Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations.

Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss. Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study. Design, Setting, and Participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021. Main Outcomes and Measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months. Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred. Conclusions and Relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials. Trial Registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes.

BACKGROUND: To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository. METHODS: Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1ß, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers. RESULTS: Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis. CONCLUSIONS: These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non-Hodgkin lymphoma subtypes. IMPACT: The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.

Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance.

Triplet combinations containing a proteasome inhibitor are a standard of care in newly diagnosed multiple myeloma (NDMM). We examined the long-term efficacy and safety of the all-oral combination of weekly ixazomib plus lenalidomide-dexamethasone (IRd), followed by single-agent ixazomib maintenance in NDMM patients. Of 65 enrolled patients, 53 received ixazomib 4 mg (days 1, 8, and 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, and 22) for up to twelve 28-day induction cycles. Twenty-three patients discontinued induction for stem cell transplantation (SCT). In the remaining 42 patients, overall response rate was 80%, including 63% ≥very good partial response (VGPR) and 32% complete responses. At a median follow-up of 56 months, median progression-free survival (PFS) was 35.4 months in the total population. Twenty-five patients received ixazomib maintenance; eight deepened their response (76% ≥VGPR), and median PFS was 37.2 months in this subgroup. Nine of 42 patients who did not proceed to SCT (14% of total population) had an adverse event requiring discontinuation. Ixazomib (median ≥ 96%) and lenalidomide (median 88-94%) relative dose intensities were maintained throughout treatment. Weekly IRd, followed by ixazomib maintenance, was highly active with acceptable toxicity, enabling long-term administration with no evidence of cumulative toxicities.

Twice-weekly ixazomib in combination with lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma.

Weekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.

Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.

BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. FINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. INTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.

Microvascular autologous breast reconstruction in the context of radiation therapy: comparing two reconstructive algorithms.

BACKGROUND: When postmastectomy radiation therapy is anticipated, delaying autologous reconstruction prevents radiation delivery issues and radiation-induced contour irregularities. Delayed-immediate autologous breast reconstruction may allow for maintenance of the breast skin envelope as compared with delayed reconstruction with the temporary insertion of a tissue expander. The authors compared perioperative complications and revision surgery rates of comparative cohorts to determine which method is preferable. METHODS: Delayed-immediate reconstruction was defined as placement of a temporary tissue expander in the first stage at the time of mastectomy before flap reconstruction, which occurred following postmastectomy radiation therapy. Delayed reconstruction was categorized as mastectomy with primary closure in the first stage followed by flap reconstruction. RESULTS: One hundred fifty-two patients and 192 breasts met the study criteria for this retrospective review (delayed reconstruction, 118 breasts; delayed-immediate autologous breast reconstruction, 74 breasts). Patient age and body mass index were similar between groups (p>0.05). Perioperative first-stage complication rates were 8.5 percent in the delayed group and 10.8 percent in the delayed-immediate cohort (p=0.81). Total flap loss (2.5 versus 4.1 percent; p=0.68) and arterial (1.7 versus 1.4 percent; p=0.82) and venous (4.3 versus 5.4 percent; p=0.73) anastomotic revision rates were similar between the cohorts, respectively. Reoperative surgery occurred in 11.9 percent versus 9.6 percent in the delayed and delayed-immediate cohorts, respectively (p=0.69). CONCLUSIONS: In comparing two treatment algorithms, flap-related complication rates are comparable. First-stage surgery results in a slightly increased complication rate in the delayed-immediate cohort. Improved overall results with delayed-immediate reconstruction are implied, given significantly decreased rates of revision surgery following flap reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Beta-blocker management of refractory hemoptysis in cystic fibrosis: a novel treatment approach.

BACKGROUND: /objective: Recurrent hemoptysis is a debilitating complication of cystic fibrosis (CF) and likely results from mucosal erosions into abnormal bronchial blood vessels due to chronic respiratory infection. We hypothesize that the use of beta-blockade will decrease mean arterial pressure resulting in lower bronchial artery blood flow and, subsequently, decrease the frequency and severity of hemoptysis, rate of hospitalizations, and usage of intravenous antibiotics. METHODS: Retrospective chart review was performed on 12 CF patients with recurrent hemoptysis, aged 13-40 years old, along with a follow-up telephone survey to assess the effectiveness of beta-blockade for hemoptysis, tolerance of inhaled respiratory medications, activity tolerance, and potential adverse effects. A beta-blocker, specifically atenolol, was initiated in all subjects within 24 hours after experiencing recurrent hemoptysis episodes. RESULTS: A majority of patients (72.7%) had complete cessation of hemoptysis. There were significant decreases in the frequency of hemoptysis (p = 0.02) and the amount of hemoptysis (p = 0.004). The rate of hospitalizations significantly decreased from 1.33 to 0.67 (p = 0.05) after initiation of atenolol. There was a trend toward statistical significance in the reduction of intravenous antibiotics use (p = 0.08). No statistical difference was found when comparing the pre- and post-treatment means of forced expiratory volume in 1-second (p = 0.59). Very minimal adverse effects were observed with only one patient reporting intermittent facial flushing. CONCLUSION: Beta-blockade, particularly with atenolol, appears to successfully treat, if not resolve, recurrent hemoptysis refractory to conservative therapy in CF. Beta-blocker therapy appears to maintain an effective safety profile in CF.

