HHV-8-associated diseases in transplantation: A case report and narrative review focused on diagnosis and prevention.

BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.

Transcriptional regulation and therapeutic potential of cyclin-dependent kinase 9 (CDK9) in sarcoma.

Sarcomas include various subtypes comprising two significant groups - soft tissue and bone sarcomas. Although the survival rate for some sarcoma subtypes has improved over time, the current methods of treatment remain efficaciously limited, as recurrent, and metastatic diseases remain a major obstacle. There is a need for better options and therapeutic strategies in treating sarcoma. Cyclin dependent kinase 9 (CDK9) is a transcriptional kinase and has emerged as a promising target for treating various cancers. The aberrant expression and activation of CDK9 have been observed in several sarcoma subtypes, including rhabdomyosarcoma, synovial sarcoma, osteosarcoma, Ewing sarcoma, and chordoma. Enhanced CDK9 expression has also been correlated with poorer prognosis in sarcoma patients. As a master regulator of transcription, CDK9 promotes transcription elongation by phosphorylation and releasing RNA polymerase II (RNAPII) from its promoter proximal pause. Release of RNAPII from this pause induces transcription of critical genes in the tumor cell. Overexpression and activation of CDK9 have been observed to lead to the expression of oncogenes, including MYC and MCL-1, that aid sarcoma development and progression. Inhibition of CDK9 in sarcoma has been proven to reduce these oncogenes' expression and decrease proliferation and growth in different sarcoma cells. Currently, there are several CDK9 inhibitors in preclinical and clinical investigations. This review aims to highlight the recent discovery and results on the transcriptional role and therapeutic potential of CDK9 in sarcoma.

No difference in midterm outcomes and complication rate between retroperitoneal and transperitoneal open aortic aneurysm repair in females.

OBJECTIVES: Abdominal Aortic Aneurysms (AAA) in females are less prevalent, have higher expansion rates and experience rupture at smaller diameters than in males. Studies have compared outcomes of the retroperitoneal (RP) and transperitoneal (TP) approach in open aortic aneurysm repair (OAR) with conflicting results. No study to date has compared the two approaches solely in females. In this study we compare midterm outcomes of the RP and TP approach in females undergoing OAR. METHODS: Single-center, retrospective review of all females undergoing OAR from 2010 to 2021. Patients undergoing elective, symptomatic and ruptured OAR were included. The cohort was stratified by surgical approach RP versus TP and midterm outcomes were compared amongst the groups. Outcomes included mortality, graft related, and non-graft related complications. RESULTS: A total of 244 patients (RP n = 133; TP n = 111) were identified. Follow-up period was 28 ± 30.7 months. Baseline perioperative characteristics were similar except that more people in the RP group had ejection fraction ((EF) > 50% (82% vs 68%), p = .037). Patients who underwent RP repair had longer visceral/renal ischemia time (p = .01), larger graft diameter (18 vs 16 mm; p = <0.001), were more likely to have a suprarenal clamp placed(70.5 vs 48.2; p < .001), and had decreased autotransfusion volume (611 vs 861 mL; p < .01) compared to those who underwent TP repair. Number of deaths was higher in the TP group during study follow-up period (36.4 vs 23.8; p = .035), but the difference of the time to event analysis was not significant. There was no difference in all-cause survival at 36 months between RP and TP (77.8 vs 76.8; p = .045). Overall midterm complications were 9.5% in both groups. Any graft related complication was 1.8% in TP versus 3% RP (p = .69). In a multivariable model, after adjusting for age, urgency, smoking, prior aneurysm repair, and ASA level, the hazard ratio decreases with the RP approach, however this did not reach significance (p = .052). CONCLUSION: In a 12-year period of OAR in females, TP and RP results were comparable at midterm analysis. The RP approach appeared to be used more often for OAR requiring suprarenal clamping. Although the TP group had increased mortality, the difference of the time to event analysis was not significant. Midterm postoperative complications in both groups were low. This suggests that both approaches are safe in the female population and decision should be driven by anatomy and surgeon's preference.

Improving symptom management for survivors of young adult cancer: rationale and study protocol for a pilot randomized controlled trial.

