Examining Human-Smartphone Interaction as a Proxy for Circadian Rhythm in Patients With Insomnia: Cross-Sectional Study.

BACKGROUND: The sleep and circadian rhythm patterns associated with smartphone use, which are influenced by mental activities, might be closely linked to sleep quality and depressive symptoms, similar to the conventional actigraphy-based assessments of physical activity. OBJECTIVE: The primary objective of this study was to develop app-defined circadian rhythm and sleep indicators and compare them with actigraphy-derived measures. Additionally, we aimed to explore the clinical correlations of these indicators in individuals with insomnia and healthy controls. METHODS: The mobile app "Rhythm" was developed to record smartphone use time stamps and calculate circadian rhythms in 33 patients with insomnia and 33 age- and gender-matched healthy controls, totaling 2097 person-days. Simultaneously, we used standard actigraphy to quantify participants' sleep-wake cycles. Sleep indicators included sleep onset, wake time (WT), wake after sleep onset (WASO), and the number of awakenings (NAWK). Circadian rhythm metrics quantified the relative amplitude, interdaily stability, and intradaily variability based on either smartphone use or physical activity data. RESULTS: Comparisons between app-defined and actigraphy-defined sleep onsets, WTs, total sleep times, and NAWK did not reveal any significant differences (all P>.05). Both app-defined and actigraphy-defined sleep indicators successfully captured clinical features of insomnia, indicating prolonged WASO, increased NAWK, and delayed sleep onset and WT in patients with insomnia compared with healthy controls. The Pittsburgh Sleep Quality Index scores were positively correlated with WASO and NAWK, regardless of whether they were measured by the app or actigraphy. Depressive symptom scores were positively correlated with app-defined intradaily variability (ß=9.786, SD 3.756; P=.01) and negatively correlated with actigraphy-based relative amplitude (ß=-21.693, SD 8.214; P=.01), indicating disrupted circadian rhythmicity in individuals with depression. However, depressive symptom scores were negatively correlated with actigraphy-based intradaily variability (ß=-7.877, SD 3.110; P=.01) and not significantly correlated with app-defined relative amplitude (ß=-3.859, SD 12.352; P=.76). CONCLUSIONS: This study highlights the potential of smartphone-derived sleep and circadian rhythms as digital biomarkers, complementing standard actigraphy indicators. Although significant correlations with clinical manifestations of insomnia were observed, limitations in the evidence and the need for further research on predictive utility should be considered. Nonetheless, smartphone data hold promise for enhancing sleep monitoring and mental health assessments in digital health research.

Longitudinal Outcomes of Resilience, Quality of Life, and Community Integration in Treatment-Resistant Depression: A Two-Group Matched Controlled Trial.

BACKGROUND: Current evidence of nonpharmacological intervention for patients with treatment-resistant depression (TRD) is lacking. AIMS: To examine whether an 8-week nurse-led cognitive-behavioral based group intervention would enhance resilient coping and life quality among community-based patients with TRD. METHOD: The participants were randomly sampled from a cohort of TRD recruited from two general teaching hospitals. The two groups were assessed with multiple outcome measures at baseline (T0); 8-week post-baseline (T1); and at 3, 6, and 9 months after T1 (T2-4). Psychoeducation was nested in the cognitive behavioral group intervention to facilitate discussion. RESULTS: Of the 23 participants (mean age 56 years, 69.6% female) in the experimental group, higher resilient coping and lower mental distress levels at T1 as well as later improved quality of life and community integration at T2-4 were observed compared to the controls across COVID-19 (T3). Overall, the scores of resilience and community integration were higher throughout the four follow-up points of observations for the experimental group. CONCLUSION: The findings indicated that an 8-week nurse-led cognitive-behavioral based group intervention may enhance the TRD patients' resilient coping and mental distress levels while providing the potentials for community reintegration after mental health psychoeducation engagement. It is imperative for the nurses caring for patients with TRD to extend from clinical-based intervention to community-based self-care approach, with the importance of short-term stress management and healthy lifestyle development highlighted during the community reintegration trajectory.

