Pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutations: a phase II study.

PURPOSE: To evaluate the efficacy and safety of pamiparib in patients with locally advanced or metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCA1/2 m). METHODS: In this open-label, phase II, multicenter study in China (NCT03575065), patients with triple-negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+/HER2- cohort) and ≤ 2 prior lines of chemotherapy received pamiparib 60 mg orally twice daily in 28-day, continuous cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee. RESULTS: In total, 88 patients were enrolled (TNBC cohort: 62; HR+/HER2- cohort: 26). Median age was 45.5 (range: 27-67) years, and 60 patients (68.2%) had received 1 or 2 prior lines of chemotherapy; 42 patients (47.7%) had previously received platinum chemotherapy. In the TNBC cohort, ORR was 38.2% (95% confidence interval [CI] 25.4-52.3) and median duration of response (DoR) was 7.0 months (95% CI 3.9-not estimable). In the HR+/HER2- cohort, ORR was 61.9% (95% CI 38.4-81.9) and median DoR was 7.5 months (95% CI 5.6-14.8). The most common treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and ≥ Grade 3 TEAEs were hematologic (including anemia, decreased neutrophil count, and decreased white blood cell count). Overall, 64.8% of patients had TEAEs leading to dose reduction and 2.3% had TEAEs leading to treatment discontinuation. CONCLUSION: Pamiparib showed encouraging efficacy and an acceptable safety profile in patients with locally advanced and metastatic HER2- breast cancer with gBRCA1/2 m. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03575065; July 2, 2018.

Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies.

BACKGROUND: Janus kinase (JAK)-mediated cytokine signalling contributes to local and systemic inflammation in hidradenitis suppurativa (HS). OBJECTIVES: To describe the safety and efficacy results from two multicentre phase II trials of the JAK1 inhibitor INCB054707 in patients with moderate-to-severe HS. METHODS: Patients received open-label INCB054707 15 mg once daily (QD; Study 1) or were randomized to INCB054707 30, 60 or 90 mg QD or placebo (3 : 1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18-75 years and had moderate-to-severe HS (Hurley stage II/III disease), lesions present in at least two anatomical locations, and a total abscess and inflammatory nodule count ≥ 3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures. RESULTS: Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8; placebo, n = 9). Overall, 70% of patients in Study 1 and 81% of patients receiving INCB054707 in Study 2 experienced at least one treatment-emergent adverse event; 30% and 42% of patients, respectively, had at least one treatment-related adverse event. Among the evaluable patients, three (43%) in Study 1 and 17 (65% overall: 30 mg, 56%; 60 mg, 56%; 90 mg, 88%) receiving INCB054707 vs. 4 patients (57%) receiving placebo in Study 2 achieved HiSCR at week 8. CONCLUSIONS: INCB054707 was well tolerated, with responses observed in patients with moderate-to-severe HS. The safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS. The studies are registered on ClinicalTrials.gov (NCT03569371 and NCT03607487).

Comprehensive, Individualized, Person-Centered Management of Community-Residing Persons with Moderate-to-Severe Alzheimer Disease: A Randomized Controlled Trial.

BACKGROUND/AIMS: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. METHODS: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinician's Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. RESULTS: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. CONCLUSION: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

Time-dependent classification accuracy curve under marker-dependent sampling.

Evaluating the classification accuracy of a candidate biomarker signaling the onset of disease or disease status is essential for medical decision making. A good biomarker would accurately identify the patients who are likely to progress or die at a particular time in the future or who are in urgent need for active treatments. To assess the performance of a candidate biomarker, the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) are commonly used. In many cases, the standard simple random sampling (SRS) design used for biomarker validation studies is costly and inefficient. In order to improve the efficiency and reduce the cost of biomarker validation, marker-dependent sampling (MDS) may be used. In a MDS design, the selection of patients to assess true survival time is dependent on the result of a biomarker assay. In this article, we introduce a nonparametric estimator for time-dependent AUC under a MDS design. The consistency and the asymptotic normality of the proposed estimator is established. Simulation shows the unbiasedness of the proposed estimator and a significant efficiency gain of the MDS design over the SRS design.

Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).

BACKGROUND: Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA. METHODS: A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model. RESULTS: Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021). CONCLUSION: Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates. CLINICAL TRIAL REGISTRATION: NCT01165710 (http://www.clinicaltrials.gov).

Three-Dimensional Lumbosacral Reconstruction by An Artificial Intelligence-Based Automated MR Image Segmentation for Selecting the Approach of Percutaneous Endoscopic Lumbar Discectomy.

