Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma.

PURPOSE: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM. METHODS: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. RESULTS: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively. CONCLUSIONS: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

A comparison on the percentage of polymerase chain reaction positivity for SARS-CoV-2 between Public Health Center referrals and direct walk-in patients: A single center retrospective analysis in Tokyo.

INTRODUCTION: The Public Health Center (PHC)-known as hokenjo in Japan-assume a crucial role in disease control. Coronavirus disease 2019 (COVID-19) is one of many designated infectious diseases monitored by the agency. During the present pandemic, patients who suspected COVID-19 were instructed to call the Coronavirus Consultation Center in the PHC prior to visiting the hospital. The aim of this study was to elucidate the differences in polymerase chain reaction (PCR) positivity between PHC referrals and direct walk-in patients. METHODS: The present was a single-center, retrospective cohort study conducted at the Tokyo Metropolitan Hospital from March to September, 2020. Patients who received a PCR test for SARS-CoV-2 were included and categorized into the PHC referral or direct walk-in groups. The outcomes included the total number of patients undergoing PCR tests and the percentage of PCR positivity in each group. RESULTS: We identified 1680 patients (781 PHC referred and 899 direct walk-in groups). The percentage of PCR positivity did not significantly differ between the PHC referral and direct walk-in groups during the first wave (30.5% vs. 29.2%; p = 0.78). PCR positivity was significantly higher in the PHC referral group than the direct walk-in group during the second wave (30.1% vs. 23.1%; p = 0.051) and entire study period (30.2% vs. 24.7%; p = 0.011). CONCLUSIONS: Despite health authority recommendations, the number of direct walk-in patients were higher than PHC referral patients. The percentage of PCR positivity was significantly higher in the PHC referral group than in the direct walk-in group.

Model-Based Determination of Elotuzumab Pharmacokinetics in Japanese Patients With Multiple Myeloma Incorporating Time-Varying M Protein.

A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time-varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2-compartment model with parallel linear (nonspecific) and Michaelis-Menten elimination from the central compartment and target-mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target-mediated elimination rate (Vmax ) were statistically significant but not considered clinically relevant (magnitude < 20%). Time-varying M protein on Vmax was statistically significant, and the magnitude was >20%; however, clinical implications in the setting of combination therapy were not expected. Model-predicted steady-state elotuzumab exposure in cycle 12 were similar in Japanese and non-Japanese patients and in Japanese patients with 0 and ≥1 prior lines of therapy. Elotuzumab 20 mg/kg intravenously every 4 weeks beginning in cycle 19 produced time-averaged concentrations similar to elotuzumab 10 mg/kg intravenously every 2 weeks, although maximum and minimum concentrations after elotuzumab 20 mg/kg intravenous every-4-week dosing were slightly higher and lower, respectively. In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time-varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma.

Sumo-Associated Traumatic Vertebral Artery Dissection Precipitating Subarachnoid Hemorrhage in Association with Bifid Origins of the Posterior Inferior Cerebellar Artery.

BACKGROUND: Traumatic vertebral artery dissection (tVAD) is frequently accompanied by cerebellar infarction, but subarachnoid hemorrhage (SAH) is rare. CASE DESCRIPTION: We report a unique case of tVAD precipitating SAH, from which the patient fully recovered, most likely because of the protective effects of an anomalously duplicated posterior inferior cerebellar artery (PICA) origin. A 17-year-old Sumo wrestler experienced a brief loss of consciousness after an attack by an opponent to his neck. Head computed tomography imaging demonstrated diffuse posterior fossa SAH; cerebral angiography demonstrated left vertebral artery (VA) occlusion, which was thought to be most likely attributable to tVAD. Angiography revealed distal PICA reconstitution, supplied by collateral arterial flow from the meningeal branch of the proximal ipsilateral VA. An external ventricular drain was placed acutely for treatment of SAH-induced hydrocephalus; however, the patient had an otherwise uneventful course, and remained without clinical evidence of ischemic infarct. A repeat imaging confirming a probable duplicated PICA origin from the VA, distal to the tVAD-associated thrombosis. CONCLUSIONS: Of particular interest, the patient's abnormal anatomy may have been a mixed blessing, with a more fragile bifid PICA potentially underlying the unexpected development of SAH, whereas the sister branch simultaneously spared him a potentially catastrophic infarction via arterial collateralization.

