underused because of a lack of consensus as to when it should be administered and an inappropriate fear of using epinephrine and potential adverse effects from the medication. The authors emphasize that SARs and anaphylaxis should be considered as a spectrum, and that affected individuals be educated on its safety and repeatedly given instructions as to when and how epinephrine should be used at the first symptoms or signs of SAR and anaphylaxis.

OBJECTIVE. To test the hypothesis that an altered gut microbiota (dysbiosis) plays a role in obesity-associated osteoarthritis (OA). METHODS. Stool and blood samples were collected from 92 participants with BMI ≥ 30 kg/m(2) recruited from the Johnston County Osteoarthritis Project. OA cases (n=50) had hand plus knee OA (Kellgren-Lawrence [KL] grade ≥2 or arthroplasty). Controls (N=42) had no hand OA and KL grade 0–1 knees. Compositional analysis of stool samples was carried out by 16S rRNA amplicon sequencing. Alpha and beta diversity and differences in taxa relative abundances were determined. Blood samples were used for multiplex cytokine analysis and measures of lipopolysaccharide (LPS) and LPS binding protein. Germ-free mice were gavaged with case or control pooled fecal samples and placed on a 40% fat, high sucrose diet for 40 weeks. Knee OA was evaluated histologically. RESULTS. OA cases were slightly older with more females and higher BMI, WOMAC pain and KL grades than controls. There were no significant differences in alpha or beta diversity or genus level composition between cases and controls. Cases had higher plasma levels of osteopontin (p=0.01) and serum LPS (p

Summary Objective The objective of this exploratory study was to determine if perturbations in gut microbial composition and the gut metabolome could be linked to individuals with obesity and osteoarthritis (OA). Methods Fecal samples were collected from obese individuals diagnosed with radiographic hand plus knee OA (n=59), defined as involvement of at least 3 joints across both hands, and a Kellgren-Lawrence (KL) grade 2-4 (or total knee replacement) in at least one knee. Controls (n=33) were without hand OA and with KL grade 0-1 knees. Fecal metabolomes were analyzed by a UHPLC/Q Exactive HFx mass spectrometer. Microbiome composition was determined in fecal samples by 16S ribosomal RNA amplicon sequencing (rRNA-seq). Stepwise logistic regression models were built to determine microbiome and/or metabolic characteristics of OA. Results Untargeted metabolomics analysis indicated that OA cases had significantly higher levels of di- and tripeptides and significant perturbations in microbial metabolites including propionic acid, indoles, and other tryptophan metabolites. Pathway analysis revealed several significantly perturbed pathways associated with OA including leukotriene metabolism, amino acid metabolism and fatty acid utilization. Logistic regression models selected metabolites associated with the gut microbiota and leaky gut syndrome as significant predictors of OA status, particularly when combined with the rRNA-seq data. Conclusions Adults with obesity and knee plus hand OA have distinct fecal metabolomes characterized by increased products of proteolysis, perturbations in leukotriene metabolism, and changes in microbial metabolites compared with controls. These metabolic perturbations indicate a possible role of dysregulated proteolysis in OA.

Summary Objective Biochemical joint changes contribute to posttraumatic osteoarthritis (PTOA) development following anterior cruciate ligament reconstruction (ACLR). The purpose of this longitudinal cohort study was to compare tibiofemoral cartilage composition between ACLR patients with different serum biochemical profiles. We hypothesized that profiles of increased inflammation (monocyte chemoattractant protein-1 [MCP-1]), type-II collagen turnover (type-II collagen breakdown [C2C]:synthesis [CPII]), matrix degradation (matrix metalloproteinase-3 [MMP-3] and cartilage oligomeric matrix protein [COMP]) preoperatively to 6-months post-ACLR would be associated with greater tibiofemoral cartilage T1ρ relaxation times 12-months post-ACLR. Design Serum was collected from 24 patients (46% female, 22.1 ± 4.2 years old, 24.0 ± 2.6 kg/m2 body mass index [BMI]) preoperatively (6.4 ± 3.6 days post injury) and 6-months post-ACLR. T1ρ Magnetic Resonance Imaging (MRI) was collected for medial and lateral tibiofemoral articular cartilage at 12-months post-ACLR. A k-means cluster analysis was used to identify profiles based on biomarker changes over time and T1ρ relaxation times were compared between cluster groups controlling for sex, age, BMI, concomitant injury (either meniscal or chondral pathology), and Marx Score. Results One cluster exhibited increases in MCP-1 and COMP while the other demonstrated decreases in MCP-1 and COMP preoperatively to 6-months post-ACLR. The cluster group with increases in MCP-1 and COMP demonstrated greater lateral tibial (adjusted mean difference = 3.88, 95% confidence intervals [1.97–5.78]) and femoral (adjusted mean difference = 12.71, 95% confidence intervals [0.41–23.81]) T1ρ relaxation times. Conclusion Profiles of increased serum levels of inflammation and matrix degradation markers preoperatively to 6-months post-ACLR are associated with MRI changes consistent with lesser lateral tibiofemoral cartilage proteoglycan density 12-months post-ACLR.