BACKGROUND: Young adult (YA) cancer survivors are a growing, yet underserved population who often face significant and long-lasting cancer-related physical (e.g., pain, fatigue) and emotional (e.g., psychological distress) symptoms. Post-treatment symptoms can persist, disrupting YA's abilities to complete goals consistent with their developmental stage (e.g., completing their education, achieving autonomy and independence, building their careers, establishing peer and romantic relationships, building their families). While symptom management has been identified as a significant issue in YA's transitions to survivorship, the symptom management needs of this population largely go unmet. METHODS: We developed an eight-session, group-based behavioral intervention that is delivered using videoconferencing to address the unique symptom management needs of YA cancer survivors. The intervention was developed in conjunction with YA survivors, leading to the novel combination of traditional behavioral symptom coping strategies, home-based physical activity, strategies from contemporary cognitive-behavioral approaches (e.g., those derived from acceptance and commitment therapy, strategies to foster self-compassion), concepts from meaning centered psychotherapy, and behavioral strategies to improve communication and health care engagement. Participants receive printed intervention materials and access to a study-specific mobile application, both of which are used throughout the program. Herein, we report on a pilot study that is in progress. Recruitment has been completed. YA cancer survivors were recruited in cohorts of n = 10 or n = 11 (n = 61) and randomized to the intervention or waitlist control arms. All participants completed a baseline assessment and four additional assessments over 1 year, with each involving a battery of self-report measures. DISCUSSION: The primary objective is to evaluate intervention feasibility and acceptability. As a secondary objective, we will examine patterns of change in intervention targets (i.e., pain, fatigue, emotional distress, symptom interference). Changes from baseline among intervention targets will be estimated for each patient and compared between arms using unadjusted statistical testing. Unadjusted and adjusted multilevel modeling will be used to estimate the effect of the intervention on changes in intervention targets. Interaction models will be used to compare the trajectory of change over time between arms. We expect that this pilot trial will inform our future approach to identify, recruit, and retain participants and provide preliminary data to support a larger, fully powered randomized controlled trial evaluating the intervention. TRIAL REGISTRATION: NCT04035447 at clinicaltrials.gov; registered July 29, 2019.

Slow proliferation of BAP1-deficient uveal melanoma cells is associated with reduced S6 signaling and resistance to nutrient stress.

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.

Pedicled omental flaps for complex wound reconstruction following surgery for primary spine tumors of the mobile spine and sacrum.

OBJECTIVE: Surgery for primary tumors of the mobile spine and sacrum often requires complex reconstruction techniques to cover soft-tissue defects and to treat wound and CSF-related complications. The anatomical, vascular, and immunoregulatory characteristics of the omentum make it an excellent local substrate for the management of radiation soft-tissue injury, infection, and extensive wound defects. This study describes the authors' experience in complex wound reconstruction using pedicled omental flaps to cover defects in surgery for mobile spine and sacral primary tumors. METHODS: A retrospective cohort analysis was conducted on 34 patients who underwent pedicled omental flap reconstruction after en bloc resection of primary sacral and mobile spine tumors between 2010 and 2020. The study focused on assessing the indications for omental flap usage, including soft-tissue coverage, protection against postoperative radiation therapy, infection management, vascular supply for bone grafts, and dural defect and CSF leak repair. Patient demographic characteristics, tumor characteristics, surgical outcomes, and follow-up data were analyzed to determine the procedure's efficacy and complication rates. RESULTS: From 2010 to 2020, 34 patients underwent pedicled omental flap reconstruction after en bloc resection of sacral (24 of 34 [71%]) and mobile spine (10 of 34 [29%]) primary tumors, mostly chordomas. The patient cohort included 21 men and 13 women with a median (range) age of 60 (32-89) years. The most common indication for omental flap was soft-tissue coverage (20 of 34 [59%]). Other indications included protecting abdominopelvic organs for postoperative radiation therapy (6 of 34 [18%]), treating infections (5 of 34 [15%]), providing vascular supply for free fibular bone graft (1 of 34 [3%]), and repairing large dural defects and CSF leak (2 of 34 [6%]). The median (range) follow-up was 24 (0-132) months, during which 71% (24 of 34) of patients did not require additional surgery for wound-related complications. At last follow-up, 59% (20 of 34) had stable disease and 32% (11 of 34) had recurrence, had progression of disease, or had been discharged to hospice after treatment. CONCLUSIONS: The pedicled omentum is an effective local tissue graft that can be used for complex wound reconstruction and management of high-risk closures in primary spine tumors. This technique may have a lower rate of complications than other approaches and may influence surgical planning and flap selection in challenging cases.

