Bifunctionality and Antitumor Efficacy of ZG-126, a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule.

Analogues of hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signal through the nuclear vitamin D receptor (VDR). They have potential in combination therapies with other anticancer agents such as histone deacetylase inhibitors (HDACi's). Here, we characterize the ZG series of hybrid compounds that combine HDACi within the backbone of a VDR agonist. All display improved solubility, with ZG-126 being the most robustly bifunctional molecule in multiple cell lines. ZG-126 is well tolerated and strongly induces VDR target gene expression in vivo at therapeutic doses. Its antitumor efficacy is superior to 1,25D and the HDACi SAHA, separately or together, in mouse models of melanoma and triple-negative breast cancer (TNBC). Notably, ZG-126 treatment reduces metastases almost 4-fold in an aggressive TNBC model. ZG-126 also reduces total macrophage infiltration and the proportion of immunosuppressive M2-polarized macrophages in TNBC tumors by 2-fold. ZG-126 thus represents a bifunctional and efficacious anticancer agent with improved physicochemical properties.

An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation.

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

The natural history of isolated common femoral endarterectomy for chronic limb-threatening ischemia.

OBJECTIVE: Occlusive disease of the common femoral artery can generate profound lower extremity ischemia as the normal collateral pathways from the profunda to the superficial femoral artery cannot adequately develop. In patients with lifestyle-limiting claudication, isolated common femoral endarterectomy (CFE) is highly effective. Because CFE does not provide direct, in-line flow to the plantar arch, it has been felt to provide inadequate revascularization to patients with chronic limb-threatening ischemia (CLTI). The purpose of this retrospective clinical study was to report and assess the natural history of selected patients with CLTI treated with isolated CFE (without concomitant infrainguinal revascularization). METHODS: Consecutive CFEs performed in a large, urban hospital for CLTI between 2014 and 2021 were reviewed. Patient characteristics, limb, and anatomical stages using the Wound, Ischemia, foot Infection (WIfI) and Global Limb Anatomic Staging System were tabulated. Limb-specific and survival-related end points were analyzed. RESULTS: Fifty-eight patients presenting with CLTI underwent isolated CFE (mean age, 74 ± 10 years; 62% male, 90% current or prior smoker). Comorbidities included diabetes (52%), coronary artery disease (55%), congestive heart failure (22%), and end-stage renal failure on hemodialysis (5%). Patients presented with either rest pain (36%) or tissue loss (64%); the latter group exhibited advanced limb threat (68% in WIfI stage 3 or 4). The majority of patients had associated severe infrainguinal disease (50% Global Limb Anatomic Staging Systems 3). After a median follow-up of 17 months (range, 10-29 months), vascular reintervention was required in 7 patients (12%). One patient (2%) required major limb amputation after presentation in WIfI stage 4 (W3I3fI0). Indeed, WIfI stage 4 was a significant univariate predictor of the need for subsequent infrainguinal bypass (P = .034). CONCLUSIONS: Isolated CFE as primary therapy in highly selected patients with CLTI was safe and effective. Index limb stage is predictive of the need for associated infrainguinal revascularization in this complex population.

Morbidity and mortality of common femoral endarterectomy.

