Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. MethodsWe did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. FindingsWe included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58•0%) were male. Median gestational age at birth was 38 weeks (IQR 36-39) and median bodyweight at presentation was 2•8 kg (2•3-3•3). Mortality among all patients was 37 (39•8%) of 93 in low-income countries, 583 (20•4%) of 2860 in middle-income countries, and 50 (5•6%) of 896 in high-income countries (p<0•0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90•0%] of ten in lowincome countries, 97 [31•9%] of 304 in middle-income countries, and two [1•4%] of 139 in high-income countries; p≤0•0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2•78 [95% CI 1•88-4•11], p<0•0001; middle-income vs high-income countries, 2•11 [1•59-2•79], p<0•0001), sepsis at presentation (1•20 [1•04-1•40], p=0•016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4-5 vs ASA 1-2, 1•82 [1•40-2•35], p<0•0001; ASA 3 vs ASA 1-2, 1•58, [1•30-1•92], p<0•0001]), surgical safety checklist not used (1•39 [1•02-1•90], p=0•035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1•96, [1•4...

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score matched control group of 58 patients without CKS1B amplification that were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control group. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pre-transplant therapy and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion [del(13q)]; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control group were 15.0 months and 33.0 months (p= 0.002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control group were 62% and 91% (p=0.02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities, and a shorter PFS and OS after an auto-HCT.

With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9). On multivariate analysis a low β-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT.

Background Hepatitis B core antibody (HBcAb) seropositivity has been associated with a higher rate of hepatitis B virus (HBV) reactivation after chemotherapy, even in patients who are hepatitis B surface antigen (HBsAg) negative. We evaluated the incidence of hepatitis B reactivation and liver toxicity in patients with multiple myeloma (MM) who received high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. Methods We identified 107 MM patients with resolved HBV infection (HBcAb positive, HBsAg negative) and 125 patients with negative HBV serology (control) who were matched for age, time of auto-HCT, disease status and preparative regimen. Both groups received HDC and auto-HCT between 1991 and 2013. Primary endpoints were: 1) HBV reactivation defined as HBsAg positivity or ≥10-fold increase in HBV DNA; 2) hepatotoxicity, as defined in NCI CTCv3.0. Results Approximately 70% in each group received melphalan alone as preparative regimen. In the resolved HBV infection group, 52 patients (49%) were Hepatitis B surface antibody (HBsAb) positive, and 24 (22%) had detectable HBV DNA prior to auto-HCT. Serum HBV DNA level was <100 IU/m in 22 patients, and <300 IU/ml in 2 patients. Hepatitis B e antigen (HBeAg) was non-reactive in all 4 patients evaluated prior to auto-HCT. Only 1 patient with resolved HBV infection received pre-emptive antiviral therapy with Lamivudine, while 4 patients received Lamivudine (3) or Tenofovir (1) at reactivation for a median duration of 1 year. HBV reactivation was seen in 7 of 107 (6.5%) patients in the resolved HBV group. There was a ≥10-fold increase in HBV DNA in 5 of 7 patients with HBV reactivation, and 2 of 7 also became positive for HBeAg. Median time to HBV reactivation from auto-HCT was 16 months. The cumulative incidence of grade 2 or more hepatotoxicity in resolved HBV infection and the control groups was 30% and 22%, respectively (hazard ratio [HR] 1.3; 95% confidence interval [CI], 0.7–2.3; P = 0.4). There was a trend for higher NRM in the control group at 1 year 7% vs 1%, with a HR of 0.15 (95% CI 0.02–1.2, P = 0.08) and at 2 years 8% vs 1% with a HR of 0.13 (95% CI 0.02–1.1, P= 0.06) after auto-HCT. With a median follow up of 18 and 35 months in resolved HBV infection vs. control groups, the median progression free survival was 21 and 18 months (p=0.5), respectively. Median overall survival in resolved HBV infection and control groups was 53 vs. 67 months (p=0.2), respectively. Conclusion Resolved HBV infection is associated with a significant risk of HBV reactivation and hepatotoxicity in patients undergoing auto-HCT for MM. These complications were reversible and were not associated with a decrease in PFS or OS.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.