Breathing changes following mini-implant-supported maxillary skeletal expander treatment in late adolescent or adult patients : Assessment of objective and subjective functional breathing changes.

PURPOSE: The aim of this study was to assess objective and subjective breathing changes in adult patients who underwent maxillary skeletal expansion with the mini-implant-supported maxillary skeletal expander (MSE). METHODS: Twenty-nine patients (mean age 18.1 ± 4.3 years) who underwent expansion using the MSE were compared pre- and posttreatment and with a control group (mean age 19.9 ± 2.6 years) to assess objective and subjective functional breathing changes. Objective measurements of the airway including peak nasal inspiratory flow (PNIF) and peak oral inspiratory flow (POIF) were measured utilizing the In-Check medical device (Clement Clarke, Harlow, United Kingdom). Patients reported subjective breathing assessment utilizing the visual analog scale (VAS). Intragroup comparisons were performed with Wilcoxon tests and intergroup comparison with Mann-Whitney U tests. Spearman correlation coefficients were calculated among the studied variables (P < 0.05). RESULTS: Following MSE treatment, there were significantly higher values for PNIF total (P < 0.0001), PNIF right (P < 0.0001), PNIF left (P < 0.0001), and POIF (P < 0.01) compared to pretreatment and control group results. Also, patients reported a significant decrease in troubled breathing as measured by the VAS for breathing through the right nostril (P < 0.01), left nostril (P < 0.001), and both nostrils (P < 0.01). Comparing the objective and subjective variables for both the pre-MSE or post-MSE groups, the results indicated no significant correlation between total PNIF and total VAS. However, the values had significant correlations between PNIF and VAS on each side when the patients were asked to block one nostril. CONCLUSIONS: Objective functional breathing measurements were increased immediately after treatment with MSE. Subjective functional breathing measurements changes were significantly higher after MSE treatment and compared with the control group. MSE presents a nonsurgical alternative to achieving orthopedic expansion in adult patients which may provide a benefit for patients with nasal airway obstruction.

Long-term effects of maxillary skeletal expander treatment on functional breathing.

Objective: : To investigate the long-term effects of maxillary skeletal expander (MSE) treatment on functional breathing. Objective: measures of breathing, the peak nasal inspiratory flow (PNIF), and peak oral inspiratory flow (POIF), and subjective measures of breathing, the visual analog scale (VAS) and nasal obstruction symptom evaluation (NOSE) survey, were used to investigate the long-term effects of MSE in functional breathing. Seventeen patients, mean age 19.4 ± 3.9 years treated at the UCLA Orthodontics Clinic were assessed on their functional breathing at 3 timepoints: pre-expansion (T0), post-expansion (T1), and post-orthodontic treatment (T2). Results: : Immediately after expansion (T1), all the objective functional breathing values were significantly increased in comparison to T0 (P < 0.05). The VAS total, VAS right and VAS left were significantly lower at T1 in comparison to T0 (P < 0.05). At 26.8 ± 3.9 months after MSE expansion (T2), PNIF total, PNIF right, PNIF left, and POIF were significantly higher when compared to T0 (P < 0.05). Also, VAS total, VAS right and VAS left were significantly lower at T2 when compared to T0 (P < 0.05). Additionally, there was a positive correlation between PNIF and the magnitude of expansion at anterior nasal spine and zygomaticomaxillary point (ZMA). There was a positive correlation between total VAS and the magnitude of expansion at the ZMA. There were no significant changes for the NOSE subjective breathing measurement at all time comparisons. Conclusions: : Overall, MSE treatment produces an increased objective and subjective airway improvement that continues to remain stable in the long-term post expansion.

Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.

INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies.

PURPOSE: Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. EXPERIMENTAL DESIGN: We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. RESULTS: In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. CONCLUSIONS: Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.

The Role of Non-invasive Testing in Evaluation and Diagnosis of Pediatric Lower Urinary Tract Dysfunction.