OBJECTIVE: Common femoral endarterectomy (CFE) comprises the current standard-of-care for symptomatic common femoral artery occlusive disease. Although it provides effective inflow revascularization via a single incision, it remains an invasive procedure in an often-frail patient population. The purpose of this retrospective clinical study was to assess the morbidity and mortality of CFE in a contemporary cohort. METHODS: Consecutive CFEs performed at a large, urban hospital were reviewed. Six-month mortality, local complications (hematoma, lymphatic leak, pseudoaneurysm, wound infection, and/or dehiscence), and systemic complications were analyzed using univariate and multivariate analyses. RESULTS: A total of 129 isolated CFEs were performed over 7 years for claudication (36%), rest pain (16%), tissue loss (29%), or acute on chronic limb ischemia (21%). Mean age was 75 ± 9 years, and 68% of patients were male. Comorbidities were prevalent, including coronary artery disease (54%), diabetes (41%), chronic pulmonary disease (25%), and congestive heart failure (22%). The majority of CFEs were performed under general anesthesia (98%) with patch angioplasty using bovine pericardium (73% vs 27% Dacron). Twenty-two patients (17%) sustained local complications following the procedure; their occurrence was significantly associated with obesity (P = .002) but no technical or operative factors. Nineteen patients (15%) sustained serious systemic complications; their occurrence was significantly associated with chronic limb-threatening ischemia (P < .001), and a high American Society of Anesthesiologists (ASA) class (P = .002). By 6 months, 17 patients (13%) had died. Being on dialysis, presenting with chronic limb-threatening ischemia, and being in a high ASA class at the time of operation were all associated with 6-month mortality; a high ASA class at the time of operation was independently predictive of mortality (odds ratio, 3.08; 95% confidence interval, 1.03-9.24; P = .044). CONCLUSIONS: Although commonly performed, CFE is not a benign vascular procedure. Disease presentation, anesthetic risk, and expected longevity play an important role in clinical outcomes. Evolving endovascular approaches to the common femoral artery could serve to reduce morbidity and mortality in the future.

Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration.

The development of liver-based adeno-associated virus (AAV) gene therapies is facing concerns about limited efficiency and durability of transgene expression. We evaluated nonhuman primates following intravenous dosing of AAV8 and AAVrh10 vectors for over 2 years to better define the mechanism(s) of transduction that affect performance. High transduction of non-immunogenic transgenes was achieved, although expression declined over the first 90 days to reach a lower but stable steady state. More than 10% of hepatocytes contained single nuclear domains of vector DNA that persisted despite the loss of transgene expression. Greater reductions in vector DNA and RNA were observed with immunogenic transgenes. Genomic integration of vector sequences, including complex concatemeric structures, were detected in 1 out of 100 cells at broadly distributed loci that were not in proximity to genes associated with hepatocellular carcinoma. Our studies suggest that AAV-mediated transgene expression in primate hepatocytes occurs in two phases: high but short-lived expression from episomal genomes, followed by much lower but stable expression, likely from integrated vectors.

Validation of an Algorithm to Identify Venous Thromboembolism in Health Insurance Claims Data Among Patients with Rheumatoid Arthritis.

Purpose: Health insurance claims databases provide an opportunity to study uncommon events, such as venous thromboembolism (VTE), in large patient populations. This study evaluated case definitions for identifying VTE among patients treated for rheumatoid arthritis (RA) using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes in claims data. Patients and Methods: Study participants were insured adults who received treatment for and had a diagnosis of RA between 2016 and 2020. After a 6-month covariate assessment window, patients were observed for ≥1 month until health plan disenrollment, occurrence of a presumptive VTE, or end of the study (12/31/2020). Presumptive VTEs were identified using predefined algorithms based on ICD-10-CM diagnosis codes, anticoagulant use, and care setting. Medical charts were abstracted to confirm the VTE diagnosis. Performance of primary and secondary (less stringent) algorithms was assessed by calculating the positive predictive value (PPV; primary and secondary objectives). Additionally, a linked electronic health record (EHR) claims database and abstracted provider notes were used as a novel alternative source to validate claims-based outcome definitions (exploratory objective). Results: A total of 155 charts identified with the primary VTE algorithm were abstracted. The majority of patients were female (73.5%), with mean (standard deviation) age 66.4 (10.7) years and Medicare insurance (80.6%). Obesity (46.8%), ever smoking (55.8%), and prior evidence of VTE (28.4%) were commonly reported in medical charts. The PPV for the primary VTE algorithm was 75.5% (117/155; 95% confidence interval [CI], 68.7%, 82.3%). A less stringent secondary algorithm had a PPV of 52.6% (40/76; 95% CI, 41.4%, 63.9%). Using an alternative EHR-linked claims database, the primary VTE algorithm PPV was lower, potentially due to the unavailability of relevant records for validation. Conclusion: Administrative claims data can be used to identify VTE among patients with RA in observational studies.