Outcomes and Hemodynamic Performances of Transcatheter Aortic Valve Replacement with Two Generations of Self-Expanding Transcatheter Aortic Valves.

Background: The superiority of the new-generation self-expanding Evolut R compared with the first-generation CoreValve with regards to outcomes after transcatheter aortic valve replacement (TAVR) is unclear. The aim of this study was to investigate the hemodynamic and clinical performance of Evolut R compared with its direct predecessor, CoreValve, in a Taiwanese population. Methods: This study included all consecutive patients who underwent TAVR with either CoreValve or Evolut R between March 2013 and December 2020. Thirty-day Valve Academic Research Consortium-2 (VARC-2)-defined outcomes and hemodynamic performances were investigated. Results: There were no significant differences in baseline demographic characteristics between the patients receiving CoreValve (n = 117) or Evolut R (n = 117). Aortic valve-in-valve procedures for failed surgical bioprosthesis and procedures under conscious sedation were performed significantly more often with Evolut R. Pre-dilatation was performed significantly more often and contrast media volume was significantly higher with CoreValve. Stroke (0% vs. 4.3%, p = 0.024) and the need for emergent conversion to open surgery (0% vs. 5.1%, p = 0.012) were significantly lower in Evolut R than in CoreValve recipients. Evolut R significantly reduced 30-day composite safety endpoint (4.3% vs. 15.4%, p = 0.004). Conclusions: Advancements in transcatheter valve technologies have resulted in improved outcomes for patients undergoing TAVR with self-expanding valves. With the new-generation Evolut R, device success was high and the 30-day composite safety endpoint was significantly reduced after TAVR compared with CoreValve.

Gal-1 (Galectin-1) Upregulation Contributes to Abdominal Aortic Aneurysm Progression by Enhancing Vascular Inflammation.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a vascular degenerative disease causing sudden rupture of aorta and significant mortality in elders. Nevertheless, no prognostic and therapeutic target is available for disease management. Gal-1 (galectin-1) is a ß-galactoside-binding lectin constitutively expressed in vasculature with roles in maintaining vascular homeostasis. This study aims to investigate the potential involvement of Gal-1 in AAA progression. Approach and Results: Gal-1 was significantly elevated in circulation and aortic tissues of Ang II (angiotensin II)-infused apoE-deficient mice developing AAA. Gal-1 deficiency reduced incidence and severity of AAA with lower expression of aortic MMPs (matrix metalloproteases) and proinflammatory cytokines. TNFα (tumor necrosis factor alpha) induced Gal-1 expression in cultured vascular smooth muscle cells and adventitial fibroblasts. Gal-1 deletion enhanced TNFα-induced MMP9 expression in fibroblasts but not vascular smooth muscle cells. Cysteinyl-labeling assay demonstrated that aortic Gal-1 exhibited susceptibility to oxidation in vivo. Recombinant oxidized Gal-1 induced expression of MMP9 and inflammatory cytokines to various extents in macrophages, vascular smooth muscle cells, and fibroblasts through activation of MAP (mitogen-activated protein) kinase signaling. Clinically, serum MMP9 level was significantly higher in both patients with AAA and coronary artery disease than in control subjects, whereas serum Gal-1 level was elevated in patients with AAA but not coronary artery disease when compared with controls. CONCLUSIONS: Gal-1 is highly induced and contributes to AAA by enhancing matrix degradation activity and inflammatory responses in experimental model. The pathological link between Gal-1 and AAA is also observed in human patients. These findings support the potential of Gal-1 as a disease biomarker and therapeutic target of AAA.

Associations between lifetime mental disorders and suicidal behaviors: findings from the Taiwan psychiatry morbidity survey.

