CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.

C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8-2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%-48.2% (cycle 1) and 37.5%-44.2% (cycle 2) and occurred within 6-12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

Findings of Optical Coherence Tomography Angiography in Best Vitelliform Macular Dystrophy.

PURPOSE: To evaluate the vascular anatomy of eyes with Best vitelliform macular dystrophy (BVMD) using optical coherence tomography angiography (OCTA). METHODS: This retrospective case-control study enrolled 11 consecutive BVMD patients and 13 age-matched healthy participants. Both eyes of each participant were imaged using a macular OCTA scan (3 × 3 mm) by 70-kHz 840-nm spectral-domain OCT. The flow signal was calculated using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. RESULTS: Qualitative analysis showed uneven hypo- and hyperintense signal changes at the choriocapillary level in OCTA images of BVMD patients. Quantitative analysis showed significant reductions in the flow density of the superficial vascular layer (whole: 49.2% vs. 53.9%, p < 0.001) and the choriocapillary flow area (5.1 vs. 5.5 mm2, p = 0.02) in BVMD patients compared to controls. The choriocapillary flow area in the postvitelliform group was reduced compared to that of the vitelliform group. There was a statistically significant association between choriocapillary flow area and superficial vascular flow density (p = 0.045), choriocapillary flow area and foveal avascular zone area (p = 0.03). CONCLUSIONS: Vascular changes in BVMD were apparent in the choriocapillary layer. The changes became more striking in late stages of the disease. OCTA provides useful quantitative measurements for staging and monitoring the progression of BVMD.

High-frequency aflibercept injections in persistent neovascular age-related macular degeneration.

PURPOSE: To report the 1-year outcomes of every-4-weeks (Q4W) as-needed aflibercept treatment in resistant neovascular age-related macular degeneration (nAMD) patients who had been treated and failed prior bevacizumab or ranibizumab injections, and who also responded poorly to every-8-weeks (Q8W) aflibercept treatment. METHODS: Forty-three eyes of 39 patients with persistent nAMD despite monthly bevacizumab and/or ranibizumab injections and who were switched to Q8W 2-mg aflibercept injections, but showed persistence of fluid were included. Patients were treated with as-needed Q4W aflibercept injections with monthly monitoring. Maximum retinal thickness (MRT), central macular thickness (CMT), maximum pigment epithelial detachment height (PED) and best-corrected visual acuity (BCVA) were assessed and compared to baseline when high-frequency aflibercept was initiated. RESULTS: A mean of 8 (interquartile range, 4-11) Q4W injections were given during the follow-up. MRT and CMT significantly decreased at all follow-up visits (p < 0.05); however, there was no significant change in maximum PED height (p > 0.05) at any visit. Mean BCVA was 0.38 ± 0.28 (logMAR) (≈20/63, Snellen) at baseline, and 0.4 ± 0.34 (logMAR) (≈20/76, Snellen) at 1 year (p = 0.76). Seventy-two percent of eyes maintained a final BCVA of 20/63 or better. Twelve eyes (28 %) had some subretinal scar tissue formation and 5 eyes (11.6 %) had evidence of atrophy at 1 year. CONCLUSION: A stepwise algorithm with Q4W as-needed aflibercept treatment led to anatomic improvement in previously treated eyes which failed other therapies, including aflibercept every 8 weeks. Lack of visual improvement may be due to a ceiling effect as our eyes generally had good visual acuity.

CHARACTERISTICS OF EPIRETINAL MEMBRANE REMNANT EDGE BY OPTICAL COHERENCE TOMOGRAPHY AFTER PARS PLANA VITRECTOMY.