Cutting Edge: Aire Is a Coactivator of the Vitamin D Receptor.

Vitamin D deficiency is associated with the development of autoimmunity, which arises from defects in T cell tolerance to self-antigens. Interactions of developing T cells with medullary thymic epithelial cells, which express tissue-restricted Ags, are essential for the establishment of central tolerance. However, vitamin D signaling in the thymus is poorly characterized. We find that stromal and hematopoietic cells in the mouse thymus express the vitamin D receptor (Vdr) and Cyp27b1, the enzyme that produces hormonal 1,25-dihydroxyvitamin D (1,25D). Treatment of cultured thymic slices with 1,25D enhances expression of the critical medullary thymic epithelial cell transcription factor autoimmune regulator (Aire), its colocalization with the Vdr, and enhances tissue-restricted Ag gene expression. Moreover, the Vdr interacts with Aire in a 1,25D-dependent manner and recruits Aire to DNA at vitamin D response elements, where it acts as a Vdr coactivator. These data link vitamin D signaling directly to critical transcriptional events necessary for central tolerance.

The Emerging Pro-Algesic Profile of Transient Receptor Potential Vanilloid Type 4.

Transient receptor potential vanilloid type 4 (TRPV4) channels are Ca2+-permeable non-selective cation channels which mediate a wide range of physiological functions and are activated and modulated by a diverse array of stimuli. One of this ion channel's least discussed functions is in relation to the generation and maintenance of certain pain sensations. However, in the two decades which have elapsed since the identification of this ion channel, considerable data has emerged concerning its function in mediating pain sensations. TRPV4 is a mediator of mechanical hyperalgesia in the various contexts in which a mechanical stimulus, comprising trauma (at the macro-level) or discrete extracellular pressure or stress (at the micro-level), results in pain. TRPV4 is also recognised as constituting an essential component in mediating inflammatory pain. It also plays a role in relation to many forms of neuropathic-type pain, where it functions in mediating mechanical allodynia and hyperalgesia.Here, we review the role of TRPV4 in mediating pain sensations.

Anatomical and Clinical Concepts in Distal Radius Volar Ulnar Corner fractures.

Background Volar ulnar corner fractures are a subset of distal radius fractures that can have disastrous complications if not appreciated, recognized, and appropriately managed. The volar ulnar corner of the distal radius is the "critical corner" between the radial calcar, distal ulna, and carpus and is responsible for maintaining stability while transferring force from the carpus. Description Force transmitted from the carpus to the radial diaphysis is via the radial calcar. A breach in this area of thickened cortex may result in the collapse of the critical corner. The watershed ridge (line) is clinically important in these injuries and must be appreciated during planning and fixation. Fractures distal to the watershed ridge create an added level of complexity and associated injuries must be managed. An osteoligamentous unit comprises bone-ligament-bone construct. Volar ulnar corner fractures represent a spectrum of osteoligamentous injuries each with their own associated injuries and management techniques. The force from the initial volar ulnar corner fracture can propagate along the volar rim resulting in an occult volar ligament injury, which is a larger zone of injury than appreciated on radiographs and computerized tomography scan. These lesions are often underestimated at the time of fixation, and for this reason, we refer to them as sleeper lesions. Unfortunately, they may become unmasked once the wrist is mobilized or loaded. Conclusions Management requires careful planning due to a relatively high rate of complications after fixation. A systematic approach to plate positioning, utilizing several fixation techniques beyond the standard volar rim plate, and utilizing fluoroscopy and/or arthroscopy is the key strategy to assist with management. In this article, we take a different view of the volar ulnar corner anatomy, applied anatomy of the region, associated injuries, and management options.

Treatment planning system commissioning of the first clinical biology-guided radiotherapy machine.