BACKGROUND: East Asia has high suicide rates but low prevalence of mental disorders. We examined the associations between prior lifetime mental disorders (mood disorders, anxiety disorders, substance use disorders, and impulse control disorders) and subsequent suicidal behaviors (suicidal ideation and attempts in the general population and suicide plans, planned attempts, and unplanned attempts in suicidal ideators) in Taiwan. METHODS: This survey applied the World Mental Health Survey Composite International Diagnostic Interview to a population representative sample of noninstitutionalized adults between 2003 and 2005. Odds ratios (ORs) obtained using discrete-time survival analysis were used to estimate population attributable fractions (PAFs) of suicidal behaviors due to lifetime mental disorders. RESULTS: Lifetime mental illness was a significant risk factor for subsequent suicidal behaviors (except unplanned attempts among ideators) despite the relatively low prevalence of mental disorders in people with suicidality (16.1%-35.0%). Each diagnosis increased the odds of suicidal ideation. In terms of acting on suicidal ideation, mood disorders were most strongly associated with having plans (OR = 10.0; 95% confidence interval, CI 4.3-21.1), whereas substance use disorders most strongly with either planned (OR = 27.3; 95% CI 6.3-118.5) or unplanned attempts (OR = 14.5; 95% CI 1.7-121.5). PAFs of all mental disorders on suicidality lay between 20 and 30% (except 11% of unplanned attempts among ideators). Mood, anxiety, and substance use disorders had higher PAFs than impulse control disorders. CONCLUSIONS: In addition to mood disorders, considering anxiety and substance use disorders is essential in devising population-based suicide prevention strategies.

Aortic remodeling of the provisional extension to induce complete attachment technique in DeBakey type IIIb aortic dissection.

BACKGROUND/PURPOSE: Data about volumetric remodeling of the provisional extension to induce complete attachment (PETTICOAT) technique on DeBakey type IIIb aortic dissection in acute and subacute phases were scarce. The proper timing to perform this technique to promote false lumen reduction was also unknown. METHODS: Patients with DeBakey type IIIb aortic dissection who underwent the PETTICOAT technique between December 2005 and March 2017 were reviewed and divided into acute (treatment occurred ≦14 days after symptom onset) and subacute (15-90 days) groups. Remodeling parameters of the true and false lumens were analyzed. Receiver operating characteristic curve was used to deduce the timing of this technique. RESULTS: In the 2-year follow-up, the acute group (N = 20) demonstrated significant true lumen expansion and false lumen regression in the thoracic, abdominal, and total aorta. However, the subacute group (N = 20) only showed significant shrinkage in the false lumen of the thoracic and total aorta. Using PETTICOAT technique within 36 days after the aortic event may result in better total false lumen reduction. CONCLUSION: For DeBakey type IIIb aortic dissection, more prominent true lumen expansion and false lumen reduction were noted when using the PETTICOAT technique in the acute phase. When performed within 36 days after symptoms onset, the PETTICOAT technique may potentiate better total false lumen regression.

Prevalence and correlates of suicidal behaviors in the Taiwan Psychiatric Morbidity Survey.

BACKGROUND/PURPOSE: Suicide is a huge global health burden. High suicide rates with a low prevalence of major depressive disorder were reported in East Asia. This study aimed to investigate the prevalence of suicidal behaviors in relation to the demographic characteristics and major depressive disorder in Taiwan. METHODS: This study was based on the Taiwan Psychiatric Morbidity Survey, conducted between 2003 and 2005, a survey of common psychiatric disorders in a nationally representative sample of non-institutionalized civilians aged 18 or above. Demographic data, major depressive disorder, and suicidal behaviors were ascertained by a face-to-face interview using the paper version of the World Mental Health Survey Composite International Diagnostic Interview. RESULTS: According to the total sample of 10,135 participants, the lifetime prevalence of suicidal ideation, plans and attempts was 7.52% (S.E = 0.46%), 1.31% (S.E. = 0.16%) and 1.29% (S.E. = 0.16%), respectively. Among suicide ideators, the conditional probability of making a suicide plan was 17.39% (S.E. = 1.92%), and a suicide attempt 17.16% (S.E. = 2.15%). Age ≤ 40, female sex, and major depressive disorder were related to a higher risk of suicidal behaviors in the general population; the former two were associated with further developing suicide attempts and the latter one developing plans among ideators. CONCLUSION: Despite low prevalence, major depressive disorder remained a significant risk factor for suicidal behaviors in Taiwan.

Technical Characteristics and Feasibility of Coronary Angiography and Percutaneous Coronary Interventions Performed after Transcatheter Aortic Valve Replacement with Self-Expanding Valves.

