Body composition and late-occurring chronic health conditions after autologous stem cell transplantation for lymphoma.

BACKGROUND: Autologous peripheral blood stem cell transplantation (aPBSCT) is the standard of care for adults with relapsed lymphoma, yet recipients remain at risk of developing chronic health conditions (CHCs). It was hypothesized that body composition measurements of skeletal muscle and fat are associated with late-onset CHCs and nonrelapse mortality after aPBSCT. METHODS: Leveraging the Blood or Marrow Transplant Survivor Study, we examined association between pre-aPBSCT body composition and new-onset grade 3-5 CHCs among 187 adults with lymphoma treated with aPBSCT (2011-2014) surviving ≥2 years after aPBSCT. Using computed tomography scans at the L3 level, skeletal muscle mass (skeletal muscle area and skeletal muscle density [SMD]) and body fat (subcutaneous adipose tissue and visceral adipose tissue) were measured and quantified as sex-specific z-scores. Competing risk models were built to study the impact of body composition on incident grade 3 through 5 CHCs and nonrelapse mortality (NRM) adjusting for confounders. RESULTS: The study cohort had a median age at aPBSCT of 57 years with 63% males, 77% non-Hispanic Whites and 81% with non-Hodgkin lymphoma. The 5-year cumulative incidence of grade 3 through 5 CHCs was 47% (95% Confidence Interval, CI, 38%-56%). Each SD increase in SMD was associated with 30% reduced risk of grade 3 through 5 CHCs (95% CI, 0.50-0.96). The 10-year cumulative incidence of NRM was 16% (95% CI, 10-22). No body composition measure was associated with NRM. CONCLUSIONS: The association between SMD and grade 3 through 5 CHCs following aPBSCT could inform development of prognostic models to identify adults with lymphoma at greatest risk of morbidity following aPBSCT.

Experiences with healthcare navigation and bias among adult women with sickle cell disease: a qualitative study.

PURPOSE: The purpose of this study was to use qualitative interviews to understand the experiences of adult women with sickle cell disease (SCD) through daily life and navigating the healthcare system. METHODS: We conducted semi-structured interviews with reproductive-aged women with SCD and performed thematic analysis. RESULTS: We analyzed interviews from 20 participants. Our data demonstrated three overarching themes: perceptions of disease, transitions of care, and stigma and bias. Participants identified feelings of both empowerment and powerlessness from SCD that evolved over time and globally impacted their lives. The transition from pediatric to adult care was a vulnerable period, both surrounding changes in disease character and challenges transitioning healthcare systems. Finally, participants faced discrimination and prejudice within SCD care, which manifested as disvaluing of their own disease expertise or perpetuation of a "drug-seeking" stereotype. In the context of this bias, some participants prioritized seeking same-race providers. CONCLUSION: Experiences with SCD contribute significantly to daily quality of life in women with SCD, and ongoing care gaps exist in relation to their disease. Within our population, SCD as a physical and mental stressor requiring interdisciplinary support should not be underestimated. More robust systems to support the transition from pediatric to adult care are also necessary, both on a healthcare institution level and to support patients' engagement in their care. Finally, provider education and training on anti-racist practice and both recognizing and eliminating bias are essential to improving care of SCD patients. Possible interactions between sex, gender, and race in the experience of SCD warrant further exploration.

This study uses patient interviews to describe the experiences of women with sickle cell disease (SCD) navigating the healthcare system. The goal of the study is to highlight patients' own experiences in order to prioritize patient-centered care in the management of SCD. Our results showed that different individuals perceive living with SCD differently, in both a positive and negative light. The transition from receiving pediatric to adult medical care for their SCD was a vulnerable time period where individuals had to face changes in both their disease and the healthcare system they were navigating. Finally, patients often experienced stigma and biased care from healthcare staff, manifesting as questioning of their own expertise on their disease and perpetuation of "drug-seeking" stereotypes, leading some to value the importance of having same-race providers. These results help better understand how women with SCD experience living with their disease and identify clinical care gaps that need to be filled, such as more robust systems for supporting the transition from pediatric to adult care and increased recognition and directed training on implicit and explicit bias.