PURPOSE: The RefleXion X1 is a novel radiotherapy machine designed for image-guided radiotherapy (IGRT) and biology-guided radiotherapy (BgRT). Its treatment planning system (TPS) generates IMRT and SBRT plans for a 6MV-FFF beam delivered axially via 50 firing positions with the couch advancing every 2.1 mm. The purpose of this work is to report the TPS commissioning results for the first clinical installation of RefleXion™ X1. METHODS: CT images of multiple phantoms were imported into the RefleXion TPS to evaluate the accuracy of data transfer, anatomical modeling, plan evaluation, and dose calculation. Comparisons were made between the X1, Eclipse™, and MIM™. Dosimetric parameters for open static fields were evaluated in water and heterogeneous slab phantoms. Representative clinical IMRT and SBRT cases were planned and verified with ion chamber, film, and ArcCHECK@ measurements. The agreement between TPS and measurements for various clinical plans was evaluated using Gamma analysis with a criterion of 3%/2 mm for ArcCHECK@ and film. End-to-end (E2E) testing was performed using anthropomorphic head and lung phantoms. RESULTS: The average difference between the TPS-reported and known HU values was -1.4 ± 6.0 HU. For static fields, the agreements between the TPS-calculated and measured PDD10 , crossline profiles, and inline profiles (FWHM) were within 1.5%, 1.3%, and 0.5 mm, respectively. Measured output factors agreed with the TPS within 1.3%. Measured and calculated dose for static fields in heterogeneous phantoms agreed within 2.5%. The ArcCHECK@ mean absolute Gamma passing rate was 96.4% ± 3.4% for TG 119 and TG 244 plans and 97.8% ± 3.6% for the 21 clinical plans. E2E film analysis showed 0.8 mm total targeting error for isocentric and 1.1 mm for off-axis treatments. CONCLUSIONS: The TPS commissioning results of the RefleXion X1 TPS were within the tolerances specified by AAPM TG 53, MPPG 5.a, TG 119, and TG 148. A subset of the commissioning tests has been identified as baseline data for an ongoing QA program.

Predictors of Amputation-free Survival after Endovascular Intervention for Chronic Limb-Threatening Ischemia in the Modern era.

BACKGROUND: Chronic limb-threatening (CLTI) is associated with 25% limb loss and 25% mortality at 1-year. Its lethality increases to 45% in patients subjected to a major amputation. Percutaneous peripheral intervention (PPI) constitutes an attractive and less morbid treatment option for patients with CLTI. The purpose of this study was to assess amputation-free survival (AFS) in a contemporary cohort treated with endovascular recanalization and assess its predictors. METHODS: Patients with CLTI undergoing endovascular revascularization at a single regional hospital between 2015-2019 were reviewed. Baseline demographic characteristics, Wound, Ischemia, and foot Infection (WIfI) stage, technical details, and clinical outcomes were tabulated. The primary endpoint was AFS; a P-value < 0.05 was used for univariate screening and inclusion in a multivariable model. RESULTS: A total of 137 limbs in 111 patients were studied. Comorbidities were prevalent and included diabetes (65%), congestive heart failure (21%), and dialysis dependence (18%). The majority of revascularized limbs presented with advanced wounds (66% WIfI stages 3-4; 47% Rutherford category 6). Presenting WIfI stages were similar across races (P = 0.26). Peripheral interventions most commonly targeted femoropopliteal disease (69%), although 26% were multilevel. Percutaneous atherectomy, stenting, and paclitaxel-coated or eluting devices were utilized in 68%, 28%, and 15% of cases, respectively. After a median follow-up of 16 months (interquartile range IQR = 4-29 months), significant independent predictors of reduced AFS included nonWhite race (HR = 2.96 [1.42-6.17]; P = 0.004) and WIfI stage 4 wounds (HR = 2.23 [1.10-4.52]; P = 0.026). At one year following successful revascularization, only 59% ± 1% of patients were alive with their limb intact. CONCLUSIONS: Despite considerable and consistent advances in urban health care delivery and the techniques of PPI, CLTI remains a morbid and deadly disease. Even in the endovascular era, nearly half of all patients presenting with CLTI will lose their limb and/or life within the first year. Unfortunately, late-stage presentation continues to be commonplace. Although endovascular intervention can reliably restore patency to affected arteries, this appears insufficient to restore most patients to health.

Transposition of left subclavian artery with reimplantation of isolated left vertebral artery before thoracic endovascular aneurysm repair for type B aortic dissection.

Understanding and recognizing anatomic anomalies of the aortic arch is important when planning extra-anatomic debranching before thoracic endovascular aortic repair. A rare anomaly is the left vertebral artery aberrantly arising from the aortic arch; found in ∼5% of adults. When present, the artery courses through the carotid sheath at a variable length before entering the third or fourth cervical transverse foramen. In the present report, we have described the case of a 49-year-old man with a symptomatic, enlarging type B aortic dissection with an aberrant left vertebral artery and the novel methods used to surgically correct his pathology.

Beam commissioning of the first clinical biology-guided radiotherapy system.

This study reports the beam commissioning results for the first clinical RefleXion Linac. METHODS: The X1 produces a 6 MV photon beam and the maximum clinical field size is 40 × 2 cm2 at source-to-axis distance of 85 cm. Treatment fields are collimated by a binary multileaf collimator (MLC) system with 64 leaves with width of 0.625 cm and y-jaw pairs to provide either a 1 or 2 cm opening. The mechanical alignment of the radiation source, the y-jaw, and MLC were checked with film and ion chambers. The beam parameters were characterized using a diode detector in a compact water tank. In-air lateral profiles and in-water percentage depth dose (PDD) were measured for beam modeling of the treatment planning system (TPS). The lateral profiles, PDDs, and output factors were acquired for field sizes from 1.25 × 1 to 40 × 2 cm2 field to verify the beam modeling. The rotational output variation and synchronicity were tested to check the gantry angle, couch motion, and gantry rotation. RESULTS: The source misalignments were 0.049 mm in y-direction, 0.66% out-of-focus in x-direction. The divergence of the beam axis was 0.36 mm with a y-jaw twist of 0.03°. Clinical off-axis treatment fields shared a common center in y-direction were within 0.03 mm. The MLC misalignment and twist were 0.57 mm and 0.15°. For all measured fields ranging from the size from 1.25 × 1 to 40 × 2 cm2 , the mean difference between measured and TPS modeled PDD at 10 cm depth was -0.3%. The mean transverse profile difference in the field core was -0.3% ± 1.1%. The full-width half maximum (FWHM) modeling was within 0.5 mm. The measured output factors agreed with TPS within 0.8%. CONCLUSIONS: This study summarizes our specific experience commissioning the first novel RefleXion linac, which may assist future users of this technology when implementing it into their own clinics.

Molecular mechanisms of bifunctional vitamin D receptor agonist-histone deacetylase inhibitor hybrid molecules in triple-negative breast cancer.

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), and its analogues signal through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor, and have been extensively investigated as anticancer agents. 1,25D and its analogs have potential in combination therapies because they exhibit synergistic activities with other anticancer agents such as histone deacetylase inhibitors (HDACi). We have developed a series of hybrid molecules that combine HDACi within the backbone of a VDR agonist and thus represent fully integrated bifunctional molecules. They exhibit anti-tumor efficacy in reducing tumor growth and metastases in an aggressive model of triple-negative breast cancer. However, their solubility is limited by their hydrophobic diarylpentane cores. Our goals here were two-fold: (1) to improve the solubility of hybrids by introducing nitrogen into diarylpentane cores, and (2) to investigate the molecular mechanisms underlying their anti-tumor efficacy by performing comparative gene expression profiling studies with 1,25D and the potent HDACi suberoylanilide hydroxamic acid (SAHA). We found that substituting aryl with pyrydyl rings did not sacrifice bifunctionality and modestly improved solubility. Notably, one compound, AM-193, displayed enhanced potency as a VDR agonist and in cellular assays of cytotoxicity. RNAseq studies in triple negative breast cancer cells revealed that gene expression profiles of hybrids were very similar to that of 1,25D, as was that observed with 1,25D and SAHA combined. The effects of SAHA alone on gene expression were limited and distinct from those 1,25D or hybrids. The combined results suggest that efficacy of hybrids arises from targeting HDACs that do not have a direct role in gene regulation. Moreover, pathways analysis revealed that hybrids regulate numerous genes controlling immune cell infiltration into tumors and suppress the expression of several secreted molecules that promote breast cancer growth and metastasis.