The 2-Minute Spontaneous Swallowing Screening Predicts Independence on Enteral Feeding in Patients with Acute Stroke.

BACKGROUND: It is recommended that enteral feeding should be offered to patients with dysphagia estimated to be unable to take adequate diet orally within 7 days of admission after acute stroke, but there is no clear criterion for initiation of enteral feeding. Recent studies have reported that the frequency of spontaneous swallowing is useful in screening for dysphagia in acute stroke. The present study was aimed to investigate whether measurement of frequency of spontaneous swallowing for 2 minutes could predict independence on enteral feeding 1 week after admission in patients with acute stroke. METHODS: Patients with acute stroke were subjected. Within 72 hours of stroke onset, the number of swallows for 2 minutes was measured by auscultation. Subsequently, 1-hour frequency of spontaneous swallowing was measured using a laryngeal microphone. Functional Oral Intake Scale (FOIS) was evaluated 1 week after admission. RESULTS: Twenty-six out of 40 patients were independent on enteral feeding 1 week after admission based on FOIS. The presence of spontaneous swallowing for 2 minutes had .89 sensitivity, .54 specificity to predict independence on enteral feeding 1 week after admission, whereas the 1-hour frequency of spontaneous swallowing had 1.00 sensitivity, .46 specificity. Logistic regression analysis demonstrated that the presence of spontaneous swallowing for 2 minutes was independent predictor for independence on enteral feeding 1 week after admission, independently of age, sex, and NIHSS. CONCLUSIONS: The 2-minute spontaneous swallowing screening predicts independence on enteral feeding 1 week after admission in patients with acute stroke.

Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle.

Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF165), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.

Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis.

We present a highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidation potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivatives and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.

Relationship Between Frequency of Spontaneous Swallowing and Salivary Substance P Level in Patients with Acute Stroke.

The frequency of spontaneous swallowing is useful for screening of dysphagia in acute stroke. Low levels of substance P (SP) in saliva attenuate the swallowing reflex. The aim of this study was to determine the relationship between the frequency of spontaneous swallowing and salivary SP levels. In 40 subjects, saliva was collected within 72 h after stroke onset and salivary SP levels were measured using ELISA kit at a later date. The frequency of spontaneous swallowing was measured over 1 h using a microphone placed on the neck. Pneumonia was diagnosed by the presence of pyrexia and at least two respiratory problems of four categories (sputum, cough or breathing pattern, breath sound, and gas change). The presence of detectable levels of SP in the saliva was confirmed in 17 patients (high SP group), whereas the level was below the detection limit of the ELISA kit in 23 patients (low SP group). The frequency of spontaneous swallowing was significantly lower in low SP group (16.1 ± 11.6 per hour) than in the high SP group (30.4 ± 20.4, p = 0.016). As the result of multiple regression analysis, salivary SP levels were correlated with frequency of spontaneous swallowing independently of age, NIHSS, and GCS. The incidence of pneumonia was significantly higher in the low than high SP group (p < 0.001). In conclusion, the frequency of spontaneous swallowing was decreased in acute stroke patients with low salivary SP levels. Salivary SP levels can be potentially a useful biomarker of risk of stroke-associated pneumonia in the acute stage.

Regioselective Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions.

The dienone-phenol rearrangement is a useful tool for the synthesis of highly substituted phenols. In our previous study of the rearrangement of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienone under deoxyfluorination conditions, bond migration proceeded with very poor regioselectivity. In this paper, an acid-mediated rearrangement of O-perfluoroalkylsulfonyl difluorides with regioselective migration toward the ß'-carbon is reported. This method allowed the synthesis of a fluorinated analog of allocolchicinoids with improved total yield. Successful application to other substrates was also demonstrated.

Benzylic C-H Trifluoromethylation via Photoenol.

Photoenols generated in situ from ortho-methyl-substituted phenylketones such as benzophenones and acetophenones were trifluoromethylated with Togni reagent without any additive or catalyst. This trifluoromethylation reaction proceeded smoothly under photoirradiation conditions (365 nm). Various functional groups were tolerant of the reaction conditions. Interestingly, the trifluoromethyl group was exclusively introduced at the ortho-benzylic position. Mechanistic studies suggested that this reaction proceeds via formation of a photoenol, not via a radical pathway.

