Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: A randomised crossover pharmacokinetic study.

AIMS: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut-specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80 mg/m2 . METHODS: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615 mg/m2 divided over 3 days and encequidar 15 mg orally 1 hour prior, followed by IVP 80 mg/m2 , or the reverse sequence. PK blood samples were taken up to Day 9 for oPac+E and Day 5 for IVP. RESULTS: Forty-two patients were enrolled; 35 completed both treatment periods. AUC0-∞ was 5033.5 ± 1401.1 ng.h/mL for oPac+E and 5595.9 ± 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.50% (90% CI 83.89-95.50). Mean absolute bioavailability of oPac+E was 12% (CV% = 23%). PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment-emergent adverse events occurred in seven (18%) pts with oPac+E and two (5%) with IVP. Seventy-five per cent of patients preferred oPac+E over IVP. CONCLUSIONS: GMR for AUC was within the predefined acceptable range of 80-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E could be an alternative to IVP.

Bioequivalence Study of 2 Capsule Formulations of Fingolimod 0.5 mg Assessing Both Parent Drug and Active Metabolite in New Zealand Healthy Subjects (Truncated Design).

Fingolimod is indicated for the treatment of patients with the relapsing-remitting form of multiple sclerosis. The primary study objective was to evaluate the bioequivalence of a test formulation, 0.5 mg fingolimod HCl capsule (Lebrina, Asofarma Sociedad Anónima Industrial y Comercial, Argentina) relative to a reference formulation, 0.5 mg fingolimod capsule (Gilenya, Novartis Pharmaceutical, Australia). In a single-center, randomized, single-dose, single-blinded, 2-way crossover study, 33 New Zealand healthy subjects of both sexes were enrolled to receive a 0.5-mg dose of 3 capsules of each fingolimod formulation under fasting conditions, with a 42-day washout period between administrations. Additional pharmacokinetic information regarding its main active metabolite, fingolimod phosphate, was also provided. The point estimate and 90% confidence intervals of the ratios of maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours were 99.07 (95.83-102.41) and 97.64 (95.33-100.00) for fingolimod, and 95.60 (90.95-100.49) and 98.54 (96.19-100.96), for fingolimod phosphate. Primary parameters, maximum concentration and area under the plasma concentration-time curve from time 0 to 72 hours for fingolimod and fingolimod phosphate were found to have no significant difference when test and reference formulations were compared. Fingolimod and fingolimod phosphