Treatment-related Comorbidities Research Articles

Clinical Manifestations and Challenges in Adolescent and Adult Females With Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a rare genetic condition that results in cortisol deficiency and excess production of adrenal androgens. While the introduction of newborn screening for CAH has reduced morbidity and mortality, management of CAH remains challenging. Lifelong treatment with glucocorticoids is required to replace the endogenous cortisol deficiency and reduce excess adrenal androgens. Undertreatment or overtreatment with glucocorticoids can lead to multiple disease- and treatment-related comorbidities, including impaired growth and compromised final height, menstrual irregularities and reduced fertility in females, and long-term cardiometabolic complications. In addition to avoiding adrenal crisis and sudden death, treatment goals in adolescent females with CAH are to obtain normal growth and bone maturation and normal timing of puberty. Management of adolescents is particularly challenging due to changes in growth and sex hormone levels that can lead to inadequate suppression of adrenal androgens and increasing independence that can affect treatment adherence. During the transition to adult care, treatment goals focus on preventing symptoms of hyperandrogenism, preserving menstrual regularity and fertility, and providing education and support for issues related to sexuality, atypical genitalia, and/or complications from previous surgical treatment. In addition, patients must be monitored continuously to prevent long-term complications such as decreased bone mineral density, obesity, diabetes, and hypertension. In this review, we discuss the challenges faced by adolescent and adult females with CAH and provide guidance to health-care professionals to help patients to navigate these challenges.

A Remotely Delivered Light-Intensity Physical Activity Intervention for Older Cancer Survivors: Protocol for a Feasibility Randomized Controlled Trial.

Older cancer survivors face age- and treatment-related comorbidities, including physical functional impairment, which are exacerbated by physical inactivity and sedentary behavior. Regular physical activity can reduce this risk, yet less than 30% of older cancer survivors meet the recommended guidelines for physical activity. This study aims to describe the design, methods, and rationale for a remotely delivered intervention that uses a whole-of-day approach to physical activity in older cancer survivors. This approach focuses on the accumulation of intermittent bouts of light-intensity activity throughout the entire day by disrupting and reducing sedentary activity. The intervention was guided by social cognitive and self-determination theories and incorporated motivational interviewing. The 12-week Move for Your Health trial randomly assigned 64 older cancer survivors to a theory-based physical activity intervention or a waitlist control. A Fitbit (Google) activity tracker and smartphone app were used to promote awareness of activity levels and enable self-monitoring of both activity and inactivity in tandem with health coaching phone calls. Motivational interviewing was used to engage participants and tailor strategies to achieve goals during the 12-week intervention. Data were collected at baseline, immediately after the intervention, and at longer-term follow-up (3 months thereafter). Feasibility outcomes included recruitment, retention, adherence, adverse events, and acceptability. Other outcomes included obtaining the parameter estimates for changes in physical function, physical performance, physical activity, sedentary behavior, and quality of life. Recruitment for the Move for Your Health randomized controlled trial was completed in June 2023. Data collection was completed in March 2024. Data analyses are ongoing. The results of this trial will provide information on the feasibility of implementing this intervention in the target patient population, as well as data that will provide information about the potential impact of the intervention on the outcomes. Both of these outcomes will inform the design of a larger randomized controlled trial to more fully test a physical activity intervention in an older cancer survivor population. ClinicalTrials.gov NCT05582889; https://clinicaltrials.gov/study/NCT05582889. DERR1-10.2196/59504.

Empowering survivors, elevating care: The vital role of oncology primary care clinics.

362 Background: Due to increasing numbers of cancer survivors, there is a greater focus on the longitudinal management of treatment-related comorbidities. Cancer survivors have increased risk of cardiovascular (CV) disease, CV-related mortality, and second primary cancers (SPCs). Primary care providers (PCPs) are responsible for most of the care of long-term survivors, however, many report uncertainty around long-term effects and survivorship guidelines. While fostering strong primary care-oncology relationships is one approach to support those impacted by cancer, the development of oncology primary care clinics enhances patient outcomes and ensures patients receive comprehensive survivorship care. Despite this, few tertiary cancer care centers offer such clinics. Methods: In 2021, the University of Cincinnati Cancer Center established an oncology primary care clinic. Patients are eligible if they have a current or prior cancer diagnosis or cancer hereditary syndrome (CHS). The clinic is comprised of two-family medicine physicians, one with survivorship experience, and one fellowship-trained in palliative and hospice medicine. Clinical team members include an RN with oncology experience, medical assistants, a clinical service specialist, two oncology clinical pharmacists, and an oncology social worker. A clinical registry was developed to longitudinally measure patient outcomes. Electronic medical records of patients (n=683) seen between 1/2021 and 1/2024 were extracted and entered in REDCap. Data was summarized using SAS. Results: The mean age was 56 years (range 20-93), and 12% received a diagnosis in the pediatric/adolescent/young adult age range (0-39 years). The most common types included breast (23%),hematologic cancers (15%), and CHS (16%). Notably 43% of patients are on active treatment and 53% completed or are on maintenance treatment. Over 61% struggle with obesity, while 45% report being a current or former smoker. Comorbidities were common with 79% of patients having at least one CV diagnosis. Of 57% patients eligible for cardiomyopathy screening, 78% received recommended echocardiograms. Many patients received their recommended screenings including breast (79%), colon (43%), cervical (56%), prostate (46%), and lung (55%). Patients were referred to a variety of supportive services including physical therapy (42%), cancer exercise (18%) and psychiatry (14%). Conclusions: This model of care is a viable option for connecting cancer survivors with PCPs knowledgeable about survivorship care. CV-related comorbidities were common, and their management is a critical need during and after cancer. Survivors have increased risk of SPCs, and while the number of patients up to date on recommended cancer screenings is low, screenings are on the rise with ongoing efforts. Patient registries enable objective measurement of outcomes and can inform future research and care.