Potentially inappropriate medications in geriatric blood or marrow transplantation (BMT) survivors: A BMT Survivor Study report.

BACKGROUND: Blood or marrow transplantation (BMT) is increasingly offered to older individuals with hematologic malignancies. The high prevalence of chronic health conditions in such individuals necessitates use of multiple medications. Beers Criteria represent a list of potentially inappropriate medications (PIMs) shown to increase the risk of health problems in the elderly. We sought to determine the prevalence and predictors of PIM use in older BMT survivors and identify associations with health problems. METHODS: Study participants were drawn from the BMT Survivor Study, a cohort study of patients transplanted at three US transplant centers between 1974 and 2014 and surviving ≥2 years. For this report, the survivors were aged ≥65 years. Siblings served as a comparison group. Participants self-reported sociodemographics, chronic health conditions, and medication use. Logistic regression analyses identified predictors of PIM use and associations with health problems. RESULTS: Overall, PIM use was comparable between BMT survivors (49.4%) and siblings (49.3%) (odds ratio [OR] = 0.9; 95% CI, 0.7-1.2); however, BMT survivors were more likely to use >1 PIM (17.4% vs. 12.4%; OR = 1.5; 95% CI, 1.01-2.4) and central nervous system-related PIMs (8.3% vs. 4.3%; OR = 2.18; 95% CI, 1.17-4.09). Predictors of PIM use included presence of severe/life-threatening chronic health conditions (OR = 1.5; 95% CI, 1.1-2.0), and chronic graft versus host disease (OR = 1.7; 95% CI, 1.1-2.7). Survivors taking >1 PIM reported more issues with vertigo (OR = 2.3; 95% CI, 1.1-4.7), balance (OR = 2.6; 95% CI, 1.7-4.1), faintness/dizziness (OR = 2.8; 95% CI, 1.8-4.6), and personal care (OR = 4.5; 95% CI, 1.4-14.8). CONCLUSIONS: This study shows the health problems associated with PIM use and identifies vulnerable populations at higher risk for PIM use, providing evidence for caution in using PIMs in high-risk populations.

Severe, life-threatening, and fatal chronic health conditions after allogeneic blood or marrow transplantation in childhood.

BACKGROUND: A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied. METHODS: Seven hundred eighty-nine allogeneic BMT recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255-item survey self-reporting sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life-threatening], or 5 [fatal]) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3-5 conditions. Logistic regression was used to estimate the risk of grade 3-4 conditions in BMT recipients who were alive at the time of this study compared with siblings. RESULTS: The median age at transplantation was 11.3 years (range, 0.4-22.0 years), and the median length of follow-up was 11.7 years (range, 2.0-45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemia/myelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3-4 condition was 53.8% (95% CI, 46.7%-60.3%). The adjusted odds ratio of a grade 3-4 condition was 15.1 in survivors (95% CI, 9.5-24.0) compared with siblings. The risk of a grade 3-5 condition increased with age at BMT (hazard ratio [HR], 1.03; 95% CI, 1.01-1.05) and was higher among females (HR, 1.27; 95% CI, 1.02-1.59), patients who received total body irradiation (HR, 1.71; 95% CI, 1.27-2.31), and those reporting chronic graft-versus-host disease (HR, 1.38; 95% CI, 1.09-1.74). CONCLUSIONS: Two-year survivors of allogeneic BMT in childhood have an increased risk of grade 3-4 chronic health conditions compared with siblings, suggesting the need for long-term follow-up.

Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1.