PURPOSE: To evaluate the incidence, characteristics, and the progression of epiretinal membrane (ERM) remnant edge seen by optical coherence tomography after ERM peeling. METHODS: A retrospective chart review was conducted for 86 eyes of 85 consecutive patients who were diagnosed with ERM and underwent pars plana vitrectomy for epiretinal membrane peeling between 2013 and 2014. Data collected and analyzed included age, gender, preoperative and postoperative visual acuity, use of indocyanine green dye to stain internal limiting membrane, tamponade used after vitrectomy, ERM edge boundaries, presence of cystoid macular edema, and central foveal thickness. RESULTS: An ERM remnant edge was detected in 33/86 study eyes (38.4%) at the first postoperative optical coherence tomography scan. Compared with those without an ERM remnant, patients with an ERM remnant after surgery were significantly older at baseline and had a higher incidence of ERM recurrence at their last visit. They were not significantly different in terms of gender, preoperative and postoperative visual acuity, reduction of central foveal thickness from baseline, proportion of eyes with preoperative ERM elevation on optical coherence tomography, presence of macular edema before surgery, intraoperative use of indocyanine green staining for ILM peeling, or tamponade used. Based on the edge morphology, we classified the ERM remnant into three types: Type 1 was flat and blended with the retina (14/33 eyes, 42.4%), Type 2 was flat but stepped (17/33 eyes, 51.5%), and Type 3 was elevated (2/33 eyes, 6.0%). A significantly higher risk of ERM recurrence was seen in Type 2 and Type 3 ERM remnants (75% and 100%, respectively) than Type 1 ERM remnants (10%). CONCLUSION: An ERM remnant edge was detected by optical coherence tomography after ERM peeling in 38.4% of eyes. The presence of a postoperative ERM edge was associated with a higher risk of ERM recurrence, particularly in Type 2 and Type 3 ERM remnants.

Congenital aniridia with cataract: case series.

BACKGROUND: This study evaluates patients with congenital aniridia and cataract who underwent phacoemulsification, capsular tension ring placement, and foldable intraocular lens implantation. METHODS: In this prospective case series, 10 patients (17 eyes) underwent cataract surgery via a 3.2 mm clear corneal incision. A continuous circular capsulorhexis with <6 mm diameter was employed. A capsular tension ring and HOYA yellow foldable posterior chamber intraocular lens was implanted. All patients wore color contact lenses postoperatively. Paired t test was used to compare visual acuity, intraocular pressure, and corneal endothelial changes before and after surgery. RESULTS: A single surgeon performed all surgeries. The best-corrected visual acuity improved from value 1.03 ± 0.27LogMAR preoperatively to value 0.78 ± 0.26LogMAR postoperatively (p = 0.000). The photophobic symptoms improved significantly after surgery. The mean corneal endothelial cell density before and after surgery was 3280 ± 473 cells/mm2 and 2669 ± 850 cells/mm2, respectively (p = 0.006). None of the patients developed corneal endothelial decompensation or secondary glaucoma after surgery. CONCLUSIONS: Treatment of congenital aniridia and coexistent cataract by phacoemulsification, posterior chamber foldable lens implantation, capsular tension ring placement was safe and effective. Use of colored contact lenses in the postoperative period can reduce photophobic symptoms in this group of patients. TRIAL REGISTRATION: ChiCTR-OOC-17011638 (retrospectively registered at 12,June,2017).

Impaled Orbital TASER Probe Injury Requiring Primary Enucleation.

The Conducted Electrical Weapon is a weapon often used by law enforcement agencies as a method of less lethal means to subdue a suspect. Injuries to the eye with these devices are usually due to the projectile force of the metal probes that are released when these devices are engaged. The authors report what may be the first case of an impaled orbital TASER probe that required primary enucleation for globe perforation.

Successive bootstrapping deep learning approach and airborne EM-borehole data fusion to understand salt water in the Mississippi River Valley Alluvial Aquifer.

Increasing demands from agriculture and urbanization have decreased groundwater level and increased salinity worldwide. Better aquifer characterization and soil salinity mapping are important for proactive groundwater management. Airborne electromagnetic (AEM) is a powerful tool for aquifer characterization and salinity delineation. However, AEM needs to be interpreted with caution before being used for groundwater quality analysis. This study introduces a framework that utilizes the AEM data for both lithologic modeling and salinity delineation. A resistivity-to-lithology (R2L) model is developed to interpret AEM resistivity to lithology based a depth-dependent multi-resistivity thresholds. Then, a cokriging method is used to integrate AEM data from two different EM systems to predict resistivity at the aquifer. Finally, a resistivity-to-chloride concentration (R2C) model utilizes the resistivity model to estimate chloride concentrations at sand facies. A deep learning artificial neural network (DL-ANN) model is introduced with a successive bootstrapping approach to estimate total dissolved solids first and then use it together with resistivity data to estimate chloride concentration. The methodology was applied to delineating salinity plumes in the Mississippi River Valley alluvial aquifer (MRVA). This study found that the salinity distribution in MRVA is highly correlated with the Jurassic salt basin, salt domes, faulting, seismicity, and river water quality. The result indicates salinity upconing due to excessive pumping.