BACKGROUND: Assessing the 3-dimensional (3D) relationship between critical anatomical structures and the surgical channel can help select percutaneous endoscopic lumbar discectomy (PELD) approaches, especially at the L5/S1 level. However, previous evaluation methods for PELD were mainly assessed using 2-dimensional (2D) medical images, making the understanding of the 3D relationship of lumbosacral structures difficult. Artificial intelligence based on automated magnetic resonance (MR) image segmentation has the benefit of 3D reconstruction of medical images. OBJECTIVES: We developed and validated an artificial intelligence-based MR image segmentation method for constructing a 3D model of lumbosacral structures for selecting the appropriate approach of percutaneous endoscopic lumbar discectomy at the L5/S1 level. STUDY DESIGN: Three-dimensional reconstruction study using artificial intelligence based on MR image segmentation. SETTING: Spine and radiology center of a university hospital. METHODS: Fifty MR data samples were used to develop an artificial intelligence algorithm for automatic segmentation. Manual segmentation and labeling of vertebrae bone (L5 and S1 vertebrae bone), disc, lumbosacral nerve, iliac bone, and skin at the L5/S1 level by 3 experts were used as ground truth. Five-fold cross-validation was performed, and quantitative segmentation metrics were used to evaluate the performance of artificial intelligence based on the MR image segmentation method. The comparison analysis of quantitative measurements between the artificial intelligence-derived 3D (AI-3D) models and the ground truth-derived 3D (GT-3D) models was used to validate the feasibility of 3D lumbosacral structures reconstruction and preoperative assessment of PELD approaches. RESULTS: Artificial intelligence-based automated MR image segmentation achieved high mean Dice Scores of 0.921, 0.924, 0.885, 0.808, 0.886, and 0.816 for L5 vertebrae bone, S1 vertebrae bone, disc, lumbosacral nerves, iliac bone, and skin, respectively. There were no significant differences between AI-3D and GT-3D models in quantitative measurements. Comparative analysis of quantitative measures showed a high correlation and consistency. LIMITATIONS: Our method did not involve vessel segmentation in automated MR image segmentation. Our study's sample size was small, and the findings need to be validated in a prospective study with a large sample size. CONCLUSION: We developed an artificial intelligence-based automated MR image segmentation method, which effectively segmented lumbosacral structures (e.g., L5 vertebrae bone, S1 vertebrae bone, disc, lumbosacral nerve, iliac bone, and skin) simultaneously on MR images, and could be used to construct a 3D model of lumbosacral structures for choosing an appropriate approach of PELD at the L5/S1 level.

Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first-line platinum-based chemotherapy: Phase 2 study results.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB-290) is a small molecule inhibitor of PARP1 and PARP2. METHODS: The PARALLEL-303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. The primary endpoint of this double-blind, randomized, global phase 2 study was progression-free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. RESULTS: In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. CONCLUSIONS: Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

A Maximum-Use Trial of Ruxolitinib Cream in Adolescents and Adults with Atopic Dermatitis.

BACKGROUND: Ruxolitinib cream is a topical formulation of ruxolitinib, an inhibitor of Janus kinase 1 and Janus kinase 2. OBJECTIVE: We aimed to determine the safety, tolerability, and bioavailability of 1.5% ruxolitinib cream under maximum-use conditions in patients with atopic dermatitis. Efficacy was evaluated as an exploratory objective. METHODS: Eligible patients aged ≥ 12-65 years with atopic dermatitis, an Investigator's Global Assessment score ≥ 2, and ≥ 25% affected body surface area were enrolled in an open-label, maximum-use phase I study conducted in the USA and Canada. Patients applied 1.5% ruxolitinib cream twice daily to lesions identified at baseline for the first 28 days and continued use only on active lesions for an additional 28 days (extension period). Safety was assessed by frequency, duration, and severity of treatment-emergent adverse events. Plasma concentrations of ruxolitinib and pharmacokinetic parameters were assessed as secondary endpoints. RESULTS: Overall, 41 patients (median age, 17 years; 51% male) were enrolled and 37 (90.2%) entered the extension period, all of whom completed the study. Treatment-emergent adverse events were reported in 13 patients (31.7%). Treatment-related adverse events were reported in four patients (9.8%). The mean (standard deviation) steady-state plasma concentration was 104 (309) nM during the first 28 days, well below the half-maximal inhibitory concentration of Janus kinase-mediated myelosuppression in the bone marrow (281 nM), and decreased further during the extension period. Higher plasma concentrations were detected in a few patients who were treated for a very high affected body surface area. At day 56, 94.6% of patients achieved ≥ 75% improvement in the Eczema Area and Severity Index. CONCLUSIONS: Under maximum-use conditions, ruxolitinib cream was generally well tolerated, with approximately one-third of patients experiencing treatment-emergent adverse events and few treatment-related adverse events. The mean steady-state plasma concentration of ruxolitinib was well below the level expected to affect bone marrow production of blood cells, with a small number of patients exhibiting higher plasma concentrations. In addition, ruxolitinib cream showed a high level of efficacy in patients with atopic dermatitis involving ≥ 25% affected body surface area. GOV IDENTIFIER: NCT03920852.