PURPOSE Diagnosis of AIDS lymphoma in low-resource settings, like South Africa, is often delayed, leaving patients with limited treatment options. In tuberculosis (TB) endemic regions, overlapping signs and symptoms often lead to diagnostic delays. Assessment of plasma cell-free DNA (cfDNA) by next-generation sequencing (NGS) may expedite the diagnosis of lymphoma but requires high-quality cfDNA. METHODS People living with HIV with newly diagnosed aggressive B-cell lymphoma and those with newly diagnosed TB seeking care at Chris Hani Baragwanath Academic Hospital and its surrounding clinics, in Soweto, South Africa, were enrolled in this study. Each participant provided a whole blood specimen collected in cell-stabilizing tubes. Quantity and quality of plasma cfDNA were assessed. NGS of the immunoglobulin heavy chain was performed. RESULTS Nine HIV+ patients with untreated lymphoma and eight HIV+ patients with TB, but without lymphoma, were enrolled. All cfDNA quantity and quality metrics were similar between the two groups, except that cfDNA accounted for a larger fraction of recovered plasma DNA in patients with lymphoma. The concentration of cfDNA in plasma also trended higher in patients with lymphoma. NGS of immunoglobulin heavy chain showed robust amplification of DNA, with large amplicons (> 250 bp) being more readily detected in patients with lymphoma. Clonal sequences were detected in five of nine patients with lymphoma, and none of the patients with TB. CONCLUSION This proof-of-principle study demonstrates that whole blood collected for cfDNA in a low-resource setting is suitable for sophisticated sequencing analyses, including clonal immunoglobulin NGS. The detection of clonal sequences in more than half of patients with lymphoma shows promise as a diagnostic marker that may be explored in future studies.

PURPOSE Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570 ). PATIENTS AND METHODS Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis. RESULTS Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation ( P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred. CONCLUSION nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

BACKGROUND Chemotherapy-induced oral mucositis can result in severe pain. Intravenous (IV) opioids are recommended, but management protocols vary. We systematically reviewed studies reporting IV opioid use for pain related to chemotherapy-induced severe oral mucositis in children and conducted a large single-center case series. METHODS Ovid MEDLINE, PubMed, and Cochrane databases were searched for studies reporting IV opioid duration and/or dose requirements for severe mucositis. Secondly, our pain service database was interrogated to describe episodes of opioid administration by patient- or nurse-controlled analgesia (PCA/NCA) for children with mucositis and cancer treatment-related pain. RESULTS Seventeen studies (six randomized trials, two prospective observational, three retrospective cohort, six retrospective case series) included IV opioid in 618 patients (age 0.3-22.3 years), but reported parameters varied. Mucositis severity and chemotherapy indication influenced IV opioid requirements, with duration ranging from 3 to 68 days and variable dose trajectories (hourly morphine or equivalent 0-97 mcg/kg/h). Our 7-year series included PCA/NCA for 364 episodes of severe mucositis (302 patients; age 0.12-17.2 years). Duration ranged from 1 to 107 days and dose requirements in the first 3 days from 1 to 110 mcg/kg/h morphine. Longer PCA/NCA duration was associated with: higher initial morphine requirements (ρ = 0.46 [95% CI 0.35, 0.57]); subsequent increased pain and need for ketamine co-analgesia (118/364 episodes with opioid/ketamine 13.9 [9.8-22.2] days vs opioid alone 6.0 [3.9-10.8] days; median [IQR]); but not with age or sex. CONCLUSIONS Management of severe mucositis pain can require prolonged IV opioid therapy. Individual and treatment-related variability in analgesic requirements highlight the need for regular review, titration, and management by specialist services.

Purpose To describe a transient positive scotoma and corresponding optical coherence tomography (OCT) structural and angiographic findings. Methods The patient was evaluated with a comprehensive ophthalmic examination to include OCT structural and angiographic imaging with two different instruments, the Zeiss Plex Elite and the Optovue RTVue XR Avanti. Results A 45-year-old man had a sudden onset of a positive scotoma in the visual field of the left eye. No abnormalities were noted by ophthalmoscopy or fundus photography. Optical coherence tomography angiography was performed to evaluate the macular perfusion status. With each instrument, a small hyperreflective area, 175 μm in diameter, was imaged in the inner nuclear layer. The OCT angiographic images suggested a small area of decreased perfusion in the deep capillary plexus. Except for the diminutive size, the lesion had an appearance suggestive of paracentral acute middle maculopathy. The symptoms lessened rapidly, and when examined 4 days later, the lesion was less hyperreflective. Two weeks after presentation, the positive scotoma was not present and there was no longer any hyperreflectivity in the inner nuclear layer. Conclusion Detection of the lesion was aided by using OCT angiographic scans, which have a much higher scan density than conventional OCT evaluations. The diminutive abnormality was consistent with a paracentral acute middle maculopathy lesion, although smaller than those previously reported. Micro-paracentral acute middle maculopathy lesions should be considered in the differential diagnosis of positive scotomas.

Introduction Treatment toxicities are common in older adults with cancer and consequently, treatment modifications are sometimes considered. We evaluated the prevalence and factors associated with treatment modifications at the first cycle in older patients receiving palliative systemic treatment. Methods Patients (n = 369) from the GAP 70+ Trial ( NCT02054741 ; PI: Mohile) usual care arm were included. Enrolled patients were aged 70+ with advanced cancer and ≥ 1 Geriatric Assessment (GA) domain impairment. Treatment modification was defined as any change from National Comprehensive Cancer Network guidelines or published clinical trials. Baseline variables included: 1) sociodemographic factors; 2) clinical variables; 3) GA domains; and 4) physician beliefs about life expectancy. Bivariate analyses and multivariable cluster-weighted generalized estimating equation model were conducted to assess the association of baseline variables with cycle 1 treatment modifications. Results Mean age was 77.2 years (range: 70–94); 62% had lung or gastrointestinal cancers, and 35% had treatment modifications at cycle 1. Increasing age by one year (odds ratio (OR) 1.1, 95% confidence interval [CI] 1.0–1.2), receipt of ≥second line of chemotherapy (OR 1.8, CI 1.1–3.0), functional impairment (OR 1.6, CI 1.1–2.3) and income ≤$50,000 (OR 1.7, CI 1.1–2.4) were independently associated with a higher likelihood of cycle 1 treatment modification. Conclusion Treatment modifications occurred in 35% of older adults with advanced cancer at cycle 1. Increasing age, receipt of ≥second line of chemotherapy, functional impairment, and lower income were independently associated with treatment modifications. These findings emphasize the need for evidence-based regimens in older adults with cancer and GA impairments.