Disease and treatment-related comorbidities in rheumatoid arthritis

Disease and treatment-related comorbidities in rheumatoid arthritis

Applying Artificial Intelligence Machine Learning to Discover Factors That Shorten Duration of Treatment in Patients with Multiple Myeloma Using Real-World Patient-Level Longitudinal Data from Medical Data Vision Database

Introduction: To maximize the benefit of treatment in multiple myeloma (MM), it is important to continue treatment for appropriate duration . Our recent real-world study using the Medical Data Vision (MDV) claim database showed that median duration of treatment (DoT) of 1 line (L), 2L and 3L treatment was rather short (range: 6.7 to 8.6 months) in Japanese non-transplant patients with MM (Handa H, et al. Plos one. 2023). However, the broad range of treatment patterns in Japan makes it difficult to identify the cause of shortened DoT. Therefore, we assessed the predictive factors that shorten DoT at threshold of <3, <6 and <12 months by applying machine learning (ML) model using real-world clinical data of MM patients from the MDV database. Methods: This retrospective cohort study was conducted on 4848 individual treatments (2,762 patients; 1L for stem cell transplant-not conducted, 2L/3L) in patients (aged ≥18 years) with transplant-ineligible (newly diagnosed or relapsed/refractory) MM between 2003-21. An explainable deep learning model (point-wise linear model, PWL) was developed using 647 feature variables (evaluated before, during, and after treatment; Table) from the MDV database to identify the important predictors associated with DoT. The PWL model generated a custom-made logistic regression model for each sample, which was very familiar to medical researchers and allowed to analyze the importance of the feature variables. Predictive performance of the PWL model was compared with elastic-net regularized logistic regression and XGBoost models and calculated by area under the curve (AUC) and evaluated by 10-fold double cross validation. To stratify the patients with shorter DoT, a clustering analysis of 4848 individual treatment was conducted based on the similarity of coefficients of the custom-made logistic regression models generated from the PWL model. To understand characteristics of samples belonging to each cluster, the relationship between predicted DoT and MM treatment-related comorbidity management was investigated ( Table). Results: The AUC score of the PWL model to predict DoT of <3, <6 and <12 months was 0.61, 0.64 and 0.66, respectively ( Figure). As per clustering analysis, there were 2 clusters (cluster A and B) at DoT of <3 months and 3 clusters (cluster A, B and C) each at DoT of <6 and <12 months, respectively. At <3 months, cluster B showed lower median of prediction probability, and had a significantly (P<0.01) higher previous treatment lines, pre-treatment Charlson Comorbidity Index (CCI) versus cluster A. At <6 months, cluster C showed lower median of prediction probability, and had significantly (P<0.01) higher CCI and comorbidities, and cluster B had significantly (P<0.01) lower estimated glomerular filtration rate, among the clusters. At <12 months, cluster C showed lower median of prediction probability, and had significantly (P<0.01) higher lactate dehydrogenase (LD), previous treatment lines, pre-treatment CCI, degree of care requirement at diagnosis of MM, pre-treatment tube and parenteral nutrition, and comorbidities, among clusters. Additionally, in cluster B (at <3 months), and cluster C (at <6 and <12 months), use of immunomodulatory drugs (IMiDs) in treatment for MM was significantly higher in patients who met predicted DoT at each threshold versus the ones who were not. However, age and history of infectious diseases (antibacterial agents, γ globulin, etc.) was not affected. In addition, IMiDs and aspirin use at <3 and <6 months, and IMiDs use at <12 months had significant differences in events during and after treatment, which are important for considering treatment strategies for MM patients and may lead to the optimization of treatment plans. Study limitation included exclusion of important prognostic factors (cytogenetic profile, R-ISS stage, and presence of all plasmacytomas). Conclusions: TheML technique with PWL model yielded efficient results to understand the trend associated with event in treatment and characteristics of Japanese patients with MM whose DoT were shortened. Patient's condition and management related factors might have associated with shortened DoT, in consistent with clinical findings. These results are critical to continually improving MM management, achieving optimal patients care, and understanding the burden of disease and health services available to Japanese patients with MM in the real-world.

