Effects of CYP3A4 inhibition/induction and OATP inhibition on the pharmacokinetics of atogepant in healthy adults.

Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: Cmax and AUC of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer.

Calcitonin gene-related peptide (CGRP) is involved in migraines, a neurological disorder with severe headache and sensory disturbances. A medication called atogepant is a CGRP receptor antagonist that can block the effect of CGRP and is approved by the FDA for the preventive treatment of migraines. If you take a drug, such as itraconazole, a strong inhibitor of an enzyme called CYP3A4, that metabolizes atogepant, at the same time as atogepant, it can increase the amount of atogepant in your body. OATPs are membrane transport proteins that facilitate liver uptake of atogepant. If you take a drug that is an OATP inhibitor with atogepant, it can increase the amount of atogepant in your body. However, if you take a CYP3A4 inducer such as rifampin, which increases the activity of CYP3A4, it can decrease the amount of atogepant in your body. Your doctor may adjust the dose of atogepant accordingly.

Transfer of the Dorsal Cutaneous Branch of the Ulnar Nerve for Restoration of Median Nerve Sensation: A Cadaveric Study.

The use of dorsal cutaneous branch of the ulnar nerve (DCBUN) transfer for median nerve (MN) sensory restoration has not been evaluated anatomically and histologically in humans. The purpose of this study was to evaluate the feasibility of DCBUN to MN transfer for sensory restoration with respect to nerve branch pattern, length, and fascicle count match.Using seven fresh frozen cadaveric upper limb specimens, the DCBUN and its branch patterns, lengths, and sizes were recorded. The MN was exposed within the carpal tunnel and dissected distally to identify the common digital nerves (CDN). Simulated nerve transfer was performed with palmar coaptation of the DCBUN branches with the CDNs. Histological analysis of each nerve branch was performed. The seven specimens had a mean of 3.57 branches (range 2-4) off the DCBUN. The longest branch innervated the dorsal 4th web space, on average reaching 7.6 cm distal to the wrist crease. Transferring the DCBUN branches palmarly did not substantially change their maximum distance distal to the wrist crease. The MN CDNs and DCBUN branches had mean cross-sectional areas of 6.37 and 1.99 mm2 , respectively, and mean fascicle counts of 10.4 and 4.05, respectively. The DCBUN provides 2-4 branches suitable for tension-free end-to-end transfer to the MN CDNs. The individual size of the DCBUN branch is smaller than CDN; however, combining two or more branches of the DCBUN would overcome the fascicle and size mismatch to reconstruct the 1st web space CDN for critical sensory restoration. Clin. Anat. 31:1006-1012, 2018. © 2018 Wiley Periodicals, Inc.

Marginal Skin Flap Advancement: A Technique to Optimize the Skin Graft Interface Following Tumor Resections.

Split-thickness skin graft (STSG) for soft tissue defects is often required following tumor resections. There is often a step-off with subcutaneous adipose tissue along the defect margins. This review of 20 years of experience was performed to determine the success of marginal skin flap advancement, a simple surgical technique addressing this issue. Seventy-one cases were identified that underwent sarcoma resection and this technique. Marginal skin flap advancement decreased the defect size from 217 s 162 cm2 to 128 s 101 cm2 (p < .001). STSG was successfully applied in 69 cases (97%) with a mean 96% take of the skin graft. Although 29 cases (41%) had wound healing complications of any nature, only 11 (15%) required a secondary operation. Marginal skin flap advancement, in conjunction with vacuum-assisted closure therapy, decreases the defect surface area requiring STSG by 41% and provides an excellent reconstructive option for soft tissue defects following sarcoma resections. (Journal of Surgical Orthopaedic Advances 27(2):102-108, 2018).

Immunohistochemistry and alternative FISH testing in breast cancer with HER2 equivocal amplification.

PURPOSE: While HER2 testing is well established in directing appropriate treatment for breast cancer, a small percentage of cases show equivocal results by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Alternative probes may be used in equivocal cases. We present a single community-based institution's experience in further evaluating these cases. PATIENTS AND METHODS: Between 2014 and 2016, 4255 samples were submitted for HER2 amplification testing by alternative probes, TP53, RAI1, and RARA. Of the patients tested by FISH, 505/3908 (12.9%) also had IHC data. RESULTS: Most (73.9%) FISH equivocal cases remained equivocal after IHC testing. However, 50.5% of equivocal cases were classified as HER2 amplified by alternative probes. Most cases were positive by more than one probe: 78% of positive cases by RAI1 and 73.9% by TP53. There was a significant difference between IHC and FISH alternative testing (p < 0.0001) among the equivocal cases by conventional FISH testing, 44% of IHC negative cases became positive while 36% of the positive IHC cases became negative by alternative FISH testing. Available data showed that 41% of patients were treated with palbociclib and were positive by alternative FISH. CONCLUSION: The prevalence of double HER2 equivocal cases and the discrepancy between IHC and alternative FISH testing suggest that FISH alternative testing using both RAI1 and TP53 probes is necessary for conclusive classification. Because almost half of FISH equivocal cases converted to HER2 amplified upon alternative testing, clinical studies to determine the benefit of anti-HER2 therapy in these patients are urgently needed.

Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer.

BACKGROUND: The role of MET amplification in lung cancer, particularly in relation to checkpoint inhibition and EGFR WT, has not been fully explored. In this study, we correlated PD-L1 expression with MET amplification and EGFR, KRAS, or TP53 mutation in primary lung cancer. METHODS: In this retrospective study, tissue collected from 471 various tumors, including 397 lung cancers, was tested for MET amplification by FISH with a MET/centromere probe. PD-L1 expression was evaluated using clone SP142 and standard immunohistochemistry, and TP53, KRAS, and EGFR mutations were tested using next generation sequencing. RESULTS: Our results revealed that PD-L1 expression in non-small cell lung cancer is inversely correlated with EGFR mutation (P=0.0003), and positively correlated with TP53 mutation (P=0.0001) and MET amplification (P=0.004). Patients with TP53 mutations had significantly higher MET amplification (P=0.007), and were more likely (P=0.0002) to be EGFR wild type. There was no correlation between KRAS mutation and overall PD-L1 expression, but significant positive correlation between PD-L1 expression and KRAS with TP53 co-mutation (P=0.0002). A cut-off for the ratio of MET: centromere signal was determined as 1.5%, and 4% of lung cancer patients were identified as MET amplified. CONCLUSIONS: This data suggests that in lung cancer both MET and TP53 play direct roles in regulating PD-L1 opposing EGFR. Moreover, KRAS and TP53 co-mutation may cooperate to drive PD-L1 expression in lung cancer. Adding MET or TP53 inhibitors to checkpoint inhibitors may be an attractive combination therapy in patients with lung cancer and MET amplification.

Disseminated Cryptococcal Osteomyelitis to the Hand in an Immunosuppressed Lymphoma Patient.

Fungal osteomyelitis of the hand is rare with limited evidence-based literature to guide diagnosis and management. We report a case of disseminated cryptococcal osteomyelitis in the middle phalanx from a pulmonary fungal infection in a patient with a history of lymphoplasmacytic lymphoma. Although rare, cryptococcosis should be considered in the differential diagnosis of aggressive lytic lesions with bone pain and associated large soft tissue masses, especially in the immunosuppressed host.

Anatomical Factors Contributing to Radial Nerve Excursion at the Brachium: A Cadaveric Study.

PURPOSE: The radial nerve appears to be more vulnerable to injury in the brachium than the median and ulnar nerves. The underlying mechanism for this increased vulnerability is not well explained. We hypothesize that the radial nerve has less excursion than the median and ulnar nerves because it is anatomically tethered by the lateral intermuscular septum (LIS) and that elbow positioning and LIS release will improve its excursion. METHODS: Eight paired fresh-frozen cadaveric upper extremity specimens were used. The radial, median, and ulnar nerves were transected at the level of the spiral groove. Nerve excursion was determined at a constant tension of 100 g from 0° to 90° of elbow flexion and repeated for the radial nerve after releasing the LIS. The cross-sectional areas of nervous and connective tissue were then determined histologically. RESULTS: Radial and median nerve excursion correlated positively with increased elbow flexion, and ulnar nerve excursion correlated negatively with increased elbow flexion. Release of the LIS significantly improved radial nerve excursion at 0°, 60°, and 90° of elbow flexion. Release of the LIS with 90° of elbow flexion increased radial nerve excursion by approximately 3 times. Histological analysis demonstrated similar mean composition of nonnervous connective tissue among the 3 nerves. CONCLUSIONS: The radial nerve is anatomically tethered in the brachium by the LIS and has limited excursion compared with the median and ulnar nerves. Radial nerve excursion improves with elbow flexion and LIS release. Flexing the elbow to 90° doubles radial nerve excursion. Releasing the LIS as well triples the excursion of the radial nerve. Histological composition was similar among the three nerves at the brachium. CLINICAL RELEVANCE: Releasing the LIS and flexing the elbow improve radial nerve excursion. These steps may be useful during humeral fracture fixation.

Age-Dependent Schwann Cell Phenotype Regulation Following Peripheral Nerve Injury.