Key Points Patients with APL treated with ATRA-ATO reported better long-term quality of life outcomes than patients treated with chemotherapy.Late comorbidity and health problem prevalence was similar between patients with APL previously treated with ATRA-ATO or chemotherapy., Visual Abstract, The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA chemotherapy. The median time since diagnosis of the study sample was 8 years. The 2 largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ = 8.4; 95% confidence interval [CI], 0.5 to 16.3) and dyspnea (Δ = −8.5; 95% CI, −16.4 to −0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ = 4.6; 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The 2 groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA chemotherapy. This study was registered at www.clinicaltrials.gov as #NCT03096496.

Purpose To describe pulsatile filling of dilated choroidal veins in the watershed zones and propose an alteration in choroidal perfusion pressure. Methods Retrospective review of original and digital subtraction indocyanine green angiography. Results We observed pulsating blood flow within choroidal vein segments in the posterior pole in 14 eyes (diagnosis of polypoidal choroidal vasculopathy, central serous chorioretinopathy, or neovascular age-related macular degeneration). Pulsating dye front was observed in single or multiple large choroidal vein(s) in a location that is ordinarily a watershed zone between the segmental areas of venous drainage, and vessels proximal and distal were often dilated. The pulsatile venous segments filled more slowly than the neighboring veins. In digital subtraction indocyanine green angiography, the dye front advanced in an incremental fashion or oscillated in a back-and-forth manner during several cardiac cycles during the filling of these larger choroidal veins. With indocyanine green angiography, we observed dilated choroidal veins that violated the macula watershed zone, localized bulbous dilations, and arteriole-over-vein crossings with apparent compression. Conclusion These novel observations suggest the pressure gradient for flow in the affected veins varied from low gradients when the filling was slow to high gradients when the filling was faster. The vessels violated the physiological watershed zone and seem to function as anastomoses between the ordinarily segmented venous drainage of the choroid. The dilated segments may result in pooling of venous blood as part of venous outflow abnormalities that may be operative in these diseases.

In the wake of the coronavirus pandemic, the critical limb ischemia (CLI) Global Society aims to develop improved clinical guidance that will inform better care standards to reduce tissue loss and amputations during and following the new SARS‐CoV‐2 era. This will include developing standards of practice, improve gaps in care, and design improved research protocols to study new chronic limb‐threatening ischemia treatment and diagnostic options. Following a round table discussion that identified hypotheses and suppositions the wound care community had during the SARS‐CoV‐2 pandemic, the CLI Global Society undertook a critical review of literature using PubMed to confirm or rebut these hypotheses, identify knowledge gaps, and analyse the findings in terms of what in wound care has changed due to the pandemic and what wound care providers need to do differently as a result of these changes. Evidence was graded using the Oxford Centre for Evidence‐Based Medicine scheme. The majority of hypotheses and related suppositions were confirmed, but there is noticeable heterogeneity, so the experiences reported herein are not universal for wound care providers and centres. Moreover, the effects of the dynamic pandemic vary over time in geographic areas. Wound care will unlikely return to prepandemic practices. Importantly, Levels 2–5 evidence reveals a paradigm shift in wound care towards a hybrid telemedicine and home healthcare model to keep patients at home to minimize the number of in‐person visits at clinics and hospitalizations, with the exception of severe cases such as chronic limb‐threatening ischemia. The use of telemedicine and home care will likely continue and improve in the postpandemic era.

PURPOSE In contrast to 5-azacytidine (5-aza), allogeneic stem-cell transplantation (HSCT) represents a curative treatment strategy for patients with myelodysplastic syndromes (MDS), but therapy-related mortality (TRM) limits its broader use in elderly patients with MDS. The present prospective multicenter study compared HSCT following 5-aza pretreatment with continuous 5-aza treatment in patients with higher-risk MDS age 55-70 years. METHODS One hundred ninety patients with a median age of 63 years were enrolled. Patients received 4-6 cycles of 5-aza followed by HLA-compatible HSCT after reduced-intensity conditioning or by continuous 5-aza if no donor was identified. RESULTS Twenty-eight patients did not fulfill inclusion criteria (n = 20), died (n = 2) withdrew informed consent (n = 5), or were excluded for an unknown reason (n = 1). 5-aza induction started in 162 patients, but only 108 (67%) were eligible for subsequent allocation to HSCT (n = 81) or continuation of 5-aza (n = 27) because of disease progression (n = 26), death (n = 12), or other reasons (n = 16). Seven percent died during 5-aza before treatment allocation. The cumulative incidence of TRM after HSCT at 1 year was 19%. The event-free survival and overall survival after 5-aza pretreatment and treatment allocation at 3 years were 34% (95% CI, 22 to 47) and 50% (95% CI, 39 to 61) after allograft and 0% and 32% (95% CI, 14 to 52) after continuous 5-aza treatment ( P < .0001 and P = .12), respectively. Fourteen patients progressing after continuous 5-aza received a salvage allograft from an alternative donor, and 43% were alive at last follow-up. CONCLUSION In older patients with MDS, reduced-intensity conditioning HSCT resulted in a significantly improved event-free survival in comparison with continuous 5-aza therapy. Bridging with 5-aza to HSCT before is associated with a considerable rate of dropouts because of progression, mortality, and adverse events.