Leveraging a community-academic partnership to evaluate the needs of Latinx AYA cancer survivors.

10060 Background: Adult survivors of childhood cancer have an increased risk of late death and treatment-related comorbidities, yet < 20% of survivors receive guideline concordant risk-based care. Individual-level disadvantages and population-level measures of deprivation contribute to unequal health outcomes among survivors. We aimed to explore the experiences of adolescent/young adult (AYA) cancer survivors and their parents in a region in California with low socioeconomic status and high rates of non-English language preference. Methods: We formed a community-academic partnership with Jacob’s Heart, a nonprofit organization that provides material/psychosocial support to predominantly Hispanic/Latino (Latinx) families of children with cancer. Between Feb-July 2022, we conducted semi-structured interviews in-person or by video or phone with English- or Spanish-speaking AYA survivors of childhood cancer (age ≥15 years, ≥5 years post-diagnosis), parents, and Jacob’s Heart staff members, with assistance from certified medical interpreters. Data were analyzed qualitatively using reflexive thematic analysis based on grounded theory and the constant comparative method. Themes were refined through team discussions with our community partners. Results: We interviewed 12 AYAs (11 Latinx and bilingual), 11 parents (8 Latinx, 7 non-English preferred), and 7 organization staff (5 Latinx and bilingual). AYAs (5 female, 7 male) were median age (min-max) 20 (16-32) and 9 (5-19) years post-diagnosis; parents (9 female, 2 male) were median age 48 (40-60) and 14 (6-23) years post-child’s diagnosis. Cancer types were leukemia (6 AYAs, 9 parents), CNS tumors (1 AYA, 2 parents), other solid tumors (3 AYAs), lymphoma (2 AYAs). Key themes across interviews included gratitude and trust in the pediatric cancer care team and Jacob’s Heart staff, challenges obtaining healthcare outside of the pediatric cancer setting, lasting effects of cancer on the family (e.g., parental job loss, financial strain, impact on siblings, prolonged fear of recurrence in parents, unmet mental health needs in parents and AYAs), and communication barriers between Latinx families and clinicians (e.g., hesitancy to ask questions, overwhelmed by medical information) and between AYAs and parents (e.g., avoidance of talking about cancer history, cancer-related stigma, differing language preferences of AYAs and parents). Conclusions: Childhood cancer has long-lasting effects on families and those with fewer socioeconomic resources face additional burdens. Communication gaps experienced by Latinx families may be a target for intervention to improve AYA survivorship care. Future steps include sharing results with participants and partnering with the community to co-design interventions to facilitate triadic communication among Latinx AYAs, parents, and clinicians.

TRIM21 Expression as a Prognostic Biomarker for Progression-Free Survival in HNSCC

Patients with head and neck squamous cell carcinoma (HNSCC) continue to have a rather poor prognosis. Treatment-related comorbidities have negative impacts on their quality of life. TRIM21 is a cytosolic E3 ubiquitin ligase that was initially described as an autoantigen in autoimmune diseases and later associated with the intracellular antiviral response. Here, we investigated the role of TRIM21 as a biomarker candidate for HNSCC in predicting tumor progression and patient survival. We analyzed TRIM21 expression and its association with clinical-pathological parameters in our HNSCC cohort using immunohistochemistry. Our HNSCC cohort included samples from 419 patients consisting of primary tumors (n = 337), lymph node metastases (n = 156), recurrent tumors (n = 54) and distant metastases (n = 16). We found that cytoplasmic TRIM21 expression was associated with the infiltration of immune cells into primary tumors. In addition, TRIM21 expression was significantly higher in primary tumors than in lymph node metastases, and increased TRIM21 expression was correlated with shorter progression-free survival in HNSCC patients. These results suggest that TRIM21 could be a new biomarker for progression-free survival.

Sexual dysfunction is highly prevalent in male survivors of malignant lymphoma.