PURPOSE OF REVIEW: The symptoms of lower urinary tract dysfunction (LUTD) including urinary incontinence, frequency, and urgency are among the most common reasons children are referred to pediatric urologists. Despite this, the workup for LUTD is often time consuming and a source of frustration for patients, parents, and clinicians alike. In the current review, we summarize the important role non-invasive testing plays in the diagnosis and management of children with LUTD and to show how use of these tests can help avoid the need for more invasive testing in the majority of children. RECENT FINDINGS: Non-invasive tests such urine studies, uroflowmetry ± simultaneous electromyography, assessment of post-void residual, renal/bladder ultrasound, and pelvic ultrasound when used appropriately can provide valuable information to facilitate decision making during the evaluation of children with LUTD. While these tests should be employed prior to more invasive testing such as urodynamic studies, they can often act as a surrogate for the more invasive tests. Non-invasive tests can help us in our goal of improving diagnostic ability to better classify the child's LUTD into an actual condition which allows targeted treatment in the hope of better outcomes and more satisfied patients and families.

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1ß (MIP-1beta) and tumor necrosis factor-ß (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

Overactive bladder (OAB): A symptom in search of a disease - Its relationship to specific lower urinary tract symptoms and conditions.

BACKGROUND: The ICCS defines OAB by the subjective symptom of urgency; detrusor overactivity (DO) is only implied. While no other symptom is required, OAB can also be associated with urinary frequency, decreased functional bladder capacity, and incontinence. OBJECTIVE: We sought to determine how often these associated findings occur in OAB and what if any uroflow/EMG-defined conditions are found to be associated with it. METHODS: The charts of 548 children (231M, 318F; mean age 9.0 years, range 3-20) who presented sequentially with urgency (OAB), over a period of 2 years, were reviewed paying particular attention to whether or not there was a history of frequency and/or daytime incontinence in addition to the urgency. All patients had been previously diagnosed with one of the following four lower urinary tract (LUT) conditions based on specific uroflow/EMG findings: 1. dysfunctional voiding (DV; active pelvic floor EMG during voiding); 2. idiopathic detrusor overactivity disorder (IDOD; OAB with a short EMG lag time (<2 s), and quiet pelvic floor EMG during voiding); 3. detrusor underutilization disorder (DUD; willful infrequent voiding with %EBC >125%, quiet EMG during voiding); and 4. primary bladder neck dysfunction (PBND; prolonged EMG lag time (>6 s), quiet EMG during voiding, and depressed uroflow curve). Mean %EBC was compared between patients with urgency alone and those with urgency plus other symptoms. Any association with gender was analyzed. RESULTS: Urgency was accompanied by either frequency or daytime incontinence in 91% of the children (summary Table). Daytime incontinence was reported in 398 (72.6%) and frequency in 268 (48.9%). Mean %EBC was 80.9. Females were more likely to report daytime incontinence (76.7% vs. 66.7%, p = 0.02) and frequency was found more often in males (63.6% vs. 38.1%, p < 0.001). %EBC was less in males (70.0 vs. 88.8, p < 0.001). The majority of patients with urgency were diagnosed with IDOD (62%), while 15% had DV, 5% PBND, 3% DUD, and in 15%, the uroflow/EMG was not diagnostic. CONCLUSIONS: %EBC was usually normal or mildly increased in OAB when urgency is the only symptom but significantly decreases with each additional LUTS. OAB is more common in girls and they tend to have a lower incidence of frequency, more incontinence, and >%EBC than boys. Because urgency in an anatomically and neurologically normal child is the only required criterion for diagnosing OAB, it must be realized that OAB can be associated with any of a number of objectively defined LUT conditions. Thus OAB appears to be a symptom, not a condition, that is often associated with other symptoms.

INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

Can children with either overactive bladder or dysfunctional voiding transition from one into the other: Are both part of a single entity?