BACKGROUND: Coronary angiography (CA) or percutaneous coronary intervention (PCI) after transcatheter aortic valve replacement (TAVR) may become technically challenging after implantation of the self-expanding Medtronic CoreValve (MCV) device, which extends above the coronary ostia. The aim of this study was to investigate the incidence and feasibility of CA or PCI and the outcomes of PCI after TAVR with the MCV device. METHODS: From July 2014 to April 2020, among 209 patients treated with TAVR with a MCV device, 14 (7%) underwent CA or PCI after the procedure at a mean duration of 28 ± 15 months at our institution. RESULTS: The mean age of the patients was 83 ± 6 years. Thirteen (93%) patients underwent CA due to angina symptoms with a positive noninvasive test, and 1 underwent CA for acute coronary syndrome. Most of the CA and PCI procedures were performed through a radial approach: 11 patients (79%) via the right radial artery, 1 (7%) the left radial artery, and 2 (14%) through the right femoral artery. CA of the left and right coronary arteries was successfully achieved in 13 patients (93%) with Judkin left (3.5 to 5) diagnostic catheters and in 11 patients (79%) with Judkin right (4) diagnostic catheters. The second-line catheter of choice was the Amplatz left (AL) 1 catheter for the right coronary artery and AL 2 for the left coronary artery. Procedural success was achieved in all 5 patients who underwent post-TAVR PCI without procedural or in-hospital complications. The use of a Guideliner microcatheter facilitated stent delivery in one patient. CONCLUSIONS: Coronary angiography or PCI following TAVR with a MCV device is feasible and safe, but requires understanding of the three-dimensional geometry of the prosthetic valve and its relationship to the coronary ostia.

Internal iliac artery preservation outcomes of endovascular aortic repair for common iliac aneurysm: iliac branch device versus crossover chimney technique.

OBJECTIVES: To compare the outcomes of using iliac branch devices (IBD) and the crossover chimney (COCh) technique for preserving the internal iliac artery (IIA) during endovascular aortic repair in patients with common iliac aneurysm (CIA). METHODS: From February 2010 to July 2016, we recruited 61 consecutive and elective patients. Thirty of them received the IBD, and the remaining 31 received the COCh. Their medical chart was reviewed retrospectively, and computed tomographic angiography was performed at 3, 6, and 12 months postoperatively and then yearly as a follow-up. RESULTS: The median follow-up time was 19.72 ± 5.45 months. The technical success rate reached 100% in both groups. The 12-month and 24-month primary IIA patency rates between IBD and COCh group were 90.00% versus 93.54% (p = 0.67) and 83.33% versus 93.54% (p = 0.25). The numbers of stents were 1.00 ± 0.00 and 1.93 ± 0.24 in the IBD and COCh group (p < 0.001). No significant difference was observed for the incidence of type 1a (IBD/COCh = 3.33%/6.45%, p > 0.99) and type 2 endoleak (IBD/COCh = 13.33%/12.90%, p > 0.99) between two groups. Neither type 1b or type 3 endoleak nor delayed aortic rupture appeared in our series. The postoperative complication rates did not exhibit significant differences either. Free from reintervention was also similar in both groups (IBD/COCh = 22.50 ± 4.62/23.00 ± 3.87 months, p = 0.64). CONCLUSIONS: The IBD and COCh techniques exhibited similar success rates and IIA patency rates at the 24-month follow-up. Both these techniques are feasible for the preservation of IIA in patients with CIA.

Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, P = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

Women had favourable reverse left ventricle remodelling after TAVR.