Thoracobifemoral bypass for infrarenal aortic occlusion caused by retroperitoneal fibrosis.

Retroperitoneal fibrosis (RPF) is an uncommon fibrotic disorder that can cause pain, ureteral obstruction, deep venous thrombosis, hydrocele, and, rarely, aortic occlusion. Herein is described a 65-year-old man with aortic occlusion from idiopathic RPF who was treated with axillobifemoral bypass grafting, which failed in the intermediate term. On representation with critical claudication, he underwent thoracobifemoral bypass grafting via a lateral retroperitoneal tunnel created through a midline, infraumbilical counterincision. He was discharged home on postoperative day 5. This illustrates the successful use of thoracic aortic inflow to treat the aortoiliac occlusive complication of RPF.

Treatment Patterns and Disease Burden Associated with Multiple-Inhaler Triple-Therapy Use in Asthma.

BACKGROUND: Addition of a long-acting muscarinic antagonist is recommended for patients with asthma uncontrolled on inhaled corticosteroid/long-acting ß2-agonist therapy. This is the first large-scale, real-world study examining multiple-inhaler triple-therapy (MITT) use in asthma. OBJECTIVE: To describe real-world prevalence, outcomes, and treatment patterns associated with MITT. METHODS: This retrospective cohort study used medical and pharmacy claims from the Optum Research Database. Patients were diagnosed with asthma between January 01, 2013, and July 31, 2018, with evidence of MITT use (≥1 overlapping days' supply of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist). Annual MITT prevalence (primary end point) was assessed in the prevalent population; eligible patients were 18 years or older with 2 or more asthma diagnoses during the study period, and continuous enrollment for the entire year. Secondary outcomes (adherence [proportion of days covered], MITT persistence, health care resource utilization, costs) were assessed in the incident MITT population; eligible patients were 18 years or older, with 2 or more asthma diagnoses and continuous enrollment during both the 12-month baseline and 12-month follow-up periods. Patients with chronic obstructive pulmonary disease or cystic fibrosis were excluded. RESULTS: MITT prevalence was low but increased from 0.35% (95% CI, 0.32-0.37) in 2014/2015 to 1.00% (95% CI, 0.96-1.04) in 2017/2018. Among 1831 incident MITT users, there was a substantial disease burden, demonstrated by high health care resource utilization and exacerbation rates. Adherence and persistence to MITT was low (mean proportion of days covered, 0.31 ± 0.27), and 12% (n = 216) remained on MITT 12 months postinitiation. CONCLUSIONS: Overall, MITT use among patients with asthma is low. Patients initiating MITT have substantial disease burden and significant unmet needs.

Novel methods to determine complement activation in human serum induced by the complex of Dezamizumab and serum amyloid P.

