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Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Knee osteoarthritis is one of the most common causes of chronic pain worldwide, and several animal models have been developed to investigate disease mechanisms and treatments to combat associated morbidities. Here we describe a novel method for assessment of locomotor pain behavior in Yucatan swine. We used monosodium iodoacetate (MIA) to induce osteoarthritis in the hindlimb knee, and then conducted live observation, quantitative gait analysis, and quantitative weight-bearing stance analysis. We used these methods to test the hypothesis that locomotor pain behaviors after osteoarthritis induction would be detected by multiparameter quantitation for at least 12 wk in a novel large animal model of osteoarthritis. MIA-induced knee osteoarthritis produced lameness quantifiable by all measurement techniques, with onset at 2 to 4 wk and persistence until the conclusion of the study at 12 wk. Both live observation and gait analysis of kinetic parameters identified mild and moderate osteoarthritis phenotypes corresponding to a binary dose relationship. Quantitative stance analysis demonstrated the greatest sensitivity, discriminating between mild osteoarthritis states induced by 1.2 and 4.0 mg MIA, with stability of expression for as long as 12 wk. The multiparameter quantitation used in our study allowed rejection of the null hypothesis. This large animal model of quantitative locomotor pain resulting from MIA-induced osteoarthritis may support the assessment of new analgesic strategies for human knee osteoarthritis.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

Background Although rituximab‐based high‐dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto‐HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab‐based conditioning on auto‐HCT outcomes in patients who have DLBCL. Methods Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto‐HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab‐containing chemoimmunotherapy and had chemosensitive disease pre‐HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). Results The study cohort was divided into 2 groups: BEAM (n = 667) and R‐BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS ( P = .83) or progression‐free survival (PFS) ( P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse ( P = .15) or nonrelapse mortality ( P = .12) was observed. Variables independently associated with lower OS included older age at auto‐HCT ( P < .001), absence of CR at auto‐HCT ( P < .001) and early chemoimmunotherapy failure ( P < .001). Older age ( P < .0002) and non‐CR pre‐HCT ( P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. Conclusion In this large registry analysis of DLBCL patients undergoing auto‐HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto‐HCT, and early chemoimmunotherapy failure were associated with inferior survival.

PURPOSEThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.PATIENTS AND METHODSI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.RESULTSMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).CONCLUSIONThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Objective The aim of this study was to grade cartilage damage in a swine model of osteoarthritis using a whole-body photon-counting detector (PCD) CT. Materials and Methods A multienergy phantom containing gadolinium (Gd) (2, 4, 8, and 16 mg/mL) and hydroxyapatite (200 and 400 mg/cc) was scanned using a PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs, D50 reconstruction kernel) to serve as calibration for material decomposition and to assess quantification accuracy. Osteoarthritis was induced in Yucatan miniswine (n = 8) using 1.2 mg monoiodoacetate (MIA) injected into a randomized knee, whereas the contralateral control knee received saline. Twenty-one days later, a contrast bolus (gadoterate meglumine, 4 mL/knee) was intra-articularly administered into both knees. The knees were simultaneously scanned on the PCD-CT system (48 × 0.25 mm collimation, 80 kV, 800 mAs). Multienergy images were reconstructed with a sharp “V71” kernel and a quantitative “D50” kernel. Image denoising was applied to the V71 images before grading cartilage damage, and an iterative material decomposition technique was applied to D50 images to generate the Gd maps. Two radiologists blinded to the knee injection status graded the cartilage integrity based on a modified International Cartilage Repair Society scoring system. Histology was performed on excised cartilage using methylene blue/basic fuchsin. Statistical analysis of grade distribution was performed using an exact test of omnibus symmetry with P < 0.05 considered significant. Results Material decomposed images from the multienergy phantom scan showed delineation and quantification of Gd and hydroxyapatite with a root-mean-squared error of 0.3 mg/mL and 18.4 mg/cc, respectively. In the animal cohort, the radiologists reported chondromalacia in the MIA knees with International Cartilage Repair Society scores ranging from grade 1 (cartilage heterogeneity, n = 4 knees) to grade 3 (up to 100% cartilage loss, n = 4 knees). Grade 1 was characterized by cartilage heterogeneity and increased joint space in the patellofemoral compartment, whereas grade 3 was characterized by cartilage erosion and bone-on-bone articulation in the patellofemoral compartment. All control knees were scored as grade 0 (normal cartilage). Significant difference (P = 0.004) was observed in the grade distribution between the MIA and control knees. Gross examination of the excised knees showed cartilage lesions in the grade 3 MIA knees. The Gd maps from material decomposition showed lower contrast levels in the joint space of the MIA knee compared with the contralateral control knee due to joint effusion. Histology revealed chondrocyte loss in the MIA knee cartilage confirming the chondrotoxic effects of MIA on cartilage matrix. Conclusions We demonstrated a high-resolution and quantitative PCD-CT arthrography technique for grading cartilage damage in a large animal model of osteoarthritis. Photon-counting detector CT offers simultaneous high-resolution and multienergy imaging capabilities that allowed morphological assessment of cartilage loss and quantification of contrast levels in the joint as a marker of joint disease. Cartilage damage in the MIA knees was graded using PCD-CT images, and the image-based findings were further confirmed using histology and gross examination of the excised knees.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

ABSTRACT Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54-year-old female with biallelic mutation of ENPP1, c.323G &gt; T; p.Cys108Phe and c.1441C &gt; T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima-media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C-terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.