BACKGROUND: Being woman is associated with higher survival rates after transcatheter aortic valve replacement (TAVR) despite the increase in periprocedural complications. The left ventricle (LV) remodelling process that follows TAVR is considered to play an important role. We aim to investigate whether gender difference affects the process of LV remodelling after TAVR. MATERIALS AND METHODS: A total of 100 patients (50 men and 50 women) after TAVR were enrolled. Echocardiography was performed at baseline before the TAVR procedure and repeated upon discharge, and at three, nine and 12 months post-TAVR. RESULTS: Women exhibited an early regression of LV mass and the LV mass index (LVMi) decreased 12.0% from 148.3 ± 48.0 to 130.5 ± 43.7 g/m2 at just a median of 17 days after the procedure (P < .001). Almost one-half of the LVMi regression occurred by 17 days post-TAVR and the LVMi regressed 22.0% by 12 months post-TAVR. In contrast, the regression of LVMi in men seemed to be more gradual and the significant regression of LVMi from baseline began to be observed since three months later after TAVR. The LVMi reduction at nine months was 11.5% and achieved 15.4% over one year. Multivariable logistic regression analysis showed only the female sex, better LVEF and greater baseline LVMi were independently associated with greater LVMi regression after TAVR, indicating female gender is an independent predictor for favourable LV remodelling after TAVR. CONCLUSION: In conclusion, female patients with AS had favourable reverse remodelling with greater and earlier LV mass regression post-TAVR compared with the male patients.

CT Angiography Findings Predictive of Kidney Injury in Chronic Aortic Dissection.

OBJECTIVE. The purpose of this study was to compare the volume alteration and effective renal plasma flow of kidneys supplied by false lumens (FLs) with those of kidneys supplied by true lumens (TLs), to show the discrepancy in perfusion between the two lumens. We sought to corroborate malperfusion of FL-supplied kidneys with imaging characteristics observed on CT angiography. MATERIALS AND METHODS. A retrospective analysis was conducted using prospectively collected data for 87 patients with a diagnosis of residual chronic aortic dissection between 2005 and 2013 who had one kidney perfused by a TL and the other kidney perfused by a FL. RESULTS. Overall, at follow-up, FL-supplied kidneys had a mean (± SD) effective renal plasma flow (117.5 ± 42.6 vs 146.6 ± 41.0 mL/min; p = 0.004) and volume (131.1 ± 37.1 vs 146.5 ± 33.3 cm3; p = 0.004) that were lower than those of TL-supplied kidneys. Multivariate analysis revealed the presence of a proximal major inlet (odds ratio, 0.306; 95% CI, 0.103-0.910; p = 0.033) and large FL area (odds ratio, 0.104; CI, 0.012-0.880; p = 0.038) as factors protecting against malperfusion of FL-supplied kidneys. In patients with dissected renal arteries, the FL-supplied kidney had low effective renal plasma flow (mean, 88.5 ± 26.8 vs 149.6 ± 43.5 mL/min; p = 0.004) and diminished volume (mean, 120.4 ± 30.4 vs 152.3 ± 24.6 cm3; p = 0.001). CONCLUSION. In the present study, kidneys perfused by FLs showed decreased volume and reduced effective renal plasma flow during follow-up, particularly those kidneys with dissected renal arteries, a small FL area at the renal level, and lack of a proximal major inlet. Further studies are warranted to identify the clinical relevance of malperfusion in FL-supplied kidneys.

Sex difference in the prognostic role of body composition parameters in Taiwanese patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Evidence on association between body composition and outcomes of transcatheter aortic valve implantation (TAVI) is limited for Asian patients. This study investigated the prognostic role of body composition parameters in Taiwanese patients undergoing TAVI. MATERIALS AND METHODS: Data of consecutive patients undergoing TAVI for severe aortic stenosis between May 1, 2010 and August 31, 2019 were prospectively collected in this observational study. The association between body composition parameters (body mass index [BMI], body surface area [BSA], lean body mass [LBM], and LBM index) and cumulative mortality was analyzed using Cox proportional hazard regression model. RESULTS: A total of 221 patients (mean age 81.4 years), including 125 (56.6%) males, were included with median follow-up duration of 23.8 months. In males, multivariate analysis revealed that higher BMI (P = 0.035), BMI ≥ 20 kg/m2 (P = 0.026), and higher LBM index (P = 0.023) significantly predicted lower overall all-cause cumulative mortality. In females, none of the body composition parameters was significantly associated with all-cause cumulative mortality. Paradoxical association between BMI and estimated all-cause cumulative mortality was only significant among male patients. CONCLUSION: In Taiwanese TAVI patients, the prognostic effects of BMI and LBM index on cumulative mortality were only observed in males, not in females. Sex differences must be considered when stratifying risk among patients undergoing TAVI.