Cleft palate (CP), one of the most common congenital conditions, arises from failures in secondary palatogenesis during embryonic development. Several human genetic syndromes featuring CP and ectodermal dysplasia have been linked to mutations in genes regulating cell-cell adhesion, yet mouse models have largely failed to recapitulate these findings. Here, we use in utero lentiviral-mediated genetic approaches in mice to provide the first direct evidence that the nectin-afadin axis is essential for proper palate shelf elevation and fusion. Using this technique, we demonstrate that palatal epithelial conditional loss of afadin (Afdn) - an obligate nectin- and actin-binding protein - induces a high penetrance of CP, not observed when Afdn is targeted later using Krt14-Cre We implicate Nectin1 and Nectin4 as being crucially involved, as loss of either induces a low penetrance of mild palate closure defects, while loss of both causes severe CP with a frequency similar to Afdn loss. Finally, expression of the human disease mutant NECTIN1W185X causes CP with greater penetrance than Nectin1 loss, suggesting this alteration may drive CP via a dominant interfering mechanism.

The incidence and importance of the pseudogestational sac revisited.

BACKGROUND: In a pregnancy of unknown location, an intrauterine fluid collection may represent either the early gestational sac of an intrauterine pregnancy, or as reported in previous literature, the pseudogestational sac of an ectopic pregnancy. Various sonographic features have been used to distinguish these 2 entities, but the clinical relevance of the pseudogestational sac remains unclear. OBJECTIVE: To establish the incidence and relative rate of intrauterine fluid collection among ectopic and intrauterine pregnancies and to determine if the size of the collection differs between ectopic and intrauterine pregnancies STUDY DESIGN: We performed a retrospective cohort study of women with pregnancies of unknown location and pelvic or abdominal pain or bleeding. We calculated the incidences of intrauterine fluid collections among ectopic and intrauterine pregnancies, including both ongoing pregnancies and spontaneous abortions, given that that our focus was location and not viability. We calculated the relative risk of ectopic pregnancy if an intrauterine fluid collection was present, adjusting for age and vaginal bleeding. We compared the incidences of ectopic and intrauterine pregnancies among those with and without intrauterine fluid collections. Among those with collections, we compared the mean sac diameter between ectopic and intrauterine pregnancies in continuous and categorical fashions. RESULTS: We evaluated 1236 women presenting with a pregnancy of unknown location. The rates of ectopic and intrauterine pregnancies (including spontaneous abortions) were 13.1% and 63.9%, respectively, with the remainder lost to follow-up. On ultrasound, 452 women (36.6%) had an intrauterine fluid collection. Eight of 162 ectopic pregnancies (4.9%) had a collection, compared with 363 of 789 intrauterine pregnancies (46.0%) (P=.01). Of the ectopics with a fluid collection, 5 had an adnexal mass. The presence of intrauterine fluid collection decreased the risk of ectopic pregnancy (adjusted relative risk, 0.09; 95% confidence interval, 0.05-0.19) after adjusting for age and the presence of bleeding. Among those with an intrauterine fluid collection, the rate of ectopic pregnancy was 2.2%, and the rate of intrauterine pregnancy was 97.8%; among those without a collection, the rate of ectopic pregnancy was 26.7%, and the rate of intrauterine pregnancy was 73.3%. The mean sac diameter did not differ between ectopic and intrauterine pregnancies, whether analyzed continuously or categorically. CONCLUSION: In the presence of an intrauterine fluid collection, the rate of ectopic pregnancy is very low. The size of the intrauterine fluid collection in a woman with a pregnancy of unknown location cannot be used to distinguish between a gestational sac and a pseudogestational sac. Pseudogestational sacs are uncommon and of little clinical consequence. In assessing pregnancies of unknown location, clinicians should incorporate the entire clinical picture, including other sonographic findings, to avoid incorrect or delayed diagnoses.

Hernia-to-neck ratio is associated with emergent ventral hernia repair.