BACKGROUND: Schwann cells are integral to the regenerative capacity of the peripheral nervous system, which declines after adolescence. The mechanisms underlying this decline are poorly understood. This study sought to compare the protein expression of Notch, c-Jun, and Krox-20 after nerve crush injury in adolescent and young adult rats. We hypothesized that these Schwann cell myelinating regulatory factors are down-regulated after nerve injury in an age-dependent fashion. METHODS: Adolescent (2 months old) and young adult (12 months old) rats (n = 48) underwent sciatic nerve crush injury. Protein expression of Notch, c-Jun, and Krox-20 was quantified by Western blot analysis at 1, 3, and 7 days post-injury. Functional recovery was assessed in a separate group of animals (n = 8) by gait analysis (sciatic functional index) and electromyography (compound motor action potential) over an 8-week post-injury period. RESULTS: Young adult rats demonstrated a trend of delayed onset of the dedifferentiating regulatory factors, Notch and c-Jun, corresponding to the delayed functional recovery observed in young adult rats compared to adolescent rats. Compound motor action potential area was significantly greater in adolescent rats relative to young adult rats, while amplitude and velocity trended toward statistical significance. CONCLUSIONS: The process of Schwann cell dedifferentiation following peripheral nerve injury shows different trends with age. These trends of delayed onset of key regulatory factors responsible for Schwann cell myelination may be one of many possible factors mediating the significant differences in functional recovery between adolescent and young adult rats following peripheral nerve injury.

Chemical Characterization of Mainstream Smoke from SPECTRUM Variable Nicotine Research Cigarettes.

OBJECTIVE: Our objective was to characterize mainstream smoke constituent deliveries from SPECTRUM variable nicotine research cigarettes under 2 machine smoking regimens. SPECTRUM cigarettes are manufactured by the 22nd Century company for the National Institute on Drug Abuse, National Institutes of Health to contain varying (including reduced) levels of nicotine. METHODS: Mainstream smoke constituent deliveries of "tar," nicotine, carbon monoxide, tobacco-specific nitrosamines (N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)), benzo[a]pyrene, aromatic amines, and carbonyls were analyzed in 23 varieties of SPECTRUM cigarettes using ISO 17025 accredited methods. RESULTS: Data are presented as means and standard deviations of 5 replicates for all analytes. CONCLUSIONS: Under the ISO smoking regimen, mean levels of many smoke emissions for SPECTRUM varieties were comparable to the 3R4F research cigarette. Calculated SPECTRUM elasticity ranged from 1.6 to 4.0. Accordingly, under intense machine smoking conditions differences in emissions of SPECTRUM cigarettes were apparent. In addition, NNN increased with smoke nicotine while the same rate of change was not seen for NNK. It is important to monitor levels of chemicals of public health concern and regulatory interest as technologies emerge to reduce levels of nicotine or other targeted chemicals in tobacco products.

Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis-with comparison to Hodgkin-like lesion.

Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein-Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P=.01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases.

C-H-Activated Direct Arylation of Strong Benzothiadiazole and Quinoxaline-Based Electron Acceptors.

Electron acceptors are important components of π-conjugated materials, but the strong electron-withdrawing properties of the required synthetic intermediates often make them poor substrates in synthetic schemes designed around conventional organometallic cross-coupling. Here, strong benzodiimine-based acceptors, including 5,6-difluoro[2,1,3]benzothiadiazole, 5,6-dicyano[2,1,3]benzothiadiazole, 5,6-dicyanobenzo[d][1,2,3]triazole, 6,7-dicyanoquinoxaline, and 6,7-dinitroquinoxaline, are shown to undergo facile palladium-catalyzed C-H direct arylation with a variety of bromoarenes in moderate to high yields. The electrochemical characteristics of di-2-thienyl derivatives synthesized using this methodology are compared and suggest that, in an electron-transfer sense, 5,6-dicyano[2,1,3]benzothiadiazole is a comparably strong acceptor to benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole. The synthetic results suggest that high electron-withdrawing ability, which has traditionally limited reaction yields and structural variety in organic electronic materials, may be advantageous when employing C-H activated direct arylation in certain circumstances.

Surgical Algorithm and Results of Isolated Traumatic Axillary Nerve Injuries.

BACKGROUND: Axillary nerve injuries are common and typically occur during high-energy, traumatic events. The purpose of this study is to propose a treatment algorithm for acute isolated axillary nerve injuries and report the outcomes of surgically treated patients. METHODS: A retrospective review identified 14 patients surgically treated for an isolated axillary nerve injury. Axillary nerve neurolysis was performed for all patients, and a triceps branch of the radial nerve was transferred to the axillary nerve in patients without evidence of deltoid function following intraoperative axillary nerve stimulation. Four patients were treated with neurolysis alone and 10 patients received a transfer. Pre- and postoperative deltoid strength, shoulder abduction, and the Disabilities of the Arm, Shoulder, and Hand (DASH) outcome score were evaluated. RESULTS: At most recent follow-up, both the neurolysis and nerve transfer groups had significant improvement in deltoid strength, with 86% achieving M4 or greater. Shoulder abduction improved from a mean of 63 to 127 degrees. This difference was significant in the nerve transfer group and when all patients were analyzed together. DASH scores significantly improved from a mean of 47 to 34 when all patients were analyzed together. No patients experienced a decrease in elbow extension strength following nerve transfer. CONCLUSIONS: In patients with preserved triceps strength, a triceps branch of the radial nerve can be coapted directly to the axillary nerve in the absence of deltoid contraction following electrical stimulation. Functional improvements were seen in patients treated with neurolysis alone and in combination with nerve transfer, supporting the use of intraoperative axillary nerve stimulation to guide treatment.

