Physiologically-based pharmacokinetic modeling for mirabegron: a multi-elimination pathway mediated by cytochrome P450 3A4, uridine 5'-diphosphate-glucuronosyltransferase 2B7, and butyrylcholinesterase

1. This was the first study to construct a physiologically-based pharmacokinetic (PBPK) model for mirabegron which incorporates the overall elimination pathways of metabolism by cytochrome P450 (CYP) 3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7, and butyrylcholinesterase (BChE) and renal excretion. The objective was to assess the risk of drug-drug interactions (DDIs) by estimating the contribution of each elimination pathway and simulating the magnitude of the DDIs with UGT2B7 inhibitors.

2. A PBPK model for mirabegron was constructed to reproduce the plasma concentration-time curves from a phase 1 study and the magnitude of the DDI with ketoconazole taking into account the overall elimination pathways. The PBPK model was subsequently verified using data from other DDI studies.

3. The constructed PBPK model estimated the contribution for each elimination pathway: 44% and 29% for CYP3A4 and UGT2B7 in the liver, 1.6% for UGT2B7 in the kidney, 3.2% for BChE in plasma, and 22% for renal excretion.

4. Co-administration of probenecid (an UGT2B7 inhibitor) or fluconazole (an UGT2B7 and CYP3A4 inhibitor) was predicted to increase area under the curve for mirabegron to 115% or 174%, respectively.

5. In conclusion, PBPK modeling and simulation revealed a low DDI risk for mirabegron following co-administration with BChE or UGT2B7 inhibitors.

     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

Evaluation of apremilast,an oral phosphodiesterase 4 inhibitor,for refractory cutaneous dermatomyositis: A phase 1b clinical trial

Dermatomyositis, an idiopathic inflammatory myopathy, is characterized by cutaneous itchy manifestations, which are frequently refractory and recurrent even after intensive immunosuppressive treatments. To evaluate the effectiveness and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in treating skin-dominant dermatomyositis in which myositis and interstitial lung disease are absent or in remission, we performed this prospective, single-arm, interventional study. A total of five Japanese patients (one male and four females, median [range] age, 64 [37–71] years) with refractory dermatomyositis-associated cutaneous manifestations were recruited and treated with a 12-week course of oral apremilast. Among five enrolled patients, three experienced diarrhea with full-dose apremilast (30 mg twice daily), two of whom withdrew from the study and recovered quickly afterwards. A total of three evaluable female patients (median [range] age, 65 [64–71] years) received apremilast treatment for 12 weeks. A 39.4% reduction from baseline Cutaneous Dermatomyositis Disease Area and Severity Index total activity score, but not the damage score, at week 12 was observed in all three patients. Visual analog scale of itching, and quality of life by Dermatology Life Quality Index were slightly improved in one and two apremilast-treated patients, respectively. As apremilast was effective, with expected and recoverable digestive adverse events (diarrhea), in patients with refractory and recurrent dermatomyositis-associated cutaneous manifestations in this first phase Ib study, it can be suggested as a possible treatment when aggressive immunosuppressive therapies with high-dose systemic corticosteroid and/or immunosuppressive agents for other manifestations, myositis, and interstitial lung disease, are not required.     

A rare case of pulmonary typical carcinoid with prominent acinic cell differentiation,resembling acinic cell carcinoma

We herein describe a rare case of low‐grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha‐1‐antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen‐type granules (600–800 nm in diameter) in the acinic cell component, whereas neuroendocrine‐type granules (200–300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen‐type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.     

Screening and management for ischemic heart disease in patients undergoing emergency surgery for a type A acute aortic dissection

Purpose

We assessed the incidence of coronary artery disease (CAD) during hospitalization after emergency surgery for a type A acute aortic dissection.

Methods

A total of 123 patients underwent multi-slice computed tomography (MSCT) scans during an early stage after surgery. The patients were divided into two groups: group I consisted of 14 patients (11.4 %) who had coronary artery stenosis of more than 75 % on MSCT, and group II consisted of 109 patients (88.6 %) who had no coronary lesions.