Increased gallbladder wall thickness (GBWT) is a common finding. Reported causes include advanced chronic liver disease (ACLD), ascites and hypalbuminemia. GBWT is a marker for the prediction of esophageal varices. It remains unclear which of these factors is the decisive driver of GBWT. We aim to investigate whether there is a predominant factor associated with the GBWT.We enrolled 258 patients with ascites, hypalbuminemia and/or ACLD and 98 healthy volunteers that underwent abdominal ultrasound. Differences of mean GBWT in subgroups of patients with ACLD, ascites, and/or hypalbuminemia were analyzed. Correlation between various parameters and GBWT were calculated using multiple regression analysis.GBWT in patients with ACLD + ascites + hypalbuminemia (n = 59; 5.70 ± 2.05 mm) was pathologically increased compared to patients with hypalbuminemia + ascites without ACLD (n = 36; 2.14 ± 0.66 mm; p .001) and to patients with only hypalbuminemia (n = 76; 2.02 ± 0.80 mm; p .001). GBWT of patients with ACLD + hypalbuminemia (n = 30; 3.42 ± 1.52 mm) and with ACLD and normal albumin level were not different (n = 46; 3.10 ± 1.62 mm; p .999). Significant correlation was seen between GBWT and ACLD (r = .53; p .001) and ascites (r = .51; p .001) but not albumin level (r = .04; p = .510).We demonstrate that ACLD is predominantly associated with GBWT. In contrast to the current literature, serum albumin level appears not to be associated with pathological GBWT.

Purpose To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural OCT. Design Consensus meeting. Participants International group that included those with expertise in imaging and AMD basic science and histology, and those with Reading Center experience in AMD clinical trials. Methods As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA, risk of progression to GA, or both. Attendees undertook premeeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histologic features. Each of these different features were then discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees to refine the consensus definitions and descriptions further. Results Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypotransmission or hypertransmission), features frequently seen in eyes with atrophy (e.g., refractile drusen), and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). Conclusions An international consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

We investigated the incidence and predictors of failure to undergo the Fontan in children with hypoplastic left heart syndrome who survived superior cavopulmonary connection.The cohort consists of all patients with hypoplastic left heart syndrome who survived to hospital discharge after superior cavopulmonary connection between 1988 and 2017. The primary outcome was attrition, which was defined as death, nonsuitability for the Fontan, or cardiac transplantation before the Fontan. Subjects were excluded if they were awaiting the Fontan, were lost to follow-up, or underwent biventricular repair. The study period was divided into 4 eras based on changes in operative or medical management. Attrition was estimated with 95% confidence intervals, and predictors were identified using adjusted, logistic regression models.Of the 856 hospital survivors after superior cavopulmonary connection, 52 died, 7 were deemed unsuitable for Fontan, and 12 underwent or were awaiting heart transplant. Overall attrition was 8.3% (71/856). Attrition rate did not change significantly across eras. A best-fitting multiple logistic regression model was used, adjusting for superior cavopulmonary connection year and other influential covariates: right ventricle to pulmonary artery shunt at Norwood (P .01), total support time at superior cavopulmonary connection (P .01), atrioventricular valve reconstruction at superior cavopulmonary connection (P = .02), performance of other procedures at superior cavopulmonary connection (P = .01), and length of stay after superior cavopulmonary connection (P .01).In this study spanning more than 3 decades, 8.3% of children with hypoplastic left heart syndrome failed to undergo the Fontan after superior cavopulmonary connection. This attrition rate has not decreased over 30 years. Use of a right ventricle to pulmonary artery shunt at the Norwood procedure was associated with increased attrition.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

A panel of imaging experts was assembled to review neovascular age-related macular degeneration optical coherence tomography angiography descriptors published to date, and test agreement on use of these terms, which was found to be low. Optical coherence tomography angiography (OCTA) has been used to identify and characterize macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). 1 , 2 , 3 , 4 Many studies have explored OCTA morphological features of MNV that might serve as biomarkers to assess disease activity and response to treatment. 1 , 2 , 3 , 4 , 5 , 6 The proliferation of studies however has resulted in an OCTA terminology that has been variable and inconsistent. To address inconsistency of nomenclature and allow harmonization, a multidisciplinary panel of retinal imaging experts with a history of relevant research contributions to the field was assembled with the purpose of reviewing published terminology and to recommend a reduced list of key terms pertinent to OCTA. The group was called UNICORN, because of its ultimate goal of generating a UNIfied COmmentary of the committee of inteRnational experts on the nomenclature for Neovascular AMD in OCTA. In this report we describe the first steps, which included a review of OCTA descriptors of neovascular AMD (nAMD) published to date, and an exercise that tested agreement of these terms among retinal imaging experts. Prior to the first UNICORN meeting, a non-systematic review of the literature was performed, using the search terms “optical coherence tomography angiography” or “OCT angiography” or “OCT-A”, AND “neovascular macular degeneration” or “neovascular age-related macular degeneration” or “neovascular AMD” or “nAMD” or “wet age-related macular degeneration” or “wet AMD” or “wet ARMD”. A dictionary of OCTA descriptors relating to the features of MNV in AMD was generated and circulated to the panel.

Background Painful arthropathy is a long-term complication in patients with hemophilia (PWH), affecting mobility and quality of life. A major barrier for the appraisal of joint health is the absence of point-of-care (POC) imaging modalities to promptly identify and manage arthropathic changes. Accordingly, we developed the Joint tissue Activity and Damage Exam (JADE) POC musculoskeletal ultrasound (MSKUS) protocol. JADE is validated for haemophilic joint tissue recognition with high intra/inter-rater and inter-operator reliability. Aims Evaluate associations of JADE with clinical (Hemophilia Joint Health Score, [HJHS]) and functional (total arc [combined flexion and extension range of motion [ROM]]) parameters. Methodology In this multi-centre prospective study, we recruited PWH A or B with at least one arthropathic joint. We evaluated joint health (both elbows, knees, and ankles) by comparing JADE measurements (soft tissue and cartilage thickness, and osteochondral alterations) with HJHS and total arc. Results Of 44 PWH, most had hemophilia A (35/44), were severe (36/44) and had a median age of 36 years. Increasing HJHSs and declining total arc, indicating worsening arthropathy, were associated with JADE measurements in the expected direction, including (1) increasing length of osteochondral alterations, (2) diminished cartilage thickness, and (3) greater soft tissue expansion. The ankles had the highest proportion of joints without measurable (missing) cartilage. In multivariable models MSKUS measurements explained 68% and 71% of the variation in HJHS and total arc respectively for the elbow, 55% and 29% respectively for the knee, and 50% and 73% for the ankle. Conclusions This study highlights the associations of direct intra-articular ultrasonography measurements using the JADE protocol with clinical and functional parameters. Our findings underscore the clinical value of POC MSKUS using the JADE protocol as a complementary instrument for the diagnosis and management of haemophilic arthropathy.