Pathway-based analyses of gene expression profiles at low doses of ionizing radiation.

Radiation exposure poses a significant threat to human health. Emerging research indicates that even low-dose radiation once believed to be safe, may have harmful effects. This perception has spurred a growing interest in investigating the potential risks associated with low-dose radiation exposure across various scenarios. To comprehensively explore the health consequences of low-dose radiation, our study employs a robust statistical framework that examines whether specific groups of genes, belonging to known pathways, exhibit coordinated expression patterns that align with the radiation levels. Notably, our findings reveal the existence of intricate yet consistent signatures that reflect the molecular response to radiation exposure, distinguishing between low-dose and high-dose radiation. Moreover, we leverage a pathway-constrained variational autoencoder to capture the nonlinear interactions within gene expression data. By comparing these two analytical approaches, our study aims to gain valuable insights into the impact of low-dose radiation on gene expression patterns, identify pathways that are differentially affected, and harness the potential of machine learning to uncover hidden activity within biological networks. This comparative analysis contributes to a deeper understanding of the molecular consequences of low-dose radiation exposure.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Mindful Night-to-Day: A Pilot Feasibility Trial of a Mindfulness-Based Insomnia and Symptom Management Intervention for Patients with Hematologic Cancer.

OBJECTIVES: Patients with hematologic cancer experience severe symptoms (i.e. insomnia, fatigue, pain, distress). Few interventions addressing insomnia and other symptoms exist for this population. Mindfulness-Based Therapy for Insomnia (MBTI) may be appropriate but has only been tested in healthy outpatients. This study aimed to develop and test an adapted MBTI protocol for hematologic cancer patients. METHODS: Patient (n = 3) and clinician (n = 1) focus groups, and user-testing (N = 5) informed adaptation of Mindful Night-to-Day (MBTI+). A single-arm pilot trial (N = 32) evaluated feasibility (accrual, attrition, adherence), acceptability (intervention satisfaction), and changes to insomnia symptom severity (Insomnia Severity Index; primary outcome) and secondary outcomes (fatigue, pain, distress, pre-sleep arousal, mindfulness, symptom management self-efficacy) at baseline, post-intervention, and 1-month post-intervention. Descriptive statistics and paired sample t-tests were conducted. RESULTS: Qualitative feedback informed MBTI+ content, format, and delivery. Mindfulness was used to increase symptom awareness (sleepiness vs. fatigue). Meditations and behavioral skills were applied to inpatient treatment. MBTI+ met feasibility (N = 32/12 months; 8.1% attrition; 83.8% adherence) and acceptability (M = 3.52/4.00) benchmarks. Insomnia symptom severity decreased (d = 1.20) from baseline to post-intervention, as did most secondary outcomes. CONCLUSIONS: MBTI+ was feasible, acceptable, and showed promise for benefits throughout inpatient and outpatient treatment. Findings warrant further evaluation in a randomized trial.

Physicians' Human Papillomavirus Vaccine Communication With Parents of Different Skin Color: Feasibility of Measuring Indicators of Implicit Bias With Virtual Reality.

PURPOSE: Virtual reality (VR) may be a viable method to observe and describe signals of implicit bias. Using the context of the human papillomavirus vaccine counseling, we sought to describe physicians' communication practices exploring differences when counseling parents with different skin colors. METHODS: Physicians (N = 90) at an academic primary care center were recruited for a VR study in which they counseled dark or light-skinned parent avatars who expressed hesitation about human papillomavirus vaccination for their adolescent child. Investigators coded previously recorded simulations. Associations between communication and parent skin color were examined using t-tests and Chi-square tests. RESULTS: Both direct (e.g., addressing the concern immediately) and circuitous (e.g., providing alternative information) communication patterns were observed. Physicians used passive voice less commonly when counseling dark-skinned versus light-skinned avatars (p < .05). DISCUSSION: VR demonstrated feasibility in capturing clinicians' communication behaviors including measuring eight distinct indicators of implicit bias.

In vivo measurement of RBC survival in patients with sickle cell disease before or after hematopoietic stem cell transplantation.