With improved survival in patients with lymphoma, long-term toxicity and quality of life (QoL), including sexual health, have become increasingly important. We aimed to (1) determine the prevalence of erectile dysfunction (ED) in adult male lymphoma survivors; (2) determine whether testosterone deficiency, comorbidities, or lifestyle factors were associated; and (3) evaluate their impact on QoL. A cross-sectional study including 172 male survivors of Hodgkin lymphoma or diffuse large B cell lymphoma diagnosed in adulthood between 2008 and 2018 was performed. Patients were in complete metabolic remission after first-line treatment and remained in remission at follow-up (3-13years after diagnosis). Participants completed 3 questionnaires measuring sexual health and general QoL. Serum concentrations of total testosterone were measured and thorough medical history and sociodemographic factors were obtained. The Danish SEXUS Project, European Male Ageing Study, and European Organization of Research and Treatment of Cancer (EORTC) Reference Manual were used as reference values of the general population. Patient reported outcome measures including the 5-item International Index of Erectile Function, EORTC C30, and EORTC 22-item Sexual Health Questionnaire. ED was reported by 55.2%, which was higher than in an age-matched Danish population cohort (17.5%). Erectile function score (5-item International Index of Erectile Function) was negatively associated with comorbidity, body mass index, smoking, and age and positively with the number of children conceived before treatment and serum concentration of total testosterone. Overt testosterone deficiency in combination with ED was detected in 10 (5.7%) of 176 survivors, including excluded survivors in hormonal treatment, which is higher than for the general population (0.1%-3.2% for men <70years of age). Mean EORTC C30 global health score for survivors with ED was lower (67.7) than for survivors without ED (80.1) but was comparable to the general population (71.2). Furthermore, a positive association was seen between sexual function and both sexual and general QoL. Sexual health is important for QoL and related to comorbidities. The focus on improving QoL requires that both sexual health and comorbidities are addressed in the follow-up of lymphoma patients. Despite the relatively high number of included survivors, the cross-sectional design of this study warrants longitudinal studies to clarify the specific underlying causes of sexual dysfunction. ED was highly prevalent and associated with comorbidity in lymphoma survivors, and more focus on sexual health and treatment related comorbidity is needed to improve sexual and general QoL.

Effectiveness of Proton Pump Inhibitor Therapy in the Prevention of Bleeding After Prophylactic Endoscopic Variceal Band Ligation.

Background Endoscopic variceal ligation (EVL) is a surgical intervention that can work well to curb variceal bleeding in people with liver cirrhosis. However, it could make ulcer bleeding worse and be fatal in some cases. The widespread use of proton pump inhibitors (PPI) in cirrhotic individuals with variceal bleeding is empirical rather than based on scientific data. According to many studies, PPIs reduce the size of post-EVL ulcers. This study aimed to see if PPI use could reduce rebleeding after endoscopy therapy in cirrhotic patients with variceal bleeding. Methodology A retrospective cross-sectional study was conducted at a tertiary care hospital from August 2019 to September 2021. Cirrhotic patients with bleeding gastroesophageal varices(GEVs) who had undergone EVL at the same hospital were enrolled in the study. Medical records were organized, and the sample was divided into two groups based on whether or not PPI was given. Both PPI and non-PPI patients had their endoscopic findings, initial hemostasis outcomes, rebleeding rates, bleeding-related mortality rates, and treatment-related comorbidities compared. Results A total of 46 patients were selected for the study and divided into two groups (PPI group n=28 and non-PPI group n=18). The majority of the patients were males. The PPI group had a mean age of 58.6 ±7.8 years, whereas the non-PPI group had a mean age of 53.6 ±4.4 years. Hepatitis B virus (HBV) infection was the most prevalent cause of cirrhosis in both groups. After endoscopic treatment, three patients (16%) in the non-PPI group suffered a variceal hemorrhage. Bleeding-related fatalities and the time it took for the bleeding to stop varied significantly between the two groups. History of variceal bleeding (relative risk (RR)=1.45; 95% confidence interval (CI), 1.60-7.67; p=0.02), presence of gastric varices (RR=2.23; 95% CI, 2.56-9.832; p=0.035), and not administering PPIs (RR =7.542; 95% CI, 3.98-29.13; p=0.008) were linked with rebleeding. The presence of red concurrent esophageal varices (RR=6.37; 95% CI, 0.562-15.342; p=0.002) and failure to provide PPIs (RR=2.3; 95% CI, 1.621-25.64; p=0.04) were linked with post-EVL bleeding in a multivariate analysis. Conclusions Proton pump inhibitors reducethe occurrence of early bleeding and adverse events after EVL in cirrhotic patients. Not prescribing PPIs and the presence of GEVs were substantially related to a higher risk of bleeding during preventative EVL. Not initiating PPI medication immediately was the sole predictor of bleeding complications in patients who had undergone EVL without gastric varix treatment. To lower the risk of post-EVL ulcer bleeding, we recommend PPI use in patients undergoing EVL.

PSAT087 A de Novo Model for Measuring Long-Term Health Effects of Modified-Release Hydrocortisone Capsules in Adult and Adolescent Patients With Classic Congenital Adrenal Hyperplasia