BACKGROUND: The ratio of hernia size to fascial defect size, termed the hernia-to-neck ratio (HNR), has been proposed as a novel predictive factor for umbilical hernia complications. HNR ≥ 2.5 has been suggested to warrant surgery due to association with bowel strangulation, incarceration, and necrosis. The aim of this study was to evaluate the association between HNR and emergent ventral hernia repair at our institution. METHODS: A retrospective cohort study was performed of consecutive patients with ventral hernias evaluated at a large safety-net hospital from 2017 to 2019. Patients who required emergent ventral hernia repair were compared to patients who did not require repair at latest follow-up. HNR was calculated using a previously described method: maximal hernia sac size and maximal fascial defect size (termed "hernia neck size") were measured in the sagittal plane on CT scan. Data are described as mean ± standard deviation and median (interquartile range). RESULTS: A total of 166 patients were included: 84 (51%) required emergent hernia repair and 82 (49%) did not undergo repair. Median follow-up was 19 (8-27) months. Patient groups were similar except the emergent repair group had more males (50% vs. 34%, p = 0.03), umbilical hernias (93% vs. 56%, p < 0.01), recurrent hernias (31% vs. 15%, p < 0.01), and lower mean BMI (34.3 ± 9.9 vs. 39.1 ± 6.5, p < 0.01). Hernia sac size did not differ between groups (5.8 [3.8-8.4] cm vs. 6.1 [3.5-11.8] cm, p = 0.45). Hernia neck size was significantly smaller in the emergent repair group (1.5 [2.3-3.5] cm vs. 3.4 [1.8-6.2] cm, p < 0.01). Hernia-to-neck ratio was significantly higher in the emergent repair group (2.4 [1.8-3.1] vs. 1.7 [1.1-2.9], p < 0.01). CONCLUSION: This study demonstrated an association between higher HNR and increased risk of emergent ventral hernia repair. Future studies will evaluate the use of HNR to risk-stratify patients with ventral hernias in a safety-net hospital.

Stereo- and Site-Selective Crotylation of Alcohol Proelectrophiles via Ruthenium-Catalyzed Hydrogen Auto-Transfer Mediated by Methylallene and Butadiene.

Iodide-bound ruthenium-JOSIPHOS complexes catalyze the redox-neutral C-C coupling of primary alcohols with methylallene (1,2-butadiene) or 1,3-butadiene to form products of anti-crotylation with good to excellent levels of diastereo- and enantioselectivity. Distinct from other methods, direct crotylation of primary alcohols in the presence of unprotected secondary alcohols is possible, enabling generation of spirastrellolide B (C9-C15) and leucascandrolide A (C9-C15) substructures in significantly fewer steps than previously possible.

Conversion of Primary Alcohols and Butadiene to Branched Ketones via Merged Transfer Hydrogenative Carbonyl Addition-Redox Isomerization Catalyzed by Rhodium.

The first examples of rhodium-catalyzed carbonyl addition via hydrogen autotransfer are described, as illustrated in tandem butadiene-mediated carbonyl addition-redox isomerizations that directly convert primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-labeling crossover experiment reveals that the rhodium alkoxide obtained upon carbonyl addition enacts redox isomerization without dissociation of rhodium at any intervening stage.

Longitudinal trajectory of frailty in blood or marrow transplant survivors: Report from the Blood or Marrow Transplant Survivor Study.

BACKGROUND: Blood or bone marrow transplantation (BMT) survivors with frailty are at a higher risk of subsequent mortality. Longitudinal trends in the frailty state are not known and could help identify vulnerable subpopulations at risk of subsequent adverse events. METHODS: This study included a cohort of 470 autologous and allogeneic BMT recipients who had survived ≥2 years after BMT and completed a baseline questionnaire (t1) at a median of 7.3 years after BMT and a follow-up questionnaire (t2) 13.2 years after t1. The main outcome was change in frailty state between t1 and t2. Frailty phenotype was defined as exhibiting ≥3 of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The following categories of change in frailty state were evaluated: worsened, improved, and stable. RESULTS: Of the 470 participants, 36.4% were aged ≥60 years at t1, and 50.6% were men. The prevalence of frailty increased from 4.8% at t1 to 9.6% at t2. Worsening was observed in 18.8% of patients, and improvement was reported in 9.7%. Pre-BMT exposure to vincristine (odds ratio [OR], 2.1; 95% CI, 1.3-3.39) was associated with worsening. Female sex (OR, 1.5; 95% CI, 0.93-2.4) was associated with a trend toward worsening. Pre-BMT exposure to vincristine (OR, 2.79; 95% CI, 1.44-5.43), a history of chronic graft-versus-host disease (OR, 2.58; 95% CI, 1.2-5.5), and grade 3 and 4 chronic health conditions at t1 (OR, 2.1; 95% CI, 1.08-4.33) were associated with frailty at t2. CONCLUSIONS: In a cohort of BMT survivors who were followed longitudinally for a median of 20.6 years from BMT, the frailty status worsened for approximately20% over a 13-year timespan. BMT survivors who are at risk for worsening frailty could benefit from targeted interventions.