ABSTRACT: Stable, mixed-donor-recipient chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD) is sufficient for phenotypic disease reversal, and results from differences in donor/recipient-red blood cell (RBC) survival. Understanding variability and predictors of RBC survival among patients with SCD before and after HSCT is critical for gene therapy research which seeks to generate sufficient corrected hemoglobin to reduce polymerization thereby overcoming the red cell pathology of SCD. This study used biotin labeling of RBCs to determine the lifespan of RBCs in patients with SCD compared with patients who have successfully undergone curative HSCT, participants with sickle cell trait (HbAS), and healthy (HbAA) donors. Twenty participants were included in the analysis (SCD pre-HSCT: N = 6, SCD post-HSCT: N = 5, HbAS: N = 6, and HbAA: N = 3). The average RBC lifespan was significantly shorter for participants with SCD pre-HSCT (64.1 days; range, 35-91) compared with those with SCD post-HSCT (113.4 days; range, 105-119), HbAS (126.0 days; range, 119-147), and HbAA (123.7 days; range, 91-147) (P<.001). RBC lifespan correlated with various hematologic parameters and strongly correlated with the average final fraction of sickled RBCs after deoxygenation (P<.001). No adverse events were attributable to the use of biotin and related procedures. Biotin labeling of RBCs is a safe and feasible methodology to evaluate RBC survival in patients with SCD before and after HSCT. Understanding differences in RBC survival may ultimately guide gene therapy protocols to determine hemoglobin composition required to reverse the SCD phenotype as it relates directly to RBC survival. This trial was registered at www.clinicaltrials.gov as #NCT04476277.

Repeat stereotactic radiosurgery for persistent cerebral arteriovenous malformations in pediatric patients.

OBJECTIVE: The purpose of this study was to describe the long-term outcomes and associated risks related to repeat stereotactic radiosurgery (SRS) for persistent arteriovenous malformations (AVMs) in pediatric patients. METHODS: Under the auspices of the International Radiosurgery Research Foundation, this retrospective multicenter study analyzed pediatric patients who underwent repeat, single-session SRS between 1987 and 2022. The primary outcome variable was a favorable outcome, defined as nidus obliteration without hemorrhage or neurological deterioration. Secondary outcomes included rates and probabilities of hemorrhage, radiation-induced changes (RICs), and cyst or tumor formation. RESULTS: The cohort included 83 pediatric patients. The median patient age was 11 years at initial SRS and 15 years at repeat SRS. Fifty-seven children (68.7%) were managed exclusively using SRS, and 42 (50.6%) experienced hemorrhage prior to SRS. Median AVM diameter and volume were substantially different between the first (25 mm and 4.5 cm3, respectively) and second (16.5 mm and 1.6 cm3, respectively) SRS, while prescription dose and isodose line remained similar. At the 5-year follow-up evaluation from the second SRS, nidus obliteration was achieved in 42 patients (50.6%), with favorable outcome in 37 (44.6%). The median time to nidus obliteration and hemorrhage was 35.5 and 38.5 months, respectively. The yearly cumulative probability of favorable outcome increased from 2.5% (95% CI 0.5%-7.8%) at 1 year to 44% (95% CI 32%-55%) at 5 years. The probability of achieving obliteration followed a similar pattern and reached 51% (95% CI 38%-62%) at 5 years. The 5-year risk of hemorrhage during the latency period after the second SRS reached 8% (95% CI 3.2%-16%). Radiographically, 25 children (30.1%) had RICs, but only 5 (6%) were symptomatic. Delayed cyst formation occurred in 7.2% of patients, with a median onset of 47 months. No radiation-induced neoplasia was observed. CONCLUSIONS: The study results showed nidus obliteration in most pediatric patients who underwent repeat SRS for persistent AVMs. The risks of symptomatic RICs and latency period hemorrhage were quite low. These findings suggest that repeat radiosurgery should be considered when treating pediatric patients with residual AVM after prior SRS. Further study is needed to define the role of repeat SRS more fully in this population.

Association between socioeconomic deprivation and presentation with a ruptured abdominal aortic aneurysm.