[Transoral Penetrating Cranial Injury by a Chopstick:A Case Report].

Intracranial injury resultant from a chopstick penetrating the oral cavity is often fatal in children, and only 5 clinical cases have been reported. If the depth of penetration is indeterminable, due to the chopstick being removed or the remaining piece not being located, then injury management is challenging; here, we report such a case. A 26-month-old girl fell over with a plastic chopstick in her mouth. The chopstick was removed immediately and without breakage by her father. He noted that around 3 cm of the pointed end had pierced the palate. CT revealed air bubbles in the retropharyngeal space but no abnormality in the cranium. Subsequent complications included bacterial meningitis and right hemiparesis but neither MRI nor any alternative imaging modality could aid in locating the intracranial lesion that induced the weakness. Neurological findings suggested injury of the right lateral corticospinal tract at the lower end of the medulla oblongata. An axial T2-weighted MRI showed a 30-mm high signal path of penetration from the posterior nasopharyngeal wall to the dura at the craniocervical junction. When the route is extended 36 mm intracranially from the wound orifice, the path makes superficial contact with the right lateral portion of the medulla oblongata, which corresponds with the lateral corticospinal tract. We therefore hypothesize that this was the lesion location but that it was too small to be detected using MRI.

Cranioplasty Outcomes and Analysis of the Factors Influencing Surgical Site Infection: A Retrospective Review of More than 10 Years of Institutional Experience.

BACKGROUND: As a large amount of clinical evidence supports the use of craniectomy, the frequency of subsequent cranioplasty is increasing. Conflicting complication rates and risk factors of cranioplasty have been reported. We reviewed >10 years of institutional experience to identify risk factors of surgical site infection (SSI) after cranioplasty. METHODS: A retrospective review was conducted of patients who underwent primary cranioplasty. Patients <16 years old, patients with a history of cranial infection, and patients who underwent ventricular shunt surgery were excluded. There were 155 patients eligible for analysis. Complication rate and the risk factors associated with SSI were determined. RESULTS: The overall complication rate was 12.3%. There were 13 cases of SSI (8.4%), 4 cases of postoperative epidural hemorrhage (2.6%), and 2 cases of postoperative wound dehiscence (1.3%). There was a significant relationship between operative time and SSI (P < 0.001). The optimal cutoff value of operative time for predicting SSI was 98 minutes, and the relative risk ratio was 7.4 in patients with an operative time of >98 minutes. CONCLUSIONS: A high number of complications can occur after cranioplasty. Close attention should be paid to SSI development in patients who require a long operative time.

Difunctionalization of Alkenes Using 1-Chloro-1,2-benziodoxol-3-(1H)-one.

Difunctionalization of alkenes with 1-chloro-1,2-benziodoxol-3-(1H)-one (1) was investigated. Various additional nucleophiles were tested, and oxychlorination, dichlorination, azidochlorination, chlorothiocyanation, and iodoesterfication were demonstrated. The oxychlorination product was obtained efficiently when the reaction was operated in water. Dichlorination occurred in the presence of a Lewis basic promoter, such as 4-phenylpyridine N-oxide, as an additive. The reaction with in situ-generated azido anion afforded azidochlorinated compounds with a chlorine atom at the terminal position, while the reaction with trimethylsilyl isothiocyanate produced chlorothiocyanation adducts with a chlorine atom at the benzylic position. On the other hand, when 1 was treated with tetra-n-butylammonium iodide prior to the addition of alkenes, only iodoesterification occurred selectively. These mild reactions enable convenient site-selective difunctionalizations of substrates having two alkene moieties. NMR experiments suggested that the electrophilic reactive species in each reaction varied depending on the nature of the added nucleophile.

Benzylic C-H trifluoromethylation of phenol derivatives.

Phenol derivatives were trifluoromethylated using copper/Togni reagent. In dimethylformamide, the benzylic C-H bond at the para position of the hydroxyl group was selectively substituted with a CF3 group. In contrast, aromatic C-H trifluoromethylation occurred in alcoholic solvents. Practical utility of the reactions was demonstrated by application to the synthesis of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor.