Abstract Objectives Classic congenital adrenal hyperplasia (C-CAH) is a rare condition caused by enzyme deficiency in cortisol biosynthesis. The condition is characterised by adrenal insufficiency and androgen excess and is associated with numerous disease- and treatment-related comorbidities that impact the length and quality of a patient's life. A de novo model was developed to investigate the long-term health effects of modified-release hydrocortisone capsules (Efmody® / MR-HC) compared to the standard glucocorticoid replacement therapies (including immediate-release hydrocortisone, dexamethasone, and prednisolone) currently used to treat patients with C-CAH. Methods The model is structured as a series of sub-models reflecting key comorbidities in C-CAH: adrenal crisis, cardiovascular disease, bone health, height (adolescents only), obesity, diabetes and infertility. Effects of both disease, i.e. where cortisol and/or androgen levels are too high or low, and the impact of treatment, i.e. physiological or supraphysiological steroid dosing, on each comorbidity are considered where relevant. The model captures accumulating health outcomes from each sub-model and allows quantification of overall impact on health-related quality of life (HRQoL) and mortality. The population is adolescent (&amp;gt;12 years onwards) and adult patients with C-CAH. The intervention is MR-HC, and comparator is standard glucocorticoid replacement therapies currently used in C-CAH. Model inputs, which were composed of MR-HC clinical trial data, published literature values, and clinical opinion, and the modelling approach were validated with seven European clinical experts. The model accumulates the health effect, which is measured as life-years (LYs) and quality-adjusted life years (QALYs), over a lifetime time horizon, from the ages of 12 to 100 years old. Results The model demonstrates that the treatment of C-CAH with standard glucocorticoid replacement therapies known to provide poor hormonal disease control and exposure to supraphysiological steroid dosing long-term have a substantial negative impact on HRQoL and life-expectancy in C-CAH, with modelled outcomes lower than those published for general population. Improved hormonal disease control and physiological steroid dosing with MR-HC compared to standard glucocorticoid replacement therapies result in improvements across the key comorbidities in patients with C-CAH. Quality-adjusted life year (QALY) gains are particularly driven by the reduction in adrenal crises, along with improved growth in the adolescent population and better weight control. Overall, the model demonstrates that long-term treatment of patients with C-CAH with MR-HC, compared to standard glucocorticoid replacement therapies, is expected to extend life by 7.58 years, and results in an additional 3.21 QALYs. Conclusion The model demonstrates that better hormonal disease control without exposing patients to supraphysiological steroid dosing with MR-HC improves key comorbidities in C-CAH resulting in improvement in both the length and the quality of life of patients with C-CAH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Correlates of common concerns in older cancer survivors of leukemia and lymphoma: results from the WHI LILAC study.

Older survivors of leukemia and lymphoma often experience long-term effects of chemotherapy. We described common concerns related to their cancer and treatment in older survivors of leukemia and non-Hodgkin lymphoma (NHL) and assessed correlates of these concerns. We utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited post-menopausal women aged 50-79. Participants diagnosed with leukemia and NHL were included (n = 420). They were asked about 14 areas of current concerns related to their cancer and treatment and to rate each from 0 (no concern) to 2 (major concern), with total scores ranging from 0 to 28. Linear regression was used to assess factors correlated with the concern score, and logistic regression for factors correlated with the three most common concerns. Mean age at assessment was 81years (range 69-99); 72% reported at least one concern, and median concern score among these survivors was 3.5 (Q1-Q3 2-5). Factors significantly correlated with concern scores were sadness, pain, distress, higher prior symptom count, and loneliness (all p < 0.05). Significant factors correlated with common concerns were (1) fatigue/sleep: sadness/depression, distress, higher prior symptom count, greater loneliness, and worse physical functioning; (2) physical functioning/activity: older age, public insurance, higher body mass index, pain, worse QoL, and higher treatment-related comorbidities; (3) memory/concentration: prior chemotherapy or radiation, worse QoL, higher prior symptom count, and greater loneliness (all p < 0.05). Almost three-quarters of older survivors of leukemia and lymphoma reported at least one concern; a multifaceted intervention may be needed to address these concerns.

Treatment of Breast Cancer in Young Adults.

Although breast cancer is rare and understudied in adults age 40 and younger, recent epidemiologic data show an increasing incidence of breast cancer among young women in the United States and ongoing inferior long-term outcomes. Given breast cancers arising at a young age are more likely to present at advanced stages and to have aggressive biology, multimodal treatments are often indicated. Elevated local recurrence risks and greater propensity for germline cancer predisposition mutations can impact local therapy choices. Recently, escalated systemic therapy regimens for triple-negative breast cancer incorporating immunotherapy, de-escalated anti-HER2 therapy, and emerging targeted agents, including CDK4/6 inhibitors and PARP inhibitors, for early-stage disease may be employed in younger and older patients alike, with some special considerations. Prognostic genomic signatures can spare low-risk young women with hormone receptor-positive breast cancer adjuvant chemotherapy, but management of intermediate-risk patients remains controversial. Ovarian function suppression and extended endocrine therapy are improving outcomes in hormone receptor-positive breast cancer, but treatment adherence is a particular problem for young patients. Young women may also face greater challenges in long-term survivorship, including impaired fertility, difficulties in psychosocial adjustment, and other treatment-related comorbidities. Consideration of these age-specific issues through dedicated multidisciplinary strategies is necessary for optimal care of young women with breast cancer.

Sarcopenia Related to Human Immunodeficiency Virus: Protective Effects of Exercise.