OBJECTIVE: Given the ongoing nature of research in the social determinants space and urges to improve United States Preventive Services Task Force screening efforts for abdominal aortic aneurysms (AAAs), this project aims to characterize the association between the level of socioeconomic deprivation, rurality, and ruptured AAA (rAAA) presentation across the United States. METHODS: We queried the Vascular Quality Initiative registry (2010-2019) for patients with AAAs. The area deprivation index (ADI) is an index from 1 to 100 used to capture socioeconomic status. ADI was grouped into quintiles, with the most deprived regions being quintile 5 and having the highest ADI index. Multivariable logistic regression assessed the association between ADI, rurality, and rAAA presentation overall and before age 65. RESULTS: Of the 82,909 patients included, 11,458 patients (14%) resided in the most socioeconomically deprived regions, and 18,083 patients (22%) lived in rural regions. Overall, 6831 patients (8.2%) experienced an rAAA, with 4696 patients (69%) residing in the three most deprived quintiles. Most patients underwent endovascular repair (n = 67,933; 82%), followed by open repair (n = 14,976; 18%). On multivariable analysis, residence in the most socioeconomically deprived region was associated with a near 1.5-fold increased odds of presenting with an rAAA compared with a residence in the least deprived regions (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.31-1.63; P < .001), whereas urban residence was associated with a decreased odds to present with an rAAA compared with rural residence (OR, 0.84; 95% CI, 0.79-0.89; P < .001). When stratifying the study population by the United States Preventive Services Task Force recommended age for AAA screening (65 years old), 14,147 patients (17%) were under 65. Of those under 65, 1381 patients (9.8%) experienced a rAAA, and 9955 patients (71%) resided in the three most deprived quintiles. Residence in the most socioeconomically deprived region was associated with an increased odds of presenting with an rAAA compared with residence in the least deprived region (OR, 1.31; 95% CI, 1.01-1.69; P = .042). However, there were no significant associations between rural residence and increased rAAA presentation among individuals under 65 (OR, 1.07; 95% CI, 0.93-1.23; P = .36). CONCLUSIONS: Among all patients in this study, patients residing in highly socioeconomically deprived or rural regions were more likely to present with an rAAA, but among those under 65, only residence in a socioeconomically deprived area was associated with increased odds of rAAA presentation. Understanding the effects of socioeconomic deprivation on rAAA presentation can identify at-risk populations for early AAA screening before rupture.

ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.

Outcome data from 15 years of cystic fibrosis newborn screening in a large UK region.

BACKGROUND: The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children's Hospital at Royal Stoke and Birmingham Children's Hospital). CF newborn bloodspot screening (NBS) in this region started in November 2006 prior to the UK national roll-out in 2007. It uses an immunoreactive trypsinogen (IRT)/DNA/IRT protocol. We report the outcomes from 15 years of CF screening. METHODS: The West Midlands CF NBS outcomes from 1 November 2006 to 31 October 2021 were reviewed. Clinical data were also obtained for babies referred to the CF centres as 'CF suspected'. RESULTS: 1 075 161 babies were screened, with 402 referred as 'CF suspected' and 205 identified as CF carriers. Of the 'CF suspected' babies, 268 were diagnosed with CF, 33 with CF screen positive, inconclusive diagnosis (CFSPID) and 17 as a CF carrier. Any CF-related diagnosis was excluded in 67. Outcome data were not available for 17, of whom 14 had died. Eighteen children with a negative CF NBS have subsequently been diagnosed with CF, 10 had meconium ileus and 8 were true 'affected not detected', presenting with respiratory symptoms or failure to thrive. This gives the West Midlands a CF birth prevalence of 1 in 4012 live births and the NBS protocol a sensitivity of 97.1% and a positive predictive value of 66.7%. CONCLUSIONS: This large regional data set has excellent case ascertainment and demonstrates successful performance of the CF NBS protocol, with low numbers identified as CFSPID or CF carriers.

Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study.

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.

Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3ß Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies.

PURPOSE: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3ß (GSK-3ß) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. PATIENTS AND METHODS: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. RESULTS: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2-2.6] and 6.9 (95% CI, 5.7-8.4) months, respectively. CONCLUSIONS: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

Late Referral and Patient Transfer is Associated with Worse Outcomes for Patients Presenting with Initially Uncomplicated Type B Aortic Dissections.