[The Impact of the COVID-19 Pandemic on the Health and Coping Behaviors of Patients With Treatment-Resistant Depression].

BACKGROUND: The COVID-19 pandemic has had a disastrous impact globally. For the general public and for people with mental illnesses, this pandemic may cause mental/physical stress and major life impacts. PURPOSE: This study was designed to explore the related changes in daily life and impacts on the well-being of a group of patients with chronic treatment-resistant depression (TRD) during the COVID-19 pandemic. METHODS: This study was a part of a long-term, follow-up study of a cohort of patients with TRD collected in 2018. All of the subjects who were diagnosed with major depression and fit the inclusion criteria were referred by the psychiatrists from two teaching hospitals. Structured interviews were used to collect data on physical and psychological changes during the pandemic period between January and May 2020. The researchers organized the key points by recording or note taking. Thematic analysis was used to summarize and classify themes and units. RESULTS: The 116 respondents revealed that the COVID-19 pandemic affected their health in the biological, psychological, and social dimensions. The three emerging themes included: The threatening of homogeneity in the whole person's health, the interaction between bio-psycho-social aspects, and positive growth of individuals with TRD. Although the participants had confidence in the prevention strategies of the government related to COVID-19, they expressed feelings of distress and restlessness with regard to COVID-19-related news reports. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic has affected the health of patients with TRD in both positive and negative ways. As the goal of government preventive strategies is to protect and promote public health, regular attention should be paid to the negative effects of long-term exposure to pandemic-related news on this vulnerable population.

Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.

Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are conflicting data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly diagnosed B-cell ALL (B-ALL) who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells. Of 148 patients, 33.1% had Ph-like, 31.1% had Ph+, and 35.8% had other B-ALL subtypes (B-other). Within the Ph-like ALL cohort, 61% had cytokine receptor-like factor 2 (CRLF2) overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS), and event-free survival compared with B-other with a 5-year survival of 23% (vs 59% for B-other, P = .006). Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity. The following were associated with inferior OS on multivariable analysis: age (hazard ratio [HR], 3.299; P < .001), white blood cell count (HR, 1.910; P = .017), platelet count (HR, 7.437; P = .005), and Ph-like ALL (HR, 1.818; P = .03). Next-generation sequencing of the CRLF2+ group identified mutations in the JAK-STAT and Ras pathway in 85% of patients, and 20% had a CRLF2 mutation. Within the CRLF2+ group, JAK2 mutation was associated with inferior outcomes. Our findings show high frequency of Ph-like ALL in adults, an increased frequency of Ph-like ALL in adults of Hispanic ethnicity, significantly inferior outcomes of adult patients with Ph-like ALL, and significantly worse outcomes in the CRLF2+ subset of Ph-like ALL. Novel strategies are needed to improve the outcome of these patients.

Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.

Outcome of drug-eluting balloon angioplasty versus endarterectomy in common femoral artery occlusive disease.

OBJECTIVE: Common femoral artery (CFA) occlusive disease remains a debatable site for endovascular therapy, and the outcome of drug-eluting balloon (DEB) angioplasty in treating CFA occlusive disease is largely unknown. This study compared the efficacy, safety, and short-term patency rate of DEB angioplasty and femoral endarterectomy for treatment of CFA occlusive disease. METHODS: From March 2013 to June 2016, there were 100 patients with symptomatic CFA occlusive disease who were retrospectively reviewed. Forty patients were treated with DEB angioplasty and 60 were treated with femoral endarterectomy. Each patient received regular follow-up. Patency rate, ankle-brachial index, target lesion revascularization, and adverse events were assessed. RESULTS: Technical success was 100% in all patients. The DEB group had a lower 1-year primary patency rate (75.0% vs 96.7%; P = .003), but the secondary patency rate was similar between the two groups (97.5% vs 98.3%; P = 1.000). At 2-year follow-up, the primary patency was lower in the DEB group (57.1%) than in the endarterectomy group (94.1%; P = .001), whereas the secondary patency rate had no significant difference (90.5% vs 97.1%; P = 1.000). Both groups had significant improvement in ankle-brachial index. Freedom from target lesion revascularization was lower in the DEB group both at 1 year (75.0% vs 96.7%; P = .003) and at 2 years (57.1% vs 94.1%; P = .001). There was no significant difference in the incidence of complications and adverse events. CONCLUSIONS: Femoral endarterectomy has a better primary patency rate compared with DEB angioplasty in treating CFA occlusive disease without significant increase in complications. In patients not suitable for endarterectomy, DEB angioplasty provides a similar secondary patency rate and could be considered an alternative treatment.