We discuss recent evidence supporting the hypothesis that sarcopenia is an emerging health concern among people with human immunodeficiency virus (HIV) because of increasing life expectancy and HIV- and treatment-related comorbidities. We also hypothesize that combined exercise at higher intensity has a key role in managing sarcopenia in this population because it directly (increases muscle strength and stimulates hypertrophy) and indirectly (prevents mitochondrial dysfunction, oxidative stress, and persistent inflammation) counteracts sarcopenia hallmarks.

Systemic lupus erythematosus: a clinical update.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease known for its complexity and heterogeneity. Striking diversity can be observed between individual patients, in terms of clinical manifestations, serological abnormalities, disease progression and response to therapy. Furthermore, dysfunction of a broad range of immune pathways underlies disease development and expression. An appreciation of this diversity is vital in order to diagnose accurately and appropriately treat patients with SLE as there is no one-size-fits-all diagnostic test or treatment. Optimal management involves identifying affected organs, assessing severity, differentiating activity from irreversible damage and tailoring immunosuppressive treatment accordingly. Non-pharmacological interventions, attention to disease and treatment-related comorbidities and addressing the significant impact on health-related quality of life are also crucial to maximising patient outcomes.

Design of a Phase 1/2 Open-Label, Dose-Escalation Study of the Safety and Efficacy of Gene Therapy in Adults With Classic Congenital Adrenal Hyperplasia (CAH) Due to 21-hydroxylase Deficiency Through Administration of an Adeno-Associated Virus (AAV) Serotype 5-Based Recombinant Vector Encoding the Human CYP21A2 Gene

Abstract The CYP21A2 gene, which encodes the 21-hydroxylase enzyme, plays a critical role in glucocorticoid (GC) and mineralocorticoid synthesis by the adrenal cortex. CYP21A2 pathogenic variants cause 21-hydroxylase deficiency (21OHD), the most common type of CAH, characterized by variable degrees of adrenal insufficiency and androgen excess. Standard treatment of classic 21OHD consists of daily doses of GC and mineralocorticoid. However, suppressive GC doses are often required to reduce androgen excess, and it is often not possible to dose exogenous GC in a manner that provides adequate disease control while avoiding overtreatment. Disease-related and treatment-related comorbidities are common and include life-threatening adrenal crises, impaired growth and development during childhood, adult short stature, virilization in females, subfertility in both sexes, obesity and cardiovascular risk factors, and decreased bone mineral density. Novel treatment approaches are needed to address these challenges and a treatment that restores the ability of the adrenals to produce cortisol and aldosterone in a physiologically-regulated manner would be particularly helpful. Here we present the design and rationale of a clinical trial using BBP-631, an AAV5 gene replacement therapy for adults with classic CAH due to 21-OHD. This treatment approach is based on the demonstration that a single intravenous administration of BBP-631 corrects the enzyme deficiency in the H2-aw18 CYP21-/- CAH mouse model of 21OHD, including response to stress. This correction was robust, dose-dependent and durable. BBP-631 treatment also resulted in robust and durable expression of the human CYP21A2 transgene in the non-human primate adrenal cortex. BBP-631 appears to be safe and well-tolerated in mice with 21-OHD, healthy mice and non-human primates. Taken together, these data support initiating clinical trials in adults with classic CAH due to 21-OHD. The trial will sequentially enroll individuals in up to 3 successive dose-escalation cohorts. Each subject will receive a single dose of BBP-631 and safety will be assessed prior to dose escalation. Endogenous production rates of adrenal steroids (cortisol, 17-hydroxyprogesterone, androstenedione) will be determined pre- and post- dose, and their concentrations assessed over a 1-year period after which subjects will roll over into an extension study for at least 4 years. The Phase 1 study will determine the tolerability of a single dose of BBP-631. The magnitude and durability of BBP-631 and effects on adrenal steroids, ACTH and, where relevant, aldosterone levels will be monitored. The ability of BBP-631 to allow tapering of GC doses will also be explored. This first in human study of gene therapy for CAH represents a milestone in the development of novel and improved treatment approaches for patients with classic CAH.