Results

The prevalence of diabetes, dyslipidemia and a smoking history was significantly higher in group I. Although the serum low-density lipoprotein cholesterol levels were similar, the high-density lipoprotein cholesterol (HDL) level was significantly lower in group I (36.4 ± 7.9 mg/dl) than in group II (49.6 ± 13.5 mg/dl, P = 0.0005). The maximum carotid intima-media thickness (IMT) was significantly thicker in group I (1.17 ± 0.37 mm) compared to group II (0.96 ± 0.33 mm, P = 0.0297). The logistic regression analysis detected that a carotid IMT over 1.1 mm (odds ratio 4.35, P = 0.0371) and HDL less than 40 mg/dl (odds ratio 3.90, P = 0.0482) were predictors for CAD.

Conclusions

CAD screening should be recommended for patients with aortic dissection who have several atherosclerosis risk factors, even after emergency surgery.     

Ependymosarcoma with eosinophilic granular cells

Ependymosarcoma is a new entity of malignant gliomas composed of ependymal and sarcomatous components. We report a rare case of ependymosarcoma with eosinophlic cells which occurred to the right trigon of the lateral ventricle. A 62‐year‐old man complained of headaches over a 2‐month period. A hard, gray mass was found in the right trigon of the lateral ventricle during the operation. Although he received radiation and chemotherapy, the patient died due to tumor disseminating through the whole brain within 7 months after the operation. The histological examination revealed that the anaplastic glial components intermingled with the sarcomatous components. Immunohistochemically, sarcomatous cells were positive for α smooth muscle actin and desmin. However, anaplastic glial cells were not positive for these markers. In addition, Masson trichrome stain showed a plethora of collagen fibers between sarcomatous cells, but no collagen fibers were produced by the glial tumor cells. Solid focal papillary lesions of the glial tumor showed dot‐like epithelial membrane antigen and diffuse cytoplasmic D2‐40 immunoreactivity. Based on the above findings, these anaplastic glial tumor cells should show focal ependymal differentiation, and sarcomatous cells show myofibroblastic differentiation. In addition, almost 10% of the tumor cells in the neoplasm showed bright eosinophilic granules in the cytoplasm. These cytoplasmic eosinophilic granules and bundles were negative on PAS staining. Intracytoplasmic eosinophilic granules of tumor cells were strongly positive for αB‐crystallin, HSP 27 and GFAP, respectively. These findings suggest that the clinicopathological characteristics of the present case should be consistent with the criterion of ependymosarcoma by Rodriguez et al.     

Detectability of Neural Tracts and Nuclei in the Brainstem Utilizing 3DAC‐PROPELLER

Despite clinical importance of identifying exact anatomical location of neural tracts and nuclei in the brainstem, no neuroimaging studies have validated the detectability of these structures. The aim of this study was to assess the detectability of the structures using three‐dimensional anisotropy contrast‐periodically rotated overlapping parallel lines with enhanced reconstruction (3DAC‐PROPELLER) imaging. Forty healthy volunteers (21 males, 19 females; 19‐53 years, average 23.4 years) participated in this study. 3DAC‐PROPELLER axial images were obtained with a 3T‐MR system at four levels of the brainstem: the lower midbrain, upper and lower pons, and medulla oblongata. Three experts independently judged whether five tracts (corticospinal tract, medial lemniscus, medial longitudinal fasciculus, central tegmental and spinothalamic tracts) and 10 nuclei (oculomotor and trochlear nuclei, spinal trigeminal, abducens, facial, vestibular, hypoglossal, prepositus, and solitary nuclei, locus ceruleus, superior and inferior olives) on each side could be identified. In total, 240 assessments were made. The five tracts and eight nuclei were identified in all the corresponding assessments, whereas the locus ceruleus and superior olive could not be identified in 3 (1.3%) and 16 (6.7%) assessments, respectively. 3DAC‐PROPELLER seems extremely valuable imaging method for mapping out surgical strategies for brainstem lesions.     

The anti-inflammatory effect of erythromycin in zymosan-induced peritonitis of mice.

The anti-inflammatory effect of erythromycin was investigated using zymosan-induced peritonitis in mice. When mice were given erythromycin 10 mg/kg/day po for 28 days, a marked suppression of inflammatory responses, including the reduced influx of leucocytes, plasma exudation and prostaglandin E2 synthesis, was observed. However, neither a 7-day treatment with erythromycin nor a 28-day treatment with clindamycin suppressed the response. The anti-inflammatory activity induced after a 28-day treatment with erythromycin was comparable to the anti-inflammatory effect conferred by a 2-day treatment with dexamethasone 40 microgram/mouse/day. Thus, these data confirm previous studies which show that erythromycin can exert an anti-inflammatory effect when used over long periods of time.