Advanced dress-up chiral columns: New removable chiral stationary phases for enantioseparation of chiral carboxylic acids.

This paper describes the preparation of new dress-up columns featuring reproducibly removable and replaceable chiral stationary phases. After synthesizing perfluroalkylated quinine and quinidine derivatives as chiral stationary phase compounds (F-CSPs), we adsorbed them reversibly onto a fluorous LC column through pumping of their solutions. Using this dress-up chiral column and fluorophobic elution of aqueous ammonium formate/MeOH mixtures, we could enantioseparate four racemic N-acetyl amino acids, dichlorprop, and sixteen fluorescent 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-derivatized amino acids. Dressing and undressing of the coated F-CSPs could be controlled by varying the fluorophilicity and fluorophobicity of the eluent. The relative standard deviations of the retention times, the retention factors, the number of theoretical plates, the enantioseparation factors, and the resolutions of each of four preparations of such dress-up columns were all less than or equal to 5.26% (from 20 repeated analyses); the reproducibilities from four different preparations were all less than or equal to 10.6%. These columns also facilitated highly sensitive and selective analyses of AQC-amino acids when detected using LC-MS/MS.

Dual catalysis with copper and rhenium for trifluoromethylation of propargylic alcohols: efficient synthesis of α-trifluoromethylated enones.

Trifluoromethylation of propargylic alcohols to provide (Z)-α-trifluoromethylated enones and ß-unsubstituted α-trifluoromethylated enones proceeded with high yield and selectivity in the presence of CuI/Re2O7. The Z isomer was formed under kinetic control, though it is less stable than the E isomer in terms of steric repulsion.

Chronic subdural hematoma in elderly patient with EDTA-dependent pseudothrombocytopenia recently treated with aspirin and warfarin: case report.

A 78-year-old man who had a history of myocardial and cerebral infarction and who was treated with aspirin and warfarin, presented with left chronic subdural hematoma. Cerebral computed tomography showed severe brain compression of hematoma with midline shift, indicating the need for emergent surgery. The hematology and clotting tests upon admission revealed severe thrombocytopenia (platelet count, 1.3 × 10(4)/µL) with normal clotting activity. Because platelet aggregation was evident in the smear, we re-examined the patient for hematology using tubes that contained heparin, showing also low platelet count (2.3 × 10(4)/µL). The day on admission, we performed irrigation and drainage of the chronic subdural hematoma through single burr-hole craniostomy. During surgery, we used 10 units of platelet concentrates (PCs) for the reason that the patient was taking aspirin and coagulopathy derived from low platelet count could not be excluded. After surgery, we re-evaluated the hematology of the blood stored in tubes that contained ethylenediaminetetraacetic acid (EDTA) with or without kanamycin (KM). Treatment with KM dissociated EDTA-induced platelet aggregation and revealed platelet counts with highest accuracy (no KM treatment, 1.3 × 10(4)/µL; KM treatment, 15.2 × 10(4)/µL). This phenomenon is called EDTA-Dependent Pseudothrombocytopenia (PTCP) defined as falsely low platelet counts reported by automated hematology analyzers due to platelet aggretgation. Awareness of the phenomenon will enable neurosurgeons to manage patients with PTCP appropriately and clinical laboratory especially in emergency hospital is recommended to prepare for the hematological tubes being added KM in routine analysis, resulting in preventing mistaken diagnosis.

Contralateral hyperacute intracerebral hemorrhage after carotid artery stenting with contralateral internal carotid artery occlusion.

An 87-year-old man sustained an intracerebral hemorrhage in the watershed area of the contralateral frontal lobe immediately after carotid artery stenting (CAS) for severe cervical internal carotid artery (ICA) stenosis. The contralateral cervical ICA was occluded. CAS resulted in increased cross-flow through the anterior communicating artery and increased flow in the contralateral middle cerebral artery. This case demonstrates that CAS in patients with contralateral ICA occlusion and insufficient collateral flow can cause dramatically increased collateral flow through the circle of Willis and result in contralateral hyperperfusion. In patients with severely compromised cerebral perfusion, measures should be taken to prevent hyperperfusion-related complications.