FRAX scores are increased in patients with ANCA-associated vasculitis

Prognosis in ANCA-associated vasculitis (AAV) has greatly improved with immunosuppressive use whereas incidence of treatment-related comorbidities such as osteoporosis has increased. However, studies investigating bone disease in AAV are limited. Fracture Risk Assesment Tool (FRAX) was developed to estimate 10-year hip and major osteoporotic fracture risks. Aim of this study was to estimate FRAX scores in AAV patients and compare them to healthy controls. 30 AAV patients and 20 healthy controls were included. Demographic, disease, and medication history were recorded from patient files. Femoral neck, lumbar spine and forearm bone mineral densitometry, and thoracolumbar radiographs were performed. FRAX fracture risk scoring was assessed for all participants. There were 18 male and 12 female patients. Mean age was 58.5 ± 11.7years. Osteoporosis and osteopenia were present in 23.3% and 50% of patients, respectively. There were fractures in eight patients (26.7%). FRAX major fracture (9.4 ± 7.3% vs 5.9 ± 3.2%, p = 0.02) and hip fracture (2.2 ± 3.2% vs 0.9 ± 0.8%, p = 0.03) scores were higher in patients than controls. In seven (23.3%) patients, the 10-year probability of hip fracture was ≥ 3% and in five (16%) patients the 10-year risk of a major osteoporosis-related fracture was ≥ 20%. None of the controls exceeded these thresholds. AAV patients are at high risk for future fractures as calculated with FRAX. Life-long monitoring for bone disease and fractures are essential. Large studies with longer follow-up are needed to determine the accuracy of FRAX risk scoring in predicting fractures.

Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment.

Simple SummaryMany modalities used to treat or control cancer lead to accelerated aging in cancer survivors. However, the effects of cancer treatments on aging in individuals with cancer remain poorly studied. In this review, we summarize the possible biological mechanisms of accelerated aging in cancer survivors induced by cancer treatments. We also discuss the importance of estimating biological age in individuals with cancer and review the methods that can be used to estimate biological age in cancer survivors.Rapid improvements in cancer survival led to the realization that many modalities used to treat or control cancer may cause accelerated aging in cancer survivors. Clinically, “accelerated aging” phenotypes in cancer survivors include secondary cancers, frailty, chronic organ dysfunction, and cognitive impairment, all of which can impact long-term health and quality of life in cancer survivors. The treatment-induced accelerated aging in cancer survivors could be explained by telomere attrition, cellular senescence, stem cell exhaustion, DNA damage, and epigenetic alterations. Several aging clocks and biomarkers of aging have been proposed to be potentially useful in estimating biological age, which can provide specific information about how old an individual is biologically independent of chronological age. Measuring biological age in cancer survivors may be important for two reasons. First, it can better predict the risk of cancer treatment-related comorbidities than chronological age. Second, biological age may provide additional value in evaluating the effects of treatments and personalizing cancer therapies to maximize efficacy of treatment. A deeper understanding of treatment-induced accelerated aging in individuals with cancer may lead to novel strategies that reduce the accelerated aging and improve the quality of life in cancer survivors.

Disease Modeling and Phenotype Rescue Using Inducible Pluripotent Stem Cells from Patients with Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a congenital ribosomopathy and bone marrow failure syndrome manifesting typically in infancy with erythroid hypoplasia. Approximately half of affected individuals also have developmental anomalies. Over time, additional cytopenias can develop, including reduced hematopoietic stem and progenitor cells (HSPC). Heterozygous loss-of-function mutations in over 20 ribosomal protein (RP) genes cause approximately 70% of DBA cases, although only 7 genes (RPS19, RPL5, RPS26, RPL11, RPL35a, RPS24 and RPS7) account for over 90% of patients with a known DBA genotype. Medical therapies including steroids, chronic transfusions are partially effective but have considerable side effects. Hematopoietic stem cell transplantation (HSCT) from matched related or unrelated donors is curative with recently reported good outcomes, although many patients lack a suitable donor and/or have serious treatment-related comorbidities that increase HSCT-related toxicities. Case reports of spontaneous genetic reversion in DBA suggest that RP gene-corrected HSPC have competitive advantage over RP-deficient cells, thus providing the rationale for gene therapy as a feasible therapeutic approach. Induced pluripotent stem cell (iPSC) technology provides a robust model of human disease and can recapitulate hematopoietic defects encountered in bone marrow failure syndromes. The goals of this study was to establish a culture system from patient-derived iPSCs that can recapitulate key aspects of DBA pathophysiology and provide a preclinical model for gene manipulation to correct the abnormal phenotype (Figure 1). We developed iPSCs from individuals with DBA who were enrolled on INSIGHT (NCT02720679), an IRB-approved, prospective study that includes biobanking of peripheral blood mononuclear cells (PBMNC) from patients with bone marrow failure syndromes. We first reprogrammed these DBA PBMNC into iPSCs using non-integrating Sendai virus to establish lines with pathogenic mutations in RPS19 (c.191&gt;T, p.Leu64Pro), RPS19 (c.184C&gt;T, p.Arg62Trp), RPL11 (c.61dupT, p.Cys21Leufs*13), and a variant of uncertain significance (VUS) in RPS7 (c.277_279delGTC, pVal93del). Undifferentiated iPSC lines exhibited abnormal ribosomal biogenesis revealed by polysome profiling and pre-rRNA analysis. Upon in vitrodifferentiation to hematopoietic lineages, the mutant iPSCs recapitulated DBA phenotypes with reduced CD34+ HSPCs, near absence of erythroid colonies (BFU-E and CFU-E) colonies and failure to produce erythroid cells in liquid culture. We used two methods to correct single nucleotide RP mutations in DBA iPSCs (Figure 1): i) CRISPR/Cas9-mediated homology-directed repair, and ii) base-editing, which utilizes catalytically inactive Cas9 fused to a deaminase that interconverts nucleotides directly in the absence of double-stranded DNA breaks. Corrected "isogenic" lines showed phenotype similar to wild type controls, with restored erythroid differentiation, and normal polysome maturation and pre-rRNA ratios. Because some patients carry large intragenic or whole RP gene deletions that are not amenable to gene correction, we also explored the feasibility of gene rescue by inserting a wild type copy of the defective gene (Figure 1). Using zinc-finger nuclease (ZFN), we inserted wild type RP cDNA constructs into the "safe harbor" AAVS1 locus on chromosome 19, thereby rescuing abnormal phenotypes of patient-derived iPSC lines with RPS19(p.Arg62Trp) and RPL11(p.Cys21Leufs*34) mutations. Additionally, we explored lentiviral gene delivery as an alternative method for RP gene replacement. We compared different promoters including MND, PGK and EF1a and found that the latter was most effective at rescuing RP gene expression in iPSC cells. Transduction of lentiviral vectors with wild type RPS19or RPL11fused to the EF1a promoter into three iPSC lines with RPS19or RPL11mutations resulted in stable transgene expression of RPS19or RPL11genes and phenotypic rescue. This study supports the feasibility of establishing iPSCs from DBA subjects with different genotypes. These iPSC lines provide a useful resource for numerous studies of DBA including preclinical approaches to gene therapy, evaluating the pathogenicity of RP gene variants of unknown significance and examining the pathophysiology of RP haploinsufficiency. Disclosures Estepp: Esperion: Consultancy; Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Eli Lilly and Co: Research Funding; Daiichi Sankyo: Consultancy. Weiss:GlaxoSmithKline: Consultancy; Rubius Inc.: Consultancy; Cellarity Inc.: Consultancy; Beam Therapeutics: Consultancy; Esperion: Consultancy.