Understanding the GERD Barrier.

Gastroesophageal reflux disease (GERD) is steadily increasing in incidence and now affects 18% to 28% of the population in the United States. A thorough understanding of the pathophysiology underlying this disease is necessary to improve the current standard of care. Most GERD pathophysiology models focus on the lower esophageal sphincter (LES) as the key element which prevents esophageal reflux. More recent research has highlighted the crural diaphragm (CD) as an additional critical component of the GERD barrier. We now know that the CD actively relaxes when the distal esophagus is distended and contracts when the stomach is distended. Crural myotomy in animal models increases esophageal acid exposure, highlighting the CD's vital role. There are also multiple physiological studies in patients with symptomatic hiatal hernia that demonstrate CD dysfunction is associated with GERD. Finally, computer models integrating physiological data predict that the CD and the LES each contribute roughly 50% to the GERD barrier. This more robust understanding has implications for future procedural management of GERD. Specifically, effective GERD management mandates repair of the CD and reinforcement of the LES. Given the high rate of hiatal hernia recurrences, it seems that novel antireflux procedures should target this essential component of the GERD barrier. Future research should focus on methods to maintain crural integrity, decrease hiatal hernia recurrence, and improve long-term competency of the GERD barrier.

Ustekinumab for the treatment of paradoxical skin reactions and cutaneous manifestations of inflammatory bowel diseases.

Ustekinumab (STELARA), a human monoclonal antibody directed against IL-12 and IL-23, is FDA-approved to treat psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. Increasing recognition of paradoxical skin reactions induced by older biologic therapies used for inflammatory bowel diseases (IBD), such as, adalimumab and infliximab, has led to the investigation of ustekinumab for the treatment of the cutaneous and gastrointestinal manifestations of IBD. In addition, ustekinumab may show efficacy in treating paradoxical cutaneous reactions to tumor necrosis factor-alpha (TNF-α) inhibitors. A search of the Medline/PubMed database, with additional citations obtained from the references section of relevant articles, yielded 22 articles that were included in this review. Ustekinumab is a safe and effective option for treating the cutaneous manifestations of IBD, such as, metastatic Crohn's disease and pyoderma gangrenosum. It is also an effective treatment for TNF-α inhibitor-induced paradoxical skin reactions, such as, psoriasis that do not remit spontaneously or with conventional treatment. Additional studies should focus on the optimal dosing of ustekinumab for dermatologic conditions beyond psoriasis.

Afamelanotide: An Orphan Drug with Potential for Broad Dermatologic Applications.

Afamelanotide (SCENESSE®) is a synthetic analogue of α-melanocyte-stimulating hormone that is FDA-approved to increase pain-free sunlight exposure in adult patients with erythropoietic protoporphyria. Its dual photoprotective and anti-inflammatory effects also make it a promising therapy for other photosensitive dermatologic diseases that are resistant to treatment. The PubMed/MEDLINE and ClinicalTrials.gov databases were searched for literature and ongoing trials describing the use of afamelanotide in treating cutaneous diseases. There is randomized controlled trial (RCT) evidence for the successful use of afamelanotide in several conditions beyond erythropoietic protoporphyria, including polymorphic light eruption and vitiligo. Smaller studies have also demonstrated its efficacy in treating acne vulgaris, Hailey-Hailey disease, and solar urticaria. No serious adverse effects with afamelanotide use have been reported, though diffuse hyperpigmentation is experienced by almost all patients. Larger scale studies are needed to confirm the efficacy of afamelanotide in treating dermatologic conditions beyond erythropoietic protoporphyria, and further research should focus on determining the safety, efficacy, and optimal dosing of afamelanotide for pediatric patients.J Drugs Dermatol. 2021;20(3):290-294. doi:10.36849/JDD.5526.