BACKGROUND: In 2018, influenza and pneumonia was the eighth leading cause of death in the United States. Since 1950, non-Hispanic blacks (NHBs) have experienced higher rates of mortality than non-Hispanic whites (NHWs). Previous studies have revealed geographic variation in mortality rates by race. The identification of areas with the greatest disparity in influenza and pneumonia mortality may assist policymakers in the allocation of resources, including for the coronavirus disease 2019 pandemic. RESEARCH QUESTION: Does geographic variation in racial disparity in influenza and pneumonia mortality exist? STUDY DESIGN AND METHODS: The Centers for Disease Control and Prevention database for Multiple Cause of Death between 1999 and 2018 for NHB and NHW decedents ≥ 25 years of age with a Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems code for influenza (J09-J11) and pneumonia (J12-J18) was used. Age-adjusted mortality rates (AAMRs) with 95% CIs were computed by race for Health & Human Services (HHS) regions and urbanization in NHBs and NHWs. RESULTS: In 1999 through 2018, there were 540,476 deaths among NHBs and NHWs 25 to 84 years of age. AAMRs were higher in NHBs than NHWs in each age group and in seven of 10 HHS regions. The greatest disparity was in HHS regions 2 (New York and New Jersey) and 9 (Arizona, California, Hawaii, and Nevada). In HHS region 2, NHBs (24.6; 95% CI, 24.1-25.1) were more likely to die than NHWs (15.7; 95% CI, 15.6-15.9). Similarly, in region 9, NHBs (23.2; 95% CI, 22.7-23.8) had higher mortality than NHWs (16.1; 95% CI, 15.9-16.2). Within these regions, disparities were greatest in the core of major metropolitan areas. A very high AAMR in NHBs was noted in large, central metropolitan areas of region 2: 28.2 (95% CI, 27.6-28.9). INTERPRETATION: In 1999 through 2018, the NHB-NHW disparity in AAMRs from influenza and pneumonia was greatest in central metropolitan areas of HHS regions 2 and 9.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

Background Inconsistent evidence suggests that use of certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), in patients using oral anticoagulants (OACs) might be associated with an elevated risk of bleeding. Objective This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy. Patients and methods A total of 30,336 AF patients (mean age 72.2 years; 54% female) on OAC therapy that started antidepressant treatment were identified from the Truven Health Analytics MarketScan Commercial and Medicare Databases for the period 2007–2015. Exposure was defined as filling a prescription for antidepressant, and categorized as SSRI, serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants (TCAs), or other antidepressants. The primary outcome was incident hospitalized bleeding. Associations of antidepressant type with bleeding were assessed calculating hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted Cox models in pairwise propensity score-matched cohorts. Results During a mean follow-up of 21 months, we identified 1612 bleeding episodes. In pairwise comparisons, SSRI use was associated with an increased risk of bleeding when compared to most other antidepressants (HR 1.22, 95% CI 0.96–1.54 vs SNRI; HR 1.10, 95% CI 0.90–1.35 vs SRI; HR 1.03, 95% CI 0.82–1.30 vs TCA). SNRI use was associated with the lowest bleeding risk. Results did not differ by OAC type, age, and sex. Conclusions Among AF patients on OAC initiating antidepressants, risk of bleeding varied across antidepressant type. This information can inform treatment choices among patients receiving OAC. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00258-3.

Osteoporosis is a silent disorder with dire consequences, and glucocorticoid use remains the most common iatrogenic cause illustrated by the fact that 30% to 50% of subjects on such long-term therapy experience fractures (Oimomi M, Nakamichi T, Ohara T, Sakai M, Igaki N, Hata F, et al. Fructose-related glycation. Diabetes Res Clin Pract 1989;7:137-9; Reid IR. Glucocorticoid osteoporosis--mechanisms and management. Eur J Endocrinol 1997;137:209-17). By directly affecting bone quality while actively used, glucocorticoids increase the risk of fracture that is independent of a subject's bone density status at the time (Weinstein RS. True strength. J Bone Miner Res 2000;15:621-5). A large number of subjects seen in an allergy and immunology clinic have asthma, chronic rhinosinusitis, or other chronic inflammatory diseases, necessitating the use of these medications and placing them at higher risk for this disease. Data on the effects of both oral and inhaled glucocorticoids on fracture risk are presented. This review concretizes the importance of osteoporosis, its pathophysiology, and provides practical guidelines to prevent and treat it. Management recommendations are tailored to 2 different age groups. The first group consists of children, adolescents, and adults 40 years or younger with a focus on attaining peak bone mass. The second group consists of adults 40 years or older where the use of imaging modalities and Fracture Risk Assessment Tool scores helps triage subjects into fracture risk categories. Those at moderate to high risk require bone-sparing medications. Universal preventive measures for both groups are reviewed. Complicated and severe cases may need additional expertise by an endocrinologist or rheumatologist.

The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.