Lack of simple and robust methods to determine complement activation in human serum induced by antigen-antibody complexes is a major hurdle for monitoring therapeutic antibody drug quality and stability. Dezamizumab is a humanized IgG1 monoclonal antibody that binds to serum amyloid P component (SAP) for potential treatment of systemic amyloidosis. The mechanism of action of Dezamizumab includes the binding of SAP, complement activation through classical pathway, and phagocytosis; however, the steps in this process cannot be easily monitored. We developed two novel methods to determine Dezamizumab-SAP complex-induced complement activation. Complement component 3 (C3) depletion was detected by homogeneous time-resolved fluorescence (HTRF), and C3a desArg fragment, formed after the cleavage of C3 to yield C3a followed by removal of its C-terminal arginine residue, was determined using Meso Scale Discovery (MSD) technology. We found that the presence of both Dezamizumab and SAP was required for complement activation via both methods. The optimal molar ratio of Dezamizumab:SAP was 6:1 in order to obtain maximal complement activation. The relative potency from both methods showed a good correlation to Dezamizumab-SAP-dependent complement component 1q (C1q) binding activity in Dezamizumab thermal-stressed samples. Both SAP and C1q binding, as determined by surface plasmon resonance and the two complement activation potency methods described here, reflect the mechanism of action of Dezamizumab. We conclude that these methods can be used to monitor Dezamizumab quality for drug release and stability testing, and the novel potency methods reported here can be potentially used to evaluate complement activity induced by other antigen-antibody complexes.

A simplified surgical approach for left ovarian vein transposition for the treatment of pelvic venous disease from nutcracker syndrome.

Nutcracker syndrome is becoming increasingly recognized as a cause of chronic pelvic pain. Several treatment options have been used, including renal vein or ovarian vein transposition to the more distal inferior vena cava and renal vein stenting. Concerned about the major scope of the surgical procedures as well as the implantation of a foreign body that must function for six to seven decades, we undertook to develop an all autogenous simpler surgical solution for the treatment of nutcracker syndrome. In 2013, we began performing left ovarian vein transposition to the left iliac vein. In our initial report, we used a minimally invasive robotic approach. For the past several years, we have used a simplified open approach to left ovarian vein transposition that takes advantage of the fact that the left ovarian vein naturally courses over the iliac vein. We have found this surgical treatment of nutcracker syndrome provides excellent relief from the associated symptoms.

The Impact of Adverse Events on Health Care Resource Utilization, Costs, and Mortality Among Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: We investigated the association between adverse events (AEs) suspected to be immune-related and health care resource utilization, costs, and mortality among patients receiving programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitor (ICI) monotherapy for urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, or Merkel cell carcinoma. PATIENTS AND METHODS: We conducted a retrospective cohort study using medical and pharmacy claims and enrollment information from U.S. commercial and Medicare Advantage with Part D enrollees in the Optum Research Database from March 1, 2014, through April 30, 2019. Claims were linked with mortality data from the Social Security Death Index and the National Death Index. Eligible patients had at least one ICI claim between September 1, 2014, and April 30, 2019. RESULTS: After adjusting for potential confounding variables, we found patients with AEs had more than double the risk of an inpatient stay (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.9-2.5) and an 80% higher risk of an emergency visit (HR, 1.8; 95% CI, 1.6-2.1) than patients without AEs. Adjusted 6-month total costs were $24,301 higher among patients with an AE versus those without ($99,037 vs. $74,736; 95% CI, $18,828-29,774; p < .001). Mean ± SD AE-related medical costs averaged $2,359 ± $7,496 per patient per month, driven by inpatient visits, which accounted for 89.9% of AE-related costs. Adjusted risk of mortality was similar in patients with and without AEs. CONCLUSION: Patients with AEs had higher risks of hospitalizations, emergency room visits, and higher health care costs, driven by inpatient stays, than patients without AEs. The adjusted risk of mortality was similar between the two cohorts. IMPLICATIONS FOR PRACTICE: Patients taking immune checkpoint inhibitors (ICIs) who had adverse events (AEs) had significantly higher health care costs and utilization, driven by inpatient stays, compared with patients who did not. Given this high cost associated with AEs and the differences in the side effect profile of ICIs versus traditional chemotherapy, it is important for physicians to be cognizant of these differences when treating patients with ICIs. Ongoing evaluation, earlier recognition, and more effective, multidisciplinary management of AEs may improve patient outcomes and reduce the need for costly inpatient stays.