BACKGROUND: Acute type B aortic dissections (TBADs) can become complicated at any time point, necessitating surgical repair. We sought to investigate the effect of interhospital transfer on the development of delayed complications in acute type B aortic dissection (dcTBAD). METHODS: All patients who presented with acute TBAD to a tertiary aortic center from 2015 to 2019 were analyzed. Patients were divided into initially complicated type B aortic dissection (icTBAD) (0-24 hours from symptom onset), dcTBAD (25 hours to 14 days), and uncomplicated type B aortic dissection (ucTBAD) groups. Criteria for complicated dissection were aortic rupture, malperfusion, or rapid aortic growth. Demographics, patient history, the timing of presentation, imaging findings, and clinical outcomes were compared between groups. RESULTS: Of 120 acute TBADs included, 27 (22%) were initially complicated (aortic rupture, n = 9; malperfusion, n = 18). Twenty-one (18%) developed delayed complications (aortic rupture, n = 3; malperfusion, n = 14; rapid growth, n = 4) at a median of 7.0 [4.0, 9.0] days from symptom onset. Seventy-two (60%) remained uncomplicated. Overall, 111 (93%) presented as transfers from outside hospitals (icTBAD, n = 25; dcTBAD, n = 21; ucTBAD, n = 65). Of those, dcTBADs were more likely to have a prolonged delay between presentation to the outside hospital and referral to the tertiary center compared to ucTBADs (median = 1.00 [0.0, 5.0] days delayed vs. 0.00 [0.0, 0.0] days delayed; P < 0.001). Initially uncomplicated patients referred for transfer ≥24 hours from presentation went on to develop dcTBAD more often than those transferred in <24 hours (73% vs 13%; P < 0.001). Of dcTBADs, 38% had no high-risk features on initial imaging. Patients with dcTBAD had significantly longer length of stay (median = 12 vs 7 days; P = 0.006). In-hospital mortality was significantly higher in dcTBADs than ucTBADs (9.5% vs 0%; P = 0.047). In-hospital mortality was not significantly different between dcTBADs and icTBADs (9.5% vs. 11%; P > 0.05). CONCLUSIONS: The incidence and consequence of dcTBADsare not insignificant. Late referral and transfer to a tertiary aortic center (≥24 hours from initial presentation) was associated with dcTBADsrequiring surgical intervention. The development of dcTBADwas associated with increased length of stay and increased in-hospital mortality.

Renal Artery Reimplantation Versus Bypass in Elective Open Aneurysm Repair.

BACKGROUND: Complex open abdominal aortic aneurysm (AAA) repair often necessitates revascularization of renal arteries by either renal artery reimplantation or bypass. This study aims to evaluate the perioperative and short term outcomes between these 2 strategies of renal artery revascularization. METHODS: We performed a retrospective review of patients who underwent open AAA repair from 2004 to 2020 at our own institution. Patients who underwent elective suprarenal, juxtarenal, or type 4 thoracoabdominal aneurysm repair were identified using current procedural terminology (CPT) codes and a retrospectively maintained database of AAA patients. Patients who had symptomatic aneurysm or significant renal artery stenosis before AAA repair were excluded. Patient demographics, intraoperative conditions, renal function, bypass patency, and perioperative and postoperative outcomes at 30 days and 1 year were compared. RESULTS: One hundred and forty-three patients underwent either renal artery reimplantation (n = 86) or bypass (n = 57) during this time period. The mean age was 69.7 years and 76.2% of the patients were male. Median preoperative creatinine was 1.2 mg/dL for the renal bypass group versus 1.06 mg/dL for reimplantation (P = 0.088). Both groups had similar median preoperative glomerular filtration rate (GFR) of >60 mL/min (P = 0.13). Bypass and reimplantation groups had similar perioperative complications including acute kidney injury (51.8% vs. 49.4% P = 0.78), inpatient dialysis (3.6% vs. 1.2% P = 0.56), myocardial infarction (1.8% vs. 2.4% P = 0.99), and death (3.5% vs. 4.7% P = 0.99), respectively. During the 30-day follow-up period, renal artery stenosis was identified in 9.8% of bypasses and 6.7% of reimplantations (P = 0.71). Six point one percent of patients in the bypass group had renal failure requiring dialysis (both acute and permanent) compared to 1.3% in reimplantation group (P = 0.3). For those who had 1-year follow-up, the reimplantation group had higher new incidence of renal artery stenosis compared to bypass group (6 vs. 0 P = 0.16). CONCLUSIONS: Given that there is no significant difference in outcomes between renal artery reimplantation and bypass within 30 days or at 1-year follow-up, both bypass and reimplantation are acceptable means for renal artery revascularization during elective AAA repair.