OBJECTIVE To apply a precision medicine approach to determine the optimal treatment regime for participants in an exercise (E), dietary weight loss (D), and D + E trial for knee osteoarthritis that would maximize their expected outcomes. METHODS Using data from 343 participants of the Intensive Diet and Exercise for Arthritis (IDEA) trial, we applied 24 machine-learning models to develop individualized treatment rules on 7 outcomes: Short Form 36 physical component score, weight loss, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain/function/stiffness scores, compressive force, and interleukin-6 level. The optimal model was selected based on jackknife value function estimates that indicate improvement in the outcomes if future participants follow the estimated decision rule compared to the optimal single, fixed treatment model. RESULTS Multiple outcome random forest was the optimal model for the WOMAC outcomes. For the other outcomes, list-based models were optimal. For example, the estimated optimal decision rule for weight loss indicated assigning the D + E intervention to participants with baseline weight not exceeding 109.35 kg and waist circumference above 90.25 cm, and assigning D to all other participants except those with a history of a heart attack. If applied to future participants, the optimal rule for weight loss is estimated to increase average weight loss to 11.2 kg at 18 months, contrasted with 9.8 kg if all participants received D + E (P = 0.01). CONCLUSION The precision medicine models supported the overall findings from IDEA that the D + E intervention was optimal for most participants, but there was evidence that a subgroup of participants would likely benefit more from diet alone for 2 outcomes.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04492-1.

PURPOSE Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell–like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell–like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

Background and Purpose: The mechanisms of brain damage during ultra-early subarachnoid hemorrhage (SAH) have not been well studied. The current study examined the SAH-induced hyperacute brain damage at 4 hours using magnetic resonance imaging and brain histology in a mouse model. Methods: SAH was induced by endovascular perforation in adult mice. First, adult male wild-type mice underwent magnetic resonance imaging T2 and T2* 4 hours after an endovascular perforation or a sham operation and were euthanized to assess brain histology. Second, male and female adult lipocalin-2 knockout mice had SAH. All animals underwent magnetic resonance imaging at 4 hours, and the brains were harvested for brain histology. Results: T2* hypointensity vessels were observed in the brain 4 hours after SAH in male wild-type mice. The numbers of T2*-positive vessels were significantly higher in SAH brains than in sham-operated mice. Brain histology showed thrombosis and erythrocyte plugs in the T2*-positive cerebral vessels which may be venules. The number of T2*-positive vessels correlated with SAH grade and the presence of T2 lesions. Brain thrombosis was also accompanied by albumin leakage and neuronal injury. LCN2 deficient male mice had lower numbers of T2*-positive vessels after SAH compared with wild-type male mice. Conclusions: SAH causes ultra-early brain vessel thrombosis that can be detected by T2* gradient-echo sequence at 4 hours after SAH. LCN2 deficiency decreased the number of T2*-positive vessels.

PURPOSE To longitudinally characterize structural/angiographic findings of retinal-choroidal anastomosis (RCA) in macular telangiectasia Type 2 (MacTel2). METHODS A combined retrospective/prospective review of patients with MacTel2 with >2 visits and >2 months follow-up, including examination, fundus photography, fluorescein angiography, spectral-domain optical coherence tomography, and projection-resolved optical coherence tomography angiography. RESULTS There were 24 eyes of 12 patients with a mean age of 61.1 (±7.3 [SD]) years and median follow-up of 447 (range 81-1,511) days. There were five eyes diagnosed with new RCA after not having any previously. Retinal-choroidal anastomosis was diagnosed in 8 (33%) eyes initially and eventually 13 (54%). In the eight eyes initially diagnosed with RCA, the number of RCAs and outer retinal hyperrflective lesions increased over the follow-up. The RCAs were found in clusters, generally temporal to the fovea. Retinal-choroidal anastomosis was uniformly associated with complete retinal subsidence, defined as the loss of outer nuclear layer substance such that the middle retinal layers sank down toward the retinal pigment epithelium (RPE), and was also present in each case. Each RCA colocalized with a region of hyperreflectivity, previously termed an outer retinal hyperreflective lesion. There was a lack of fluorescein leakage, lipid, hemorrhage, or any structural correlates with fluid exudation, and no signs of subretinal/subretinal pigment epithelium neovascularization. CONCLUSION De novo RCA development seems to be associated with retinal subsidence, and after RCAs form, they increase in number and topographic distribution over time. Initially after formation, there was no sign of exudation. These data suggest the descent of the deep capillary plexus occurs with RCA, devoid of subretinal/subretinal pigment epithelium neovascularization in MacTel2.

We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p

Study Design: Retrospective chart review.Purpose: This study compared the clinical and radiographic outcomes of patients treated with expandable and static interbody spacers following minimally invasive lateral lumbar interbody fusion (MIS-LLIF) with 12-month follow-up.Overview of Literature: A common surgical option for the treatment of degenerative disk disease (DDD) is MIS-LLIF using static or expandable spacers to restore disk height (DH), neuroforaminal height (NH), and segmental lordosis. Static spacers may require excessive trialing and aggressive impaction, potentially leading to endplate disruption and subsidence. Expandable spacers allow for in situ expansion to help address complications associated with static spacers.Methods: This is an Institutional Review Board-exempt review of 69 patients (static, n=32; expandable, n=37) diagnosed with DDD who underwent MIS-LLIF at 1–2 contiguous level(s) using static or expandable spacers. Radiographic and clinical outcomes were collected and compared at pre- and postoperative time points up to 12 months.Results: The expandable group had a significantly higher mean change in Visual Analog Scale (VAS) scores at 6 weeks, 6 months, and 12 months vs. static (∆VAS at 12 months: expandable, 6.7±1.3; static, 5.1±2.6). Mean improvement of Oswestry Disability Index (ODI) scores at 3, 6, and 12 months were significantly better for the expandable group vs. static (∆ODI at 12 months: expandable, 63.2±13.2; static, 29.8±23.4). Mean DH and NH significantly increased at final follow-up for both groups, with no significant difference in DH improvement between groups. The expandable mean NH improvement at 6 weeks and 6 months was significantly greater vs. static. Segmental lordosis significantly improved in the expandable group at all time intervals vs static. Subsidence rate at 12 months was significantly lower in the expandable group (1/46, 2.2%) vs. static (12/37, 32.4%).Conclusions: Expandable spacers resulted in a significantly lower subsidence rate, improve segmental lordosis, and VAS and ODI outcomes at 12 months vs. static.

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38–76); median number of prior systemic therapies was 5(range 0–10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation. Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).