Prevalence of Comorbidities among Older Head and Neck Cancer Survivors in the United States.

The aim of this study was to evaluate the prevalence of comorbidities among patients with head and neck squamous cell carcinoma (HNSCC) at the time of their cancer diagnosis and during their survivorship trajectory. The second aim was to evaluate the differences in comorbidities developed according to treatment type received. Retrospective cross-sectional. SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database. Individuals with a first-incident primary diagnosis of HNSCC from 2004 to 2011 per the SEER-Medicare database were included in analysis. The presence or absence of 30 comorbid conditions of interest was identified during distinct periods and analyzed according to treatment with surgery alone, primary (chemo)radiation, or surgery with (chemo)radiation. The study population consisted of 10,524 individuals diagnosed with HNSCC, with a mean age of 74.8 years. At diagnosis, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and diabetes were the most prevalent comorbidities, and they increased over time. The probability of developing treatment-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in the short and long term following treatment ( P < .05). By 5 years from cancer diagnosis, patients were most likely to have newly diagnosed hypertension, dysphagia, anemia, and weight loss. Primary surgery alone was associated with a lower risk of diagnosis with these treatment-related comorbidities, as compared with treatments involving radiation therapy and/or chemotherapy in the primary or adjuvant settings ( P < .05). There is a large burden of comorbidities among patients following HNSCC treatment, which warrant clinical attention during surveillance.

Mortality causes and trends associated with giant cell arteritis: analysis of the French national death certificate database (1980-2011).

Comprehensive analyses of cause-specific death patterns in GCA are sparse. We studied the patterns and time trends in GCA-related mortality using a large death certificate database. We obtained multiple-cause-of-death data from the French national death certificate database for 1980-2011. GCA-associated deaths were defined as decedents ⩾55 years old with GCA listed as an underlying or non-underlying cause of death. Time trends of death rates were analysed and the mean age at death with GCA and in the general population ⩾55 years old were calculated. Standardized mortality odds ratios (SMORs) were calculated for 17 selected causes of death (based on 2000-11 data). The analyses pertained to approximately 15 000 death certificates listing GCA (including approximately 6300 for 2000-11). Annual standardized death rates for GCA increased to a peak in 1997 and then decreased (Spearman's correlation test, both P < 0.0001). Mean age at death was higher for GCA than for general population decedents (Student's t-test, P < 0.0001). GCA deaths were frequently or strongly associated with aortic aneurysm and dissection (1.85% of death certificates, SMOR: 3.09, 95% CI: 2.48, 3.82), hypertensive disease (20.78%, SMOR: 2.22, 95% CI: 1.97, 2.50), diabetes mellitus (11.27%, SMOR: 1.96, 95% CI: 1.72, 2.23), certain infectious and parasitic diseases (12.12%, SMOR: 1.76, 95% CI: 1.55, 2.00) and ischaemic heart disease (16.54%, SMOR: 1.45, 95% CI: 1.35, 1.64). GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities. These findings help provide better insights into the outcomes of GCA.