Hyperglycemia is associated with intracranial injury in children younger than 3 years of age.

OBJECTIVES: The objective was to see if hyperglycemia in the emergency department predicted traumatic intracranial hemorrhage (ICH) for infants and young children. METHODS: A 6-year retrospective chart review was performed on patients younger than 3 years. Patients identified from the pediatric intensive care unit (PICU) database with ICH on computer tomography were compared with those with a history of trauma without ICH identified from a radiology database. Subgroup analysis was performed on the ICH group comparing abusive head trauma (AHT) and accidental. Primary outcomes measured were initial serum glucose level, length of stay, length of ventilation, mortality, and disability on discharge. RESULTS: Fifty-three patients were admitted to the PICU with traumatic ICH with an overall mortality of 7.5%. The average initial glucose in the emergency department was significantly higher for the patients with ICH than those without (164 vs. 99 mg/dL, P < 0.0001). Combining elevated serum glucose with any abnormality in Glasgow Coma Scale score yielded sensitivity and specificity of 100%. The average presenting glucose was higher for AHT compared with accidental injury (190 vs. 133 mg/dL, P < 0.001). Patients with AHT had greater PICU and hospital length of stay and more severe disabilities on discharge (P < 0.001). CONCLUSIONS: Elevated serum glucose is a good marker of ICH in children younger than 3 years. When correlated with an abnormal neurological examination, it is highly sensitive and specific. Patients with AHT have further elevation of serum glucose at presentation. Emergency department physicians should consider measuring the serum glucose in children younger than 3 years with abnormal neurological examinations and obtaining a head computer tomography if it is elevated.

High-frequency oscillatory ventilation in pediatric acute hypoxemic respiratory failure: disease-specific morbidity survival analysis.

BACKGROUND: Multiple ventilatory strategies for acute hypoxemic respiratory failure (AHRF) in children have been advocated, including high-frequency oscillatory ventilation (HFOV). Despite the frequent deployment of HFOV, randomized controlled trials remain elusive and currently there are no pediatric trials looking at its use. Our longitudinal study analyzed the predictive clinical outcome of HFOV in pediatric AHRF given disease-specific morbidity. METHODS: A retrospective 8-year review on pediatric intensive care unit admissions with AHRF ventilated by HFOV was performed. Primary outcomes included survival, morbidity, length of stay (LOS), and factors associated with survival or mortality. RESULTS: A total of 102 patients underwent HFOV with a 66 % overall survival rate. Survivors had a greater LOS than nonsurvivors (p = 0.001). Mortality odds ratio (OR) for patients without bronchiolitis was 8.19 (CI = 1.02, 65.43), and without pneumonia it was 3.07 (CI = 1.12, 8.39). A lower oxygenation index (OI) after HFOV commencement and at subsequent time points analyzed predicted survival. After 24 h, mortality was associated with an OI > 35 [OR = 31.11 (CI = 3.25, 297.98)]. Sepsis-related mortality was associated with a higher baseline FiO(2) (0.88 vs. 0.65), higher OI (42 vs. 22), and augmented metabolic acidosis (pH of 7.25 vs. 7.32) evaluated 4 h on HFOV (p < 0.05). CONCLUSION: High-frequency oscillatory ventilation may be safely utilized. It has a 66 % overall survival rate in pediatric AHRF of various etiologies. Patients with morbidity limited to the respiratory system and optimized oxygenation indices are most likely to survive on HFOV.

Autologous fat transplantation in the craniofacial patient: the UCLA experience.

Patients with congenital craniofacial malformations present with complex challenges for reconstruction. Successful management requires individualized treatment often involving rebuilding the facial skeleton de novo, as well as correcting the overlying soft-tissue deficiencies in the final stages. At the University of California, Los Angeles (UCLA) Craniofacial Clinic, serial autologous fat transplantation performed during staged reconstruction is the preferred method.A total of 27 patients with a diagnosis of either craniofacial microsomia/Goldenhar (CM) (n = 19) or Treacher Collins syndrome (TC) (n = 8) were treated at the UCLA Craniofacial Clinic by autologous fat transfer between July 1999 and February 2009. Two-dimensional analysis was conducted on standardized preoperative and postoperative photographs to determine facial symmetry for every patient. Results was grouped based on pathology and analyzed by comparing adipocyte donor site (abdomen vs other).The mean ages at the time of first fat transfer were 17 years for the CM group and 15 years for the TC group. The average numbers of fat transfers per patient were 2.05 (CM) and 2.12 (TC). A mean of 3.74 procedures other than fat grafting was performed in each CM patient, whereas 4.38 other procedures were performed in each TC patient. In CM patients, less than 10.5 months between procedures resulted in improved symmetry. There was an average 6.63% improvement in facial symmetry in the CM group, and a 7.67% improvement in the TC group.Based on the UCLA experience, the durability of facial asymmetry and contour correction with fat transplantation is attainable in the craniofacial patient but may also require concomitant skeletal correction in the most severe cases.