Background The transradial access (TRA) is rapidly gaining popularity for neuroendovascular procedures as there is strong evidence for its benefits compared to the traditional transfemoral access (TFA). However, the transition to TRA bears some challenges including optimization of the interventional suite set-up and workflow as well as its impact on fellowship training. Objective To compare the learning curves of TFA and TRA for diagnostic cerebral angiograms in neuroendovascular fellowship training. Methods We prospectively collected diagnostic angiogram procedural data on the performance of 2 neuroendovascular fellows with no prior endovascular experience who trained at our institution from July 2018 until June 2019. Metrics for operator proficiency were minutes of fluoroscopy time, procedure time, and volume of contrast used. Results A total of 293 diagnostic angiograms were included in the analysis. Of those, 57.7% were TRA and 42.3% were TFA. The median contrast dose was 60 cc, and the median radiation dose was 14 000 μGy. The overall complication rate was 1.4% consisting of 2 groin hematomas, 1 wrist hematoma, and 1 access-site infection using TFA. The crossover rate to TFA was 2.1%. Proficiency was achieved after 60 femoral and 95 radial cases based on fluoroscopy time, 52 femoral and 77 radial cases based on procedure time, and 53 femoral and 64 radial cases based on contrast volume. Conclusion Our study demonstrates that the use of TRA can be safely incorporated into neuroendovascular training without causing an increase in complications or significantly prolonging procedure time or contrast use.

PURPOSE OF REVIEW: Cancer Cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers, and potential therapies. RECENT FINDINGS: Both in mice and human, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in pre-cachexia. Inflammatory pathways, mitochondrial dysfunction, and gut microbiota have recently been studied to play an important role in muscle fatigue in pre-clinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. SUMMARY: Heightened inflammation within muscle, altered muscle function, and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

Weight loss is a physical representation of the impact of cancer on the body and loss of control. For patients with esophagogastric cancer (EGC), loss of appetite and weight loss lead to reduced quality of life and poor clinical outcomes. In this issue of JNCCN, Dijksterhuis et al(1) present data evaluating the prevalence of pretreatment cachexia, association of pretreatment cachexia with survival, and early integration of dietitians in the care of patients with EGC. This 3-year Dutch study included >400 patients with EGC across all stages. Half of the patients had cachexia at presentation, which was associated with decreased survival. In our opinion, the key finding of this study is that 3-month median weight loss was lower for the patients referred to a dietitian at diagnosis (0% vs 2%; P=.047).(1) These findings suggest that early involvement of dietitians may slow or stabilize weight loss in the care of patients with EGC and highlight 3 key take-away points for practicing oncologists: (1) clarify the difference between weight loss and cachexia, (2) identify precachexia and (3) refer early to dietitians.

To evaluate the clinical and radiological outcome, sum of acetabular and femoral cartilage thickness, and rate of failure in the midterm after arthroscopic treatment of femoroacetabular impingement (FAI) syndrome with femoral osteoplasty, labral repair, and rim trimming without labral detachment.This retrospective case series included patients with FAI syndrome who had undergone hip arthroscopy from January 2009 to December 2010 by a single surgeon, with a minimum follow-up of 55 months. Data from patients who had undergone arthroscopic hip procedures with labral repair, rim trimming, and femoral osteoplasty were analyzed pre- and postoperatively. Clinical outcome (nonarthritic hip score [NAHS], Short Form 36 [SF-36]), range of motion, progression of osteoarthritis (Tönnis grade), radiological parameters (α angle, lateral center-edge angle [LCEA], Tönnis angle), femoral and acetabular cartilage thickness (using magnetic resonance imaging [MRI]), and intraoperative findings were evaluated.Of 148 hip arthroscopies performed, 97 included rim trimming, labral refixation, and femoral osteoplasty. Ten cases were lost to follow-up, leaving 87 hips. Arthroscopic revision was performed on 4 hips and total hip replacement on 4 hips, and 1 hip underwent both arthroscopic revision and total hip replacement. Excluding these 9 cases of revision, for which follow-up was not possible (retrospective study), the remaining 78 hips were followed up for a minimum of 55 months (77 ± 11.4, mean ± SD; range 55 to 124). Mean NAHS (65 to 88, P.001), SF-36 physical subscale (65 to 85, P.001), and the numerical pain rating scale (NRS) (5 to 1, P.001) improved significantly. Outcome scores of minimal clinical importance (NAHS) were achieved in 67.6% of the patients. Mean range of movement improved significantly in flexion (109 to 122, P .001) and internal rotation (10 to 22.7, P.001). NAHS was positively associated with flexion of the hip postoperatively (r = 0.307, P = .011). In 16 cases, microfracture was performed (15 acetabular and 1 femoral). Preoperative α angles (anteroposterior and modified Dunn) were significantly higher in this cohort (P.001, 95% confidence interval 8.9 to 25.2, P = .001). Twenty hips (28 %) progressed to worse Tönnis grades. Initial Tönnis grades were grade 0, 38; grade 1, 48; grade 2, 8. Pre- or postoperative Tönnis grades did not show any correlation with pre- or postoperative NAHS and NRS. MRI measurements at the latest follow-up (69 patients) of the femoral and acetabular cartilage thickness did not reveal any significant reduction at the 12 o'clock position.Arthroscopic cam resection, rim trimming, and labral repair without detachment of the labrum provides good or excellent outcome in 77.1% of hips based on NAHS in the midterm. Higher range of motion in flexion is associated with higher NAHS postoperatively. Arthroscopic cam resection, rim trimming and labral repair without detachment of the labrum is a successful method for the treatment of FAI syndrome in the midterm.IV, retrospective case series.