Pain in older survivors of hematologic malignancies after blood or marrow transplantation: A BMTSS report.

BACKGROUND: Blood or marrow transplantation (BMT) is increasingly offered to older adults with hematologic malignancies; however, their risk for severe pain is poorly understood. Using the Bone Marrow Transplant Survivor Study, the current study investigated the prevalence and predictors of pain after BMT (allogeneic or autologous) as well as its association with physical performance impairments and frailty. METHODS: The cohort included 736 patients with hematologic malignancies who underwent BMT at an age ≥ 60 years at 1 of 3 transplant centers between 1974 and 2014 and survived ≥2 years after BMT; 183 unaffected siblings also participated. Study participants reported on 4 pain domains (nonminor everyday pain, moderate to severe bodily pain, prolonged pain, and moderate to extreme pain interference), and the presence of 1 or more domains was indicative of a severe and/or life-interfering pain composite variable. RESULTS: Overall, 39.4% of the BMT survivors reported severe pain with 2.6-fold greater odds of reporting pain in comparison with sibling controls. Among BMT recipients, those with less education, lower incomes, and active chronic graft-versus-host disease had higher odds of reporting pain. In multivariable analyses, BMT survivors with pain were more likely to have impaired physical performance and were more likely to meet the frailty criteria. BMT survivors reported higher use of pain medications (17.8% vs 9.3%) and opioid pain medications (6.5% vs 2.2%) in comparison with sibling controls. CONCLUSIONS: Nearly 40% of older BMT survivors who were followed for a median of 5 years after BMT reported pain, and BMT survivors had 2.6-fold higher odds of reporting severe, nonminor or life-interfering pain in comparison with siblings.

Morbidity burden in survivors of multiple myeloma who underwent autologous transplantation: A Bone Marrow Transplantation Survivor Study.

BACKGROUND: Autologous blood or bone marrow transplantation (aBMT) is considered the standard of care for patients with multiple myeloma (MM). Significantly improved survival necessitates an understanding of the morbidity burden borne by the growing survivor population. METHODS: The authors evaluated severe and/or life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs) in patients with MM who were treated with aBMT using the Bone Marrow Transplant Survivor Study. A total of 630 study participants had undergone aBMT for MM at 1 of 3 BMT centers, had survived ≥2 years after aBMT, and were aged ≥18 years at the time of survey completion. Survivors of aBMT identified 289 nearest-age siblings to constitute an unaffected comparison group. Scoring of CHCs was based on version 5 of the National Cancer Institute Common Terminology Criteria for Adverse Events to determine severity (with grade 3 indicating serious and grade 4 indicating life-threatening). RESULTS: The 10-year cumulative incidence of any grade 3 to 4 CHC among survivors of aBMT was 57.6 ± 3.2%. Survivors of MM were found to be at 40% higher odds of developing grade 3 to 4 CHCs when compared with siblings (95% confidence interval [95% CI], 1.0-1.9). Among SNs, 96% were solid tumors, yielding a 10-year cumulative incidence of 13.6% ± 2.5%. Pre-aBMT exposure to cyclophosphamide (hazard ratio [HR], 3.5; 95% CI, 1.5-8.1) and immunomodulatory drugs (HR, 3.9; 95% CI, 1.5-10.1) were associated with an increased risk of solid tumors. Melanoma (10-year cumulative incidence: 3.3% ± 1.2%) and squamous cell carcinoma (10-year cumulative incidence: 5.1% ± 1.8%), were the most common SNs. Pre-aBMT exposure to cyclophosphamide (HR, 6.02; 95% CI, 1.4-26.1) and immunomodulatory drugs (HR, 7.9; 95% CI, 0.9-68.5) was associated with an increased risk of melanoma. CONCLUSIONS: The 10-year cumulative incidence of severe and/or life-threatening CHCs was found to approach 60% in long-term survivors of MM, with solid SNs constituting a large morbidity burden. The current study has provided evidence supporting the close monitoring of survivors to manage morbidity.

Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report.

Autologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P = .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades.

Effects of Reduced Connexin43 Function on Mandibular Morphology and Osteogenesis in Mutant Mouse Models of Oculodentodigital Dysplasia.

Mutations in the gene encoding the gap-junctional protein connexin43 (Cx43) are the cause of the human disease oculodentodigital dysplasia (ODDD). The mandible is often affected in this disease, with clinical reports describing both mandibular overgrowth and conversely, retrognathia. These seemingly opposing observations underscore our relative lack of understanding of how ODDD affects mandibular morphology. Using two mutant mouse models that mimic the ODDD phenotype (I130T/+ and G60S/+), we sought to uncover how altered Cx43 function may affect mandibular development. Specifically, mandibles of newborn mice were imaged using micro-CT, to enable statistical comparisons of shape. Tissue-level comparisons of key regions of the mandible were conducted using histomorphology, and we quantified the mRNA expression of several cartilage and bone cell differentiation markers. Both G60S/+ and I130T/+ mutant mice had altered mandibular morphology compared to their wildtype counterparts, and the morphological effects were similarly localized for both mutants. Specifically, the biggest phenotypic differences in mutant mice were focused in regions exposed to mechanical forces, such as alveolar bone, muscular attachment sites, and articular surfaces. Histological analyses revealed differences in ossification of the intramembranous bone of the mandibles of both mutant mice compared to their wildtype littermates. However, chondrocyte organization within the secondary cartilages of the mandible was unaffected in the mutant mice. Overall, our results suggest that the morphological differences seen in G60S/+ and I130T/+ mouse mandibles are due to delayed ossification and suggest that mechanical forces may exacerbate the effects of ODDD on the skeleton.

Venous Thromboembolism in Autologous Blood or Marrow Transplantation Survivors: A Report from the Blood or Marrow Transplant Survivor Study.

Hemostatic complications are commonly encountered in blood or marrow transplantation (BMT) recipients, increasing their morbidity and mortality and are well described in the immediate post-transplantation period. The risk of venous thromboembolism (VTE) in long-term survivors of autologous BMT has not been studied previously. Patients who underwent autologous BMT between January 1, 1974, and December 31, 2010 for a hematologic malignancy, lived 2 years or more after transplantation, and were age ≥18 years were surveyed for long-term outcomes. The median duration of follow-up was 9.8 years (interquartile range, 6.4 to 14.3 years). We analyzed the risk of VTE in 820 autologous BMT recipients who survived for ≥2 years, compared with 644 siblings. BMT survivors were at a 2.6-fold higher risk of VTE compared with siblings (95% confidence interval [CI], 1.6 to 4.4; P =.0004), after adjusting for sociodemographic characteristics. Conditional on surviving for ≥2 years after BMT, the mean cumulative incidence of VTE was 3.9 ± .8% at 5 years and 6.1 ± 1.1% at 10 years. A diagnosis of plasma cell disorder (hazard ratio [HR], 2.37; 95% CI, 1.3 to 4.2; P = .004) and annual household income ≤$50,000 (HR, 2.02; 95% CI, 1.2 to 3.6; P = .015) were associated with increased VTE risk. Our data indicate that autologous BMT survivors are at elevated risk for developing late-occurring VTE. The development of risk prediction models to identify autologous BMT survivors at greatest risk for VTE and thromboprophylaxis may help decrease the morbidity and mortality associated with VTE.

Late Mortality after Allogeneic Bone Marrow Transplantation in Childhood for Bone Marrow Failure Syndromes and Severe Aplastic Anemia.

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P < .0001). The elevated relative risk persisted at ≥15years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.

Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2).

Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.