Impact of Renal Artery Stent-Graft Placement on Renal Function in Chronic Aortic Dissection.

PURPOSE: To evaluate the effect of renal stent-graft placement on kidney function and size alternation in chronic aortic dissection. MATERIALS AND METHODS: Twenty-five consecutive patients with chronic aortic dissection after thoracic endovascular aortic repair who underwent renal stent-graft placement between January 2015 and December 2016 were retrospectively reviewed. Forty-three patients with chronic aortic dissection who received thoracic endovascular aortic repair in the same period were reviewed as a control group for kidney volume comparison. RESULTS: Twenty-five stent-grafts were deployed over 25 renal arteries. Overall renal function was assessed by the slope of the regression line constructed from the plots of creatinine clearance versus time within 2 years after the procedure (-0.2810 vs -0.3146 mL/min-1/mo-1, P = .868), kidney volume at 12 months (129.4 ± 40.9 vs 137.0 ± 44.2 cm2, P = .193) and effective renal plasma flow at 6 months (106.3 ± 46.9 vs 124.4 ± 55.5 mL/min, P = .050) and was not significantly deteriorated. Seven treated patients (87.5%) with a renal artery supplied by a false lumen had a decrease in kidney volume, as did 14 patients (56%) in the control group (P = .206). Three patients with a dissected renal artery (75%) in the stent-graft group had an increase in kidney volume compared with 1 patient (11.1%) in the control group (P = .052). CONCLUSIONS: Occlusion of the re-entry tear by a stent-graft in the renal artery remains a safe strategy to promote false lumen thrombosis. The stent-graft poses a potential risk of reducing the kidney volume in kidneys supplied by the false lumen but may provide a positive effect in kidney volume with a concomitant dissected renal artery in chronic aortic dissection.

Factors in ProGlide® Vascular Closure Failure in Sheath Arteriotomies Greater than 16 French.

OBJECTIVES: The ProGlide® vascular closure device (Abbott Vascular, Redwood City, CA, USA) is approved for the closure of arterial punctures (typically 5-21 Fr sheath; maximum outer diameter, 26 Fr). However, a failure rate of about 2-8% is reported. This study was conducted to analyse factors predisposing to failure when the devices were used for the closure of large hole (16-26 Fr) arteriotomies, and to determine the predictive cut off values of predisposing factors. METHODS: In this retrospective study, the ProGlide® device was used to achieve vascular access site closure in 458 patients undergoing repair of abdominal aortic aneurysm, thoracic aortic aneurysm, type B aortic dissection, or transcatheter aortic valve implantation. The primary endpoint was device failure, defined as inability to achieve common femoral artery (CFA) closure; successful repair, development of acute lower limb ischaemia and haemodynamic compromise; or delayed pseudoaneurysm formation during the follow up period, requiring open repair. RESULTS: Overall, ProGlide® failure occurred in 7.6% of cases. Factors that predisposed to failure included a history of peripheral arterial disease (PAD) (p < .001), the presence of CFA calcification (p < .001), the depth of the skin puncture site ≥ 33 mm (p < .001), body mass index (BMI) of ≥28.7 kg/m2 (p < .001), and use of sheath size ≥ 19 Fr (p < .001). CONCLUSION: Factors such as BMI, history of PAD, the presence of CFA calcification, the depth of the skin puncture site, and sheath size are significantly associated with ProGlide® failure. Hence, careful patient and device selection and operating procedure are paramount to achieve successful outcomes.