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia.

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.

Longitudinal Change of PTSD Symptoms in Community Members after the World Trade Center Destruction.

The World Trade Center (WTC) Environmental Health Center (EHC) is a treatment program for community members with exposure to the 9/11 terrorist attack and its physical and emotional aftermath. Compared to the general responders program, the WTC EHC is diverse with equal gender distribution, representation of many races and ethnicities, and a wide range of social economic status. Patients in the WTC EHC were initially enrolled for physical symptoms, most of which were respiratory, however a large portion of the enrollees scored positive for probable posttraumatic stress disorder (PTSD). In this paper we identify patient characteristics associated with probable PTSD. We also determine the characteristics associated with the longitudinal change of PTSD symptoms, including persistence and remittance, using the widely used Posttraumatic Check List-17 (PCL) cut-off value of 44, as well as changes in PCL total score and symptom cluster scores in patients of Low and High PTSD symptom severity. Few patients with elevated scores achieved a score below 44. However, longitudinal improvement in PCL score at follow-up was identified for patients with High PTSD scores (PCL > 57.5). Changes in PCL symptom clusters differed between those with High and Low PCL scores. These data suggest improvement over time in PCL score that differs depending on the severity of the score and variable responses in the PCL symptom clusters.

Obstructive Sleep Apnea in Community Members Exposed to World Trade Center Dust and Fumes.

STUDY OBJECTIVES: A relationship between obstructive sleep apnea (OSA) and exposure to the World Trade Center (WTC) dust and fumes has been suggested in responders but little is known about a possible relationship in community members. We characterized sleep studies performed in community members with WTC dust exposure to improve our understanding of the relationship between the diagnosis and severity of OSA and WTC dust exposure in this population. METHODS: Single-center, retrospective study of patients enrolled in a clinical treatment program for community members with WTC dust exposure. Patients were included if they had undergone sleep studies for evaluation of possible OSA through September 2016 and provided written informed consent. RESULTS: The total number of patients included in the analysis was 143. Patients were predominantly male (61%), never smokers (59%) and had a median body mass index of 31 kg/m2. Most reported upper and lower respiratory symptoms. An apnea-hypopnea index (AHI) ≥ 5 events/h was measured in 66% of the patients, and respiratory disturbance index was ≥ 5 events/h in 97%. The proportion of patients with moderate-severe OSA (defined by the AHI 4% criteria) was 50%. Multivariate logistic regression revealed that acute WTC dust cloud exposure was associated with severity but not diagnosis of OSA. CONCLUSIONS: We identified a high rate of OSA in the WTC community cohort who were referred for sleep studies. Exposure to the massive WTC dust cloud caused by the WTC collapse was independently associated with the severity of OSA in this population. This finding highlights the role that environmental exposures may play in the development of OSA.

Long non-coding RNA RAB11B-AS1 prevents osteosarcoma development and progression via its natural antisense transcript RAB11B.

Long non-coding RNAs (lncRNAs) have been shown to exert essential roles in development and progression of tumors. Here we discovered a novel lncRNA, RAB11B antisense RNA (RAB11B-AS1), which is markedly down-regulated in human osteosarcoma (OS) and associated with OS metastasis and poor prognosis. We find that reduction of RAB11B-AS1 significantly facilitates proliferation, migration and invasiveness and prevents apoptosis of OS cells and results in lower sensitivity to cisplatin in these cells. In contrast, up-regulation of RAB11B-AS1 suppresses the aggressive behaviors of OS cells. Mechanistically, down-regulation of RAB11B-AS1 elevates its sense-cognate gene RAB11B expression at both mRNA and protein levels. RAB11B-AS1 expression correlates negatively with RAB11B expression in OS tissues. Luciferase reporter assay illuminated that RAB11B-AS1 regulates RAB11B expression through antisense pairing. Most importantly, all the effects of RAB11B-AS1 were abrogated by RAB11B down-regulation. Thus our findings revealed that lnc-RAB11B-AS1 prevents osteosarcoma development and progression via inhibiting RAB11B expression, indicating lnc-RAB11B-AS1 as a potential therapeutic target for osteosarcoma.

Early detection of Zika virus infection among travellers from areas of ongoing transmission in China.

Nine imported Zika virus (ZIKV) infections (four through temperature monitoring and epidemiological investigation at entry and five by active surveillance tracking of index case contacts during follow-up; from Venezuela [n = 5], Samoa [n = 3] and both Samoa and Fiji [n = 1]) were detected in mainland China from February 1 to 29, 2016. The minimal incubation period lasted 5.2 days, with mean lag time to diagnosis of 2.6 days. Diagnosis relied on positive real-time reverse transcriptase polymerase chain reaction for ZIKV RNA in serum (n = 7), urine (n = 4) or saliva (n = 3), respectively. All cases recovered rapidly without serious complications.