A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer.

BACKGROUND: Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer. METHODS: In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m(2) on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 + 3 dose-escalation plan was used. After induction, patients were removed from protocol. RESULTS: Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%-96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%-92.3%). Activating PI3K catalytic subunit α (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers. CONCLUSIONS: The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m(2) on day 1 of a 21-day cycle) given with pegfilgrastim support.

Pachydermoperiostosis: a rare cause of marked blepharoptosis and floppy eyelid syndrome.

A 34-year-old African-American man was referred for eyelid swelling and ocular discomfort. He was found to have floppy hypertrophic eyelids and marked bilateral mechanical ptosis that was present since childhood. Systemic examination was significant for furrows on his forehead and scalp, coarse facial features, and enlarged hands and feet with clubbing of the fingers and toes. Radiographic imaging of the long bones demonstrated periostosis, and MRI of the head revealed a pituitary macroadenoma. Pituitary and thyroid hormone levels were normal. The patient was diagnosed with pachydermoperiostosis and a non-secreting pituitary macroadenoma. Bilateral upper lid tightening via wedge resection was followed by bilateral external levator advancement ptosis repair in a staged manner. The patient achieved symptom relief and improved lid position postoperatively.

Outcome of eight working dogs with fibrotic myopathy following extracorporeal shockwave and rehabilitation therapy: a case series.

Introduction: Fibrotic myopathy of the gracilis, semitendinosus, and semimembranosus is described primarily in working German Shepherd dogs. The purpose of this case series is to describe the rehabilitation modalities and treatments utilized in working dogs with fibrotic myopathy and the time frame they were able to continue working. Methods: Medical records of patients with hindlimb lameness that were presented to the Schwarzman Animal Medical Center in New York City from 2012 to 2023 were retrospectively searched. Signalment, history, clinical evaluation, gait analysis, goniometry of stifles, and follow-up evaluation were compared among patients. Ten male working dogs met inclusion criteria. Extracorporeal Shockwave Therapy (ECSWT) was administered under sedation or general anesthesia. Rehabilitation therapy (RT), including massage, hamstring stretch, photobiomodulation, pulsed electromagnetic field therapy, warm compress, therapeutic ultrasound, underwater treadmill, and therapeutic exercises, were performed once every one to 3 weeks with varying protocols according to patient assessments. Follow-up phone calls and emails were conducted to determine long-term outcome. Results: On average, dogs were able to work full-time for 32.1 months (range 6-82; SD 23.6) from the time of diagnosis. No activity limitation was reported by the owners/handlers. Discussion: This report is the first to describe non-invasive medical treatments that may extend the working ability of dogs diagnosed with fibrotic myopathy. Further prospective randomized controlled studies are needed to demonstrate the efficacy of ECSWT and RT for treating fibrotic myopathy. Conclusion: The results of this retrospective study suggest that the combination of ECSWT and RT may allow working dogs with fibrotic myopathy to continue their working capacity for an extended period of time.

Bilateral marked dacryops following trauma.

A 35 year-old man presented for evaluation of bilateral lacrimal fossa masses. He sustained left and right periocular trauma, eight months and five years prior to presentation, respectively. The patient had marked dacryops, left greater than right, which was confirmed by orbital CT. Surgical excision of the left dacryops was performed, and excision of the right sided lesion was deferred by the patient.

Specific sorting of single bacterial cells with microfabricated fluorescence-activated cell sorting and tyramide signal amplification fluorescence in situ hybridization.

