Magnetic resonance imaging of the brainstem: normal structure and basic functional anatomy

Normal structure and basic functional anatomy of the brainstem were studied using anatomic sections obtained with a cryomicrotome whole-organ sectioning technique. Major tracts and nuclei were identified and their function summarized. Magnetic resonance imaging of the brainstem was performed on 10 normal volunteers. By comparing these images with the corresponding anatomic sections, normal structures, including major tracts and nuclei, were identified. Knowledge of location and function of clinically important brainstem nuclei and tracts is necessary for optimal magnetic resonance image interpretation.     

Why not the eighth nerve? Neurovascular compression--probable cause for pulsatile tinnitus

Carotid arteriograms on three patients with unilateral pulsatile tinnitus demonstrated an ipsilateral atypical trigeminal artery extending from the cavernous portion of the internal carotid artery to form the posterior inferior cerebellar artery. Illustrations and a dissection of a human fetus with a similar finding show this artery crossing the cochlear nerve near its insertion in the pons. Evidence is presented suggesting that neurovascular compression of the eighth nerve is the source of pulsatile tinnitus in these patients.     

The significance of positive margins in hemilaryngectomy specimens.

This clinicopathologic study was undertaken to determine the meaning of surgical margins “involved” with carcinoma. The fate of hemilaryngectomy patients whose specimens had this finding was compared with that of patients who had “uninvolved” margins. A consecutive series of 111 hemilaryngectomies performed for previously untreated invasive epidermoid carcinoma was analyzed. Serial step sections in a longitudinal plane were available for re-examination and re-evaluation of the surgical margins in each case. Clinical follow-up on every patient was current through 1972. Thirty-nine patients had cancer involvement of a margin in the hemilaryngectomy specimen. None of these patients received any immediate therapy but were followed only. Seven of these patients (18 percent) subsequently developed a biopsy proven local recurrence. Four of the 72 patients (6 percent) with uninvolved margins developed a local recurrence. The site of the positive margin in the specimen was compared with the clinical site of recurrence. The seven local recurrences in patients with positive margins were treated with full course irradiation or total laryngectomy. All of these patients are alive and free of cancer or have died of other causes without evidence of cancer. Of the four local recurrences in patients with negative margins one died of cancer; two are living and well, and one died of other causes. This study provides evidence to support the conservative management of those hemilaryngectomy patients who have involved margins in the resection specimen. No immediate treatment is required. Careful follow-up is indicated with 18 percent chance of clinical recurrence. These biopsy proven recurrences can then be successfully treated with total laryngectomy or full course irradiation. Utilizing this approach none of the 39 patients with involved margins died of cancer in the 5 to 12-year follow-up period.     

Reconstruction of hearing when malleus is absent: Torp vs. Homograft tmmi

To study the most appropriate ossicular reconstruction of patients with an absent malleus, a comparison was made utilizing a homograft tympanic membrane with attached malleus and shaped incus (TMMI) columella and the alternative use of underlay fascia tympanoplasty with a cartilage covered TORP. Forty-six patients were reconstructed with a homograft TMMI and 38 with cartilage covered TORP and underlay fascia technique; 4.5 years postoperatively, 84% of those patients reconstructed with a homograft TMMI maintained an average A/B gap of 25 dB or better. Though 1 year postoperatively the TORP hearing results were satisfactory, only 18% of the TORP patients maintained a hearing level within 25 dB A/B gap at 4 years postoperatively. Primary causes of failure of the TORP were instability with migration off the stapes footplate, protrusion or extrusion through the TM and finally, long-term softening and bending secondary to biodegradation of the Plastipore®. The discouraging long-term hearing results found in the TORP patients in this study confirm similar findings reported in 1982 by Smyth in a 5 year follow-up on. 116 TORP patients.     

Guidelines for reporting experiments involving animals: the ARRIVE guidelines

British Journal of Pharmacology (BJP) is pleased to publish a new set of guidelines for reporting research involving animals, simultaneously with several other journals; the ‘ARRIVE’ guidelines (Animals in Research: Reporting In Vivo Experiments). This editorial summarizes the background to the guidelines, gives our view of their significance, considers aspects of specific relevance to pharmacology, re-states BJP''s guidelines for authors on animal experiments and indicates our commitment to carrying on discussion of this important topic. We also invite feedback via the British Pharmacological Society website.     

Role of the signal peptide in the synthesis and processing of the glucagon-like peptide-1 receptor

Background and purpose:

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B of the G protein-coupled receptor superfamily and is a target for treatment of type 2 diabetes. Family B G protein-coupled receptors contain a putative N-terminal signal peptide, but its role in receptor synthesis and trafficking are unclear. Further, the signal peptide is not cleaved in at least one family member.

Experimental approach:

We examined receptor glycosylation and the role of the signal peptide in GLP-1R synthesis and trafficking using constructs containing epitope tags at the N- and/or C-terminus and in which the signal peptide sequence was either present or absent.

Key results:

The signal peptide was absolutely required for GLP-1R synthesis but could be substituted to some extent by increasing positive charge in the N-terminal region of the receptor flanking the signal peptide. The signal peptide is cleaved during synthesis and processing of the receptor. An enhanced GFP-epitope tag at the N-terminus of the receptor permitted synthesis of the receptor but blocked signal peptide cleavage and prevented trafficking to the plasma membrane. Cleavage site mutation allowed synthesis of a full-length receptor, blocked signal peptide cleavage and caused retention within the endoplasmic reticulum.

Conclusions and implications:

Signal peptide cleavage was not essential for receptor synthesis but was obligatory for processing and trafficking of receptors to the plasma membrane. Further, the GLP-1R is subject to N-linked glycosylation and only the mature, fully glycosylated form of the receptor is present in the plasma membrane. Inhibition of glycosylation prevents processing and cell surface expression of the GLP-1R.     

Effects of fatigue and surface instability on neuromuscular performance during jumping

It has previously been shown that fatigue and unstable surfaces affect jump performance. However, the combination thereof is unresolved. Thus, the purpose of this study was to examine the effects of fatigue and surface instability on jump performance and leg muscle activity. Twenty elite volleyball players (18 ± 2 years) performed repetitive vertical double‐leg box jumps until failure. Before and after a fatigue protocol, jump performance (i.e., jump height) and electromyographic activity of selected lower limb muscles were recorded during drop jumps (DJs) and countermovement jumps (CMJs) on a force plate on stable and unstable surfaces (i.e., balance pad on top of force plate). Jump performance (3–7%; P < 0.05; 1.14 ≤ d ≤ 2.82), and muscle activity (2–27%; P < 0.05; 0.59 ≤ d ≤ 3.13) were lower following fatigue during DJs and CMJs, and on unstable compared with stable surfaces during DJs only (jump performance: 8%; P < 0.01; d = 1.90; muscle activity: 9–25%; P < 0.05; 1.08 ≤ d ≤ 2.54). No statistically significant interactions of fatigue by surface condition were observed. Our findings revealed that fatigue impairs neuromuscular performance during DJs and CMJs in elite volleyball players, whereas surface instability affects neuromuscular DJ performance only. Absent fatigue × surface interactions indicate that fatigue‐induced changes in jump performance are similar on stable and unstable surfaces in jump‐trained athletes.     

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03201458","term_id":"NCT03201458"}}NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI’s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.     

A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors

Purpose

A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.

Patients and methods

Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6–2 mg/m²) on days 2 and 9 and IV paclitaxel at 100 mg/m² on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.

Results

Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0–9), received 318 doses (median 5, range 1–34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70–80% at the MTD of 1.8 mg/m² of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.

Conclusion

Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m².