BACKGROUND: In 1998 it was postulated by the ICCS that urge syndrome, later termed overactive bladder (OAB), and dysfunctional voiding (DV) might not be separate entities and instead represent transitional stages between each other, and that DV may be the evolutionary end product of OAB. The aim of this study was to determine not only if OAB sometimes transitions into DV but also if the reverse occurs, and, if so, might they indeed be parts of one entity. MATERIALS AND METHODS: To create an objective study of these two conditions, specific "qualifiers" supporting the diagnosis of each condition were introduced: 1) DV included the qualifier of an active EMG during voiding on two studies; 2) OAB included the qualifiers of a short lag time (<2 s) as a surrogate for detrusor overactivity (DO) and a quiet EMG during voiding. Two separate cohorts (one for DV and one for OAB) of 77 consecutive patients each were reviewed. All DV patients were treated with biofeedback and some with antimuscarinics. All OAB patients were treated with antimuscarinics. Both cohorts also received standard therapy and bowel management when indicated. All patients had multiple uroflow/EMG evaluations before and during therapy and were followed for a minimum of 6 months. RESULTS: Mean follow-up was 17.5 months and median age at diagnosis was 6.6 years for DV and 6.4 years for OAB. Of the OAB children none transitioned into DV, although two demonstrated transient DV-like EMG activity on interval testing that did not require biofeedback. Of DV children, following the initiation of biofeedback therapy, the EMG became quiet on follow-up uroflow/EMG after a mean of 9.3 months in 70 of 77 (91%). With EMG quieting, however, a short EMG lag time suggesting DO became apparent in those children with persistent irritative symptoms. This short lag time became apparent in 25 of 31 (81%) children treated with biofeedback alone versus only 8 of 39 (21%) on biofeedback plus antimuscarinics. CONCLUSION: OAB with qualifiers and DV are two distinct LUT conditions and children do not appear to transition from the one to the other. While some children with DV did demonstrate a short lag time during follow-up, this is because once the EMG quieted in response to biofeedback, it improved our ability to document the already existing DO secondary to their previous DV. A dysfunctional voiding sequence with the postulated initial step being the transition of OAB into DV does not seem to be likely as the age at initial diagnosis was similar in both groups.

Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans.

Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.

Short pelvic floor EMG lag time II: use in management and follow-up of children treated for detrusor overactivity.

OBJECTIVE: To determine utility of short pelvic floor electromyography (EMG) lag time in monitoring therapeutic response in children with idiopathic detrusor overactivity (DO) and quiet EMG during voiding (idiopathic detrusor overactivity disorder, IDOD). PATIENTS AND METHODS: 162 consecutive normal children (77M, 85F) diagnosed with IDOD and short EMG lag time were reviewed. All were treated with combined standard urotherapy and anticholinergics. Pre-treatment uroflow/EMG parameters were compared with on-treatment parameters. RESULTS: Median age at evaluation was 6.8 years and median EMG lag time was 0 s; 110 children had repeat uroflow/EMG studies while on anticholinergic therapy. With a median follow-up of 18.7 months, mean EMG lag time increased from 0.7 to 2.2 s and % expected bladder capacity for age (EBC) increased from 0.68 to 0.98 (both p < 0.01). EMG lag time increased in all patients while on therapy and normalized in 83 patients (75%). CONCLUSION: A short EMG lag time on noninvasive uroflow/EMG in a patient with urgency can be a surrogate for urodynamics study (UDS) in diagnosing DO and objectively monitoring response to therapy. When effectively treated, children with DO have amelioration of their lower urinary tract symptoms (LUTS) and normalization of both EMG lag time and bladder capacity.

Analysis of uroflow patterns in children with dysfunctional voiding.