Needle Curette Technique for Hand Surgery.

Curettage of lesions in the hand often requires fine instruments of varying angles for a thorough debridement. This can be seen with debridement of enchondromas of the phalanges when minimizing the size of the cortical window is desired. In this technical note, the authors describe the modification of an 18-G needle so that it may be used as a small curette when standard small curettes are not available or optimal.

Effect of setting of initial surgical drainage on outcome of finger infections.

This study sought to determine the optimal treatment setting (emergency department vs. operating room) for the initial incision and drainage of acute suppurative finger infections. A search of hospital medical records over a 5-year period identified 152 cases. In 108 cases (71%), a single drainage successfully resolved infection; 44 cases (29%) required multiple drainage procedures. Treatment setting did not decrease the risk for multiple procedures. Seventy-six cases (57%) of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) were identified. Bivariate analysis identified CA-MRSA infection as a significant, independent risk factor for multiple procedures. Obtaining initial cultures correlated with a decreased need for multiple procedures. In conclusion, initial surgical drainage in the emergency department is a safe alternative to the operating room. However, patients with CA-MRSA infection have an increased risk for persistent infection requiring multiple procedures. Prompt organism identification and appropriate antibiotics following surgical drainage remain most crucial for the successful treatment of finger infections.

Controllable direct arylation: fast route to symmetrical and unsymmetrical 4,7-diaryl-5,6-difluoro-2,1,3-benzothiadiazole derivatives for organic optoelectronic materials.

Arylation in the 4- and 7-positions of 2,1,3-benzothiadiazole (BT) and its monofluoro- (MFBT) and difluoro- (DFBT) derivatives by (hetero)aryl bromides using Pd-catalyzed C­H activation has been investigated. MFBT and DFBT can be diarylated in moderate to high yields (up to 96% for DFBT) by a variety of aryl bromides. DFBT can be sequentially arylated using two different aryl bromides to give differentially substituted DFBT derivatives. The moderate to high yields of doubly arylated MFBT and DFBT and the ability to obtain differentially substituted products can be applied to a variety of organic photonic and electronic materials.

Arthroscopic treatment of an osteochondral lesion in a child with chronic wrist pain: case report.

Osteochondral lesions of the wrist are rare in the pediatric and adolescent population. We report a case of an osteochondral lesion of the lunate facet of the radiocarpal joint in a 6-year-old girl with chronic wrist pain after falling on her hand. Arthroscopic debridement of the osteochondral fragment relieved the symptoms and improved wrist function. Osteochondral lesions should be considered in the differential diagnosis of chronic wrist pain in children with a history of trauma.

An ulnar intraneural ganglion arising from the pisotriquetral joint: case report.

Intraneural ganglions of the hand are rare and remain poorly understood. We report a case of an intraneural ganglion arising from the pisotriquetral joint that penetrated the ulnar nerve at Guyon's canal. Although rare, these ganglions should be considered in the differential diagnosis of any neoplasms causing compression neuropathy.

Automatic classification of lymphoma images with transform-based global features.

We propose a report on automatic classification of three common types of malignant lymphoma: chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma. The goal was to find patterns indicative of lymphoma malignancies and allowing classifying these malignancies by type. We used a computer vision approach for quantitative characterization of image content. A unique two-stage approach was employed in this study. At the outer level, raw pixels were transformed with a set of transforms into spectral planes. Simple (Fourier, Chebyshev, and wavelets) and compound transforms (Chebyshev of Fourier and wavelets of Fourier) were computed. Raw pixels and spectral planes were then routed to the second stage (the inner level). At the inner level, the set of multipurpose global features was computed on each spectral plane by the same feature bank. All computed features were fused into a single feature vector. The specimens were stained with hematoxylin (H) and eosin (E) stains. Several color spaces were used: RGB, gray, CIE-L*a*b*, and also the specific stain-attributed H&E space, and experiments on image classification were carried out for these sets. The best signal (98%-99% on earlier unseen images) was found for the HE, H, and E channels of the H&E data set.