Total elbow arthroplasty (TEA) is associated with a relatively high complication rate, and exceptionally catastrophic complications might lead to amputation. The purpose of this study was to determine the incidence and aetiology of amputation performed at our institution in upper extremity limbs with a prior TEA. Between 1973 and 2018, 1906 consecutive TEAs were performed at our institution. Upper extremity amputation was performed in seven (0.36%) elbows with five transhumeral amputations and two shoulder disarticulations. The group consisted of five females and two males with a mean age of 64 years (range, 37–80). The index TEA had been performed for rheumatoid arthritis (n = 2), rheumatoid arthritis with acute fracture (n = 2), radiation associated nonunion (n = 2), and metastatic cancer (n = 1). Mean follow-up after amputation was three years (range, 3 months–5 years). Mean time between amputation and TEA was 5 years (range, 2 months–13 years). The indications for amputation included uncontrolled deep infection in six (86%) elbows and tumor recurrence in one (14%) elbow. Only one elbow (14%) was fitted with a prosthesis. Six (86%) patients died at a mean of three years (range, 3 months–5 years) after amputation. The results of this study highlight a low incidence of amputation after TEA. Most amputations were the direct result of TEA complications, with infection being the most common cause of amputation. Outcomes after amputation are concerning, with poor overall survival and few patients being fit for a prosthesis.

Richard F Pollock,1 Gorden Muduma2 1Health Economics and Outcomes Research, Covalence Research Ltd, London, UK; 2International Market Access, Pharmacosmos A/S, Holbæk, DenmarkCorrespondence: Richard F PollockHealth Economics and Outcomes Research, Covalence Research Ltd, 51 Hayes Grove, London SE22 8DF, UKTel +44 20 8638 6525Email pollock@covalence-research.comBackground and Aims: Iron deficiency anemia (IDA) is a common sequela of inflammatory bowel disease (IBD), arising from the combined effects of gastrointestinal blood loss and reduced iron absorption. Given this, intravenous (IV) iron should be considered as the first-line treatment in patients with clinically active IBD. The present study evaluated the budget impact of administering IV iron with ferric derisomaltose (FDI) versus ferric carboxymaltose (FCM) in patients with IDA and IBD in Norway, Sweden, and Finland.Methods: A cohort level model of iron need was developed using a bivariate distribution of hemoglobin and bodyweight based on observational data from a multi-country Scandinavian study of patients with IDA and IBD. The base case analysis was conducted over 5 years in patients with IDA with mean bodyweight of 75.4 kg (SD 17.5 kg) and hemoglobin levels of 10.77 g/dL (SD 1.43 g/dL). Infusion costs were modeled using diagnosis-related groups. Sensitivity analyses were performed around different patient characteristics, care settings, and retreatment frequencies, and probabilistic sensitivity analyses were conducted.Results: Using FDI required 1.25 infusions to correct the mean iron deficit, compared with 1.64 infusions with FCM. In Norway, the per-patient cost of iron replenishment over 5 years was estimated to be NOK20,767 with FCM versus NOK15,799 with FDI, reflecting a cost saving of NOK4,968 or 23.9%. In Finland, costs were projected to decrease from EUR3075 with FCM to EUR2339 with FDI, reflecting a cost saving of EUR736 per patient. In Sweden, costs decreased from SEK27,760 with FCM to SEK21,119 with FDI.Conclusion: Using FDI in place of FCM resulted in a substantial reduction in the number of infusions required to correct iron deficits in patients with IDA and IBD. The reduction in infusions was accompanied by substantial cost savings relative to FCM over 5 years across all three Nordic countries evaluated.Keywords: iron, administration, intravenous, iron deficiency anemia, inflammatory bowel diseases, Sweden, Norway, Finland

Every infant, child, and adolescent will experience pain at times throughout their life. Childhood pain ranges from acute to chronic, and includes procedural, disease-related, breakthrough, and other types of pain. Despite its ubiquity, pain is a major challenge for individuals, families, health-care professionals, and societies. As a private mental experience, pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood, including continued chronic pain, disability, and distress. This undertreatment of pain should not continue, as there are available tools, expertise, and evidence to provide better treatment for childhood pain.

Introduction Glucocorticoids (GCs) are the primary treatment for nephrotic syndrome (NS), although ∼10% to 20% of children develop steroid-resistant NS (SRNS). Unfortunately, there are no validated biomarkers able to predict SRNS at initial disease presentation. We hypothesized that a plasma cytokine panel could predict SRNS at disease presentation, and identify potential pathways regulating SRNS pathogenesis. Methods Paired plasma samples were collected from 26 children with steroid-sensitive NS (SSNS) and 14 with SRNS at NS presentation and after ∼7 weeks of GC therapy, when SSNS versus SRNS was clinically determined. Plasma cytokine profiling was performed with a panel of 27 cytokines. Results We identified 13 cytokines significantly different in Pretreatment SSNS versus SRNS samples. Statistical modeling identified a cytokine panel (interleukin [IL]-7, IL-9, monocyte chemoattractant protein–1 [MCP-1]) able to discriminate between SSNS and SRNS at disease presentation (receiver operating characteristic [ROC] value = 0.846; sensitivity = 0.643; specificity = 0.846). Furthermore, GC treatment resulted in significant decreases in plasma interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), IL-7, IL-13, and IL-5 in both SSNS and SRNS patients. Conclusions These studies suggest that initial GC treatment of NS reduces the plasma cytokines secreted by both CD4+ TH1 cells and TH2 cells, as well as CD8+ T cells. Importantly, a panel of 3 cytokines (IL-7, IL-9, and MCP-1) was able to predict SRNS prior to GC treatment at disease presentation. Although these findings will benefit from validation in a larger cohort, the ability to identify SRNS at disease presentation could greatly benefit patients by enabling both avoidance of unnecessary GC-induced toxicity and earlier transition to more effective alternative treatments., Graphical abstract

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

BACKGROUND: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. METHODS: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. RESULTS: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). CONCLUSIONS: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization. ispartof: CURRENT ONCOLOGY vol:27 issue:6 pages:E596-E606 ispartof: location:Switzerland status: published

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.