When attempting to probe the genetic makeup of diverse bacterial communities that elude cell culturing, researchers face two primary challenges: isolation of rare bacteria from microbial samples and removal of contaminating cell-free DNA. We report a compact, low-cost, and high-performance microfabricated fluorescence-activated cell sorting (µFACS) technology in combination with a tyramide signal amplification fluorescence in situ hybridization (TSA-FISH) to address these two challenges. The TSA-FISH protocol that was adapted for flow cytometry yields a 10-30-fold enhancement in fluorescence intensity over standard FISH methods. The µFACS technology, capable of enhancing its sensitivity by ~18 dB through signal processing, was able to enrich TSA-FISH-labeled E. coli cells by 223-fold. The µFACS technology was also used to remove contaminating cell-free DNA. After two rounds of sorting on E. coli mixed with λ-phage DNA (10 ng/µL), we demonstrated over 100,000-fold reduction in λ-DNA concentration. The integrated µFACS and TSA-FISH technologies provide a highly effective and low-cost solution for research on the genomic complexity of bacteria as well as single-cell genomic analysis of other sample types.

Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors.

BACKGROUND: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. METHODS: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. RESULTS: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. CONCLUSIONS: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02955251.

Human mammalian cell sorting using a highly integrated micro-fabricated fluorescence-activated cell sorter (microFACS).

We demonstrate a high performance microfabricated FACS system with highly integrated microfluidics, optics, acoustics, and electronics. Single cell manipulation at a high speed is made possible by the fast response time (approximately 0.1 ms) of the integrated PZT actuator and the nozzle structure at the sorting junction. A Teflon AF-coated optofluidic waveguide along the microfluidic channel guides the illumination light, enabling multi-spot detection, while a novel space-time coding technology enhances the detection sensitivity of the microFACS system. The real-time control loop system is implemented using a field-programmable-gate-array (FPGA) for automated and accurate sorting. The microFACS achieves a high purification enrichment factor: up to approximately 230 fold for both polystyrene microbeads and suspended human mammalian cells (K562) at a high throughput (>1000 cells s(-1)). The sorting mechanism is independent of cell properties such as size, density, and shape, thus the presented system can be applied to sort out any pure sub-populations. This new lab-on-a-chip FACS system, therefore, holds promise to revolutionize microfluidic cytometers to meet cost, size, and performance goals.

First-in-Humans Imaging with 89Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results:89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion:89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.

Bio-inspired accommodating fluidic intraocular lens.

The invention of intraocular lens (IOL), a substitute for crystalline lens, represents a major advancement in cataract surgery. After about sixty years of IOL development, one key remaining problem is its limited accommodation range compared with natural eyes. To overcome this performance limit, we explore bio-inspired fluidic IOL. By mimicking the working principle of natural eyes, a fluidic intraocular lens can achieve an exceedingly large accommodation range. An experiment on fluidic IOL demonstrated a very high tuning range of 12 D. This accommodation range was achieved with a modest amount of force (0.06 N) and equatorial radius change (0.286 mm), in conditions matching well with the characteristics of aged eyes.

Microfluidic cell sorter with integrated piezoelectric actuator.

We demonstrate a low-power (<0.1 mW), low-voltage (<10 V(p-p)) on-chip piezoelectrically actuated micro-sorter that can deflect single particles and cells at high-speed. With rhodamine in the stream, switching of flow between channels can be visualized at high actuation frequency (micro1.7 kHz). The magnitude of the cell deflection can be precisely controlled by the magnitude and waveform of input voltage. Both simulation and experimental results indicate that the drag force imposed on the suspended particle/cell by the instantaneous fluid displacement can alter the trajectory of the particle/cell of any size, shape, and density of interest in a controlled manner. The open-loop E. Coli cell deflection experiment demonstrates that the sorting mechanism can produce a throughput of at least 330 cells/s, with a promise of a significantly higher throughput for an optimized design. To achieve close-loop sorting operation, fluorescence detection, real-time signal processing, and field-programmable-gate-array (FPGA) implementation of the control algorithms were developed to perform automated sorting of fluorescent beads. The preliminary results show error-free sorting at a sorting efficiency of micro 70%. Since the piezoelectric actuator has an intrinsic response time of 0.1-1 ms and the sorting can be performed under high flowrate (particle speed of micro 1-10 cm/s), the system can achieve a throughput of >1,000 particles/s with high purity.