Evaluation of plastic surgery training programs: integrated/combined versus independent.

BACKGROUND: The authors aimed to differentiate between combined/integrated and independent (traditional) methods of plastic surgery training with regard to quality of trainees, caliber of graduates, and practice or career outcomes once graduated. METHODS: To compare combined/integrated with independent residency program training, the authors conducted a Web-based survey of the American Society of Plastic Surgeons members looking at their experience and practice outcomes (n = 1056) and interviews of plastic surgery faculty looking at the quality of trainees (n = 72). The member survey evaluated background information, research credentials, pathway satisfaction, postgraduation activities, current practice, and academic affiliation. Faculty teacher interviews focused on knowledge base, diagnostic and treatment judgment, technical abilities, research capabilities, and prediction of future career success. RESULTS: The member survey showed no difference (p > 0.05) between combined/integrated and independent trainees in practice type (cosmetic/reconstructive), practice volume, or academic achievements. Combined/integrated trained surgeons are three times more likely to recommend their training pathway and two times more likely to enter fellowship after residency. Alpha Omega Alpha Honor Medical Society membership correlated with a greater likelihood of having an academic practice at 5 and 10 years or more and higher professorship titles. Faculty evaluations showed that combined/integrated residents were superior in knowledge (49 percent versus 32 percent) but that independent residents were superior in technical ability (51 percent versus 20 percent) and research (57 percent versus 19 percent). Most faculty were unable to choose a pathway producing superior residents. CONCLUSIONS: Regarding future practice outcomes, there was not a superior training pathway. Regarding quality of trainees, there were differences in faculty evaluations, but there was no consensus on a better pathway.

Protection of the temporomandibular joint during syndromic neonatal mandibular distraction using condylar unloading.

BACKGROUND: Neonatal distraction in severe micrognathia patients may alleviate the need for tracheostomy. The authors' objectives in evaluating syndromic neonatal distraction cases were to: (1) document preoperative temporomandibular joint pathology, (2) compare the incidence of postoperative temporomandibular joint ankylosis, and (3) determine whether "unloading" the condyle tended to prevent temporomandibular joint pathology. METHODS: Syndromic versus nonsyndromic micrognathic (and normal) patient temporomandibular joint abnormalities were compared preoperatively based on computed tomography scans and incisor opening (n = 110). Patient temporomandibular joint outcomes after neonatal mandibular distraction were compared with regard to ankylosis (n = 59). Condylar-loaded versus condylar-unloaded (with class II intermaxillary elastics) temporomandibular joint outcomes were compared based on imaging and the need for joint reconstruction (n = 25). RESULTS: Preoperative abnormalities of neonatal temporomandibular joint pathology on computed tomography scans were not significant: syndromic, 15 percent; nonsyndromic, 5.9 percent; and normal joints, 4.2 percent. Syndromic patients had a significantly greater interincisor distance decrease postoperatively (48 percent; p < 0.05) and at 1-year follow-up (28 percent; p < 0.05) compared with nonsyndromic patients. Also, computed tomography scans revealed that 28 percent of syndromic patients developed temporomandibular joint abnormalities, whereas nonsyndromic patients were unchanged. Condylar-loaded patients had worse clinical outcomes compared with condylar-unloaded patients (80 percent versus 7 percent) and required temporomandibular joint reconstruction for bony ankylosis (40 percent versus 0 percent) after distraction. CONCLUSIONS: Neonatal syndromic, micrognathia patients have increased temporomandibular joint pathology preoperatively and bony ankylosis after distraction but are protected with partial unloading of the condyle during distraction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II; Therapeutic, III.

Protection against bronchiolitis obliterans syndrome is associated with allograft CCR7+ CD45RA- T regulatory cells.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, yet markers for early detection and intervention are currently lacking. Given the role of regulatory T cells (Treg) in modulation of immunity, we hypothesized that frequencies of Treg in bronchoalveolar lavage fluid (BALF) after lung transplantation would predict subsequent development of BOS. Seventy BALF specimens obtained from 47 lung transplant recipients were analyzed for Treg lymphocyte subsets by flow cytometry, in parallel with ELISA measurements of chemokines. Allograft biopsy tissue was stained for chemokines of interest. Treg were essentially all CD45RA(-), and total Treg frequency did not correlate to BOS outcome. The majority of Treg were CCR4(+) and CD103(-) and neither of these subsets correlated to risk for BOS. In contrast, higher percentages of CCR7(+) Treg correlated to reduced risk of BOS. Additionally, the CCR7 ligand CCL21 correlated with CCR7(+) Treg frequency and inversely with BOS. Higher frequencies of CCR7(+) CD3(+)CD4(+)CD25(hi)Foxp3(+)CD45RA(-) lymphocytes in lung allografts is associated with protection against subsequent development of BOS, suggesting that this subset of putative Treg may down-modulate alloimmunity. CCL21 may be pivotal for the recruitment of this distinct subset to the lung allograft and thereby decrease the risk for chronic rejection.