Evaluation of PACE4 isoforms as biomarkers in thyroid cancer

Abstract Background To date, no single molecular marker has been demonstrated as clinically useful in differentiating malignant from benign thyroid nodules when a fine needle aspiration falls in the “unknown significance” categories of the Bethesda Classification. PACE4, a member of the proprotein convertase family of enzymes, has been shown to play a major role in the pathogenesis of prostate cancer, through the formation of an oncogenic isoform named PACE4-altCT. PACE4 isoforms have also been suggested to play a role in other cancers, including thyroid cancer, but have never been investigated in a detailed manner. Our objective is to compare the histochemical distribution of the two major PACE4 isoforms in benign and malignant thyroid nodules, in order to determine their potential usefulness as discriminatory biomarkers. Methods Thyroid tissues of patients who underwent thyroidectomy were classified according to final pathology. Corresponding tissue sections were immunostained, using two previously validated antibodies raised against the C-terminal end of the two PACE4 isoforms, namely the full-length PACE4 protein (PACE4-FL) and its alternative isoform (PACE4-altCT). Nodules were compared with adjacent normal parenchyma and immunostaining was rated as “low” or “high” by a head and neck pathologist. Results Non-lesional thyroid parenchyma did not express PACE4-FL (p = 0.002). As a group, malignant (n = 17) nodules expressed PACE4-FL significantly more than benign (n = 24) nodules (percentage of high immunostaining: 52.9% vs 4.2%; p = 0.001). Reciprocally, there was a statistically lower expression of PACE4-altCT in malignant nodules than in adjacent non-lesional parenchyma (p = 0.014). The specificity of a high PACE4-FL immunostaining in determining malignancy was 95.8% (95% CI, 78.9% to 99.9%). Conclusion This study supports the previously described relationship between PACE4-FL and PACE4-altCT through alternative splicing. It also suggests that PACE4-FL is a promising biomarker for thyroid malignancy. Its high specific expression for malignancy could make it an interesting “rule in” test for thyroid cancer. Further prospective, quantitative studies are currently being designed to address how measurements of PACE4 isoforms could be used in a clinical setting. Trial registration This study does not report the results of a health care intervention on human participants. It was nonetheless registered on ClinicalTrials.gov under reference number NCT03160482

Capsular plication in the non-deformity hip: impact on post-operative joint stability

Abstract Purpose and hypothesis The aim of this study was to evaluate the hip joint range of motion after different capsular plication. The study hypothesis proposed that capsular plication after hip arthroscopy may reduce hip external rotation and thus prevent the hip joint instability created by arthroscopic capsulotomies. Methods Six fresh frozen human cadavers were studied in the intact state (5 males, 1 females) for a total of 12 non-deformity hips tested. They were fixed to the operating room table using a custom-made apparatus. Three Steinman pins were inserted, the first into ASIS, a parallel pin into the distal femur proximal to inter-epicondylar axis and the third pin into the lateral epicondyle. Simulation of arthroscopic capsulotomies was done progressively with simulation of three capsular plication techniques. The first plication technique consisted of a primary plication shift of the antero-lateral capsule. The distal-medial arm of the iliofemoral ligament was shifted toward the proximal-lateral arm. The second plication technique consisted in adding a longitudinal arm to the capsulotomy, between the lateral arm and the medial arm of the iliofemoral ligament, to create a T-shaped capsulotomy. The resulting two triangular capsular flaps were overlaid onto each other by approximately 5 mm, plicated fully and tighly sutured in a double-breast manner. The third plication technique, called redrapping, consisted in excising the inferior capsular triangular flap (previously made in the second technique), and suturing the latero-anterior superior capsular flap to the medial arm of the iliofemoral ligament, superimposing the capsular edges for closure. External rotation of the hip at 0°, 15° and 30° of flexion were obtained after the capsulotomy and each capsular plication technique to quantify the increase in hip stability after plication. Data were assessed using a two-way repeated measure analysis of variance (ANOVAs) and Student’s T-test when necessary to determine if the change in external rotation was significantly different. Results After capsulotomy, external rotation averaged 26.3°, 29.1° and 31.1° at 0°, 15° and 30° of flexion. With the primary plication shift, external rotation averaged 24.9°, 30.3° and 34.0°. With the two-triangle technique, external rotation averaged 26.1°, 31.9° and 33.3°. With the re-draping technique, external rotation averaged 25.8°, 30.9° and 32.0°. A significant relationship was found between «Plication Technique» and «Angle of flexion» factors for the measured angle of external rotation (P = 0.04). A decomposition of the interaction showed that external rotation decreased at 0° of hip flexion and increased as the hip flexion angle increased. The only significant difference found corresponded to the two triangles technique at 15° flexion (mean difference compared to the non-repaired state = 2.8° ± 3.8° or 8.8% increase in external rotation; P = 0.03). Conclusions Different techniques of capsular plication result in a non-significant increase in hip external rotation when compared to unrepaired capsulotomies. Therefore, special attention should be paid at the time of capsular plication, which could be disadvantageous when done overzealously aiming to increase postoperative stability

Salvage laryngectomy and laryngopharyngectomy: Multicenter review of outcomes associated with a reconstructive approach

Background Surgeons have developed various reconstructive techniques to minimize the rate of pharyngocutaneous fistula and optimize functional outcome after salvage laryngectomy or laryngopharyngectomy. Methods Multicenter retrospective review at 33 institutions of 486 patients with a history of squamous cell carcinoma (SCC) of the larynx or hypopharynx previously treated with primary chemoradiotherapy (CRT) who required salvage surgery. Outcomes evaluated were overall fistula rate, fistula requiring reoperation, and 12‐month speech and swallowing function. Results Primary closure of the hypopharynx was associated with a statistically higher overall fistula rate and fistula requiring reoperation compared to reconstruction with vascularized tissue augmentation. Vascularized tissue augmentation with muscle led to worse 12‐month “understandability of speech” and “nutritional mode” scores compared to vascularized tissue augmentation without muscle. Conclusion Vascularized tissue augmentation reduces the overall fistula rate and fistula requiring reoperation but vascularized tissue augmentation with muscle may impair speech and swallowing outcomes