OBJECTIVE: Although a staccato uroflow pattern is considered representative of dysfunctional voiding (DV), we recently found that only a third of children with staccato flow had an active pelvic floor electromyography (EMG) during voiding. Here, we analyzed the reverse, that is, how often a staccato flow pattern occurs in children with documented DV. In addition, we reviewed what other flow patterns are prevalent in this condition. MATERIALS AND METHODS: We reviewed our LUT dysfunction registry for children with EMG-confirmed DV. Uroflow patterns were categorized as staccato, interrupted, mixed (i.e., staccato and interrupted patterns), or grossly normal. RESULTS: Of 596 children who underwent a uroflow/EMG examination, 121 had an active pelvic floor EMG during voiding, that is a finding consistent with the diagnosis of DV. The flow patterns identified in those diagnosed with DV were staccato in 70 (58%), interrupted in 22 (19%), mixed in 12 (10%), and a bell-shaped or depressed curve in 17 (14%). Staccato pattern became normal in 96% following successful treatment with biofeedback. CONCLUSIONS: While a staccato uroflow pattern was the most common pattern seen in children diagnosed with DV by a uroflow/EMG, nearly a third had an interrupted or mixed flow pattern underscoring the importance of performing simultaneous pelvic floor EMG during a uroflow study, especially when trying to rule out DV. Failure of the staccato flow pattern to normalize after therapy strongly suggests either inadequate therapy or an incorrect diagnosis.

Outcomes of vesicoureteral reflux in children with non-neurogenic lower urinary tract dysfunction treated with dextranomer/hyaluronic acid copolymer (Deflux).

OBJECTIVE: There has been hesitancy to use dextranomer/hyaluronic acid copolymer (DHXA, Deflux for vesicoureteral reflux (VUR) in the setting of lower urinary tract (LUT) dysfunction because of the limited number of published studies, the possibility of less success, and the manufacturer's recommendations contraindicating its use in patients with active LUT dysfunction. We report on our experience using DXHA in this subset of patients whose VUR persisted despite targeted therapy for their LUT condition. MATERIALS AND METHODS: We reviewed patients diagnosed with both a LUT condition and VUR who underwent subureteric DXHA while still undergoing treatment for their LUT dysfunction. Persistence of VUR was confirmed by videourodynamic studies (VUDS)/VCUG (voiding cystourethrogram) and all patients were on targeted treatment (TT) and antibiotic prophylaxis prior to and during DXHA injection. VUR was reassessed post-injection. RESULTS: Fifteen patients (22 ureters; 21F,1M) met inclusion criteria (mean age 6.1 years, range 4-12). Following one to three DXHA injections, VUR resolved in 17 ureters (77%) including eight of nine ureters in dysfunctional voiding (DV) patients, five of nine in idiopathic detrusor overactivity disorder (IDOD), and four of four in detrusor underutilization disorder (DUD) patients. CONCLUSIONS: DXHA is safe and effective in resolving VUR in children with associated LUT dysfunction, even before their LUT condition has fully resolved. Highest resolution rates were noted in patients with either DV or DUD or who were least symptomatic prior to injection.

The bladder of willful infrequent voiders: underactive or underutilized?

OBJECTIVE: We previously described a lower urinary tract (LUT) condition (detrusor underutilization disorder, DUD) characterized by chronic or episodic willful deferment of voiding resulting in an expanded capacity in patients with LUT symptoms. We now further characterize these DUD patients. MATERIALS AND METHODS: We reviewed our database identifying neurologically/anatomically normal children diagnosed with DUD. Bladder capacity had to be at least >125% EBC for age to be included. LUTS, diaries and uroflow/EMG findings were analyzed. RESULTS: Fifty-five children (mean age 10.5 years, range 3.7-20.2; 34F, 19M) with LUTS were diagnosed with DUD. The most common reasons for presentation included incontinence (43.6%), history of urinary tract infection (UTI) (49.1%), and urgency (30.9%). Mean percent estimated bladder capacity for age was 1.67 and following treatment mean %EBC decreased to 1.10. CONCLUSIONS: DUD patients typically present with infrequent voiding, incontinence, urgency, and UTIs. They have less bowel dysfunction and frequency, and larger bladder capacities than typically found in children with overactive bladder and dysfunctional voiding. Although the symptoms associated with DUD overlap in part with those considered by the International Children's Continence Society to be typical for "underactive bladder" and "voiding postponement", DUD, we feel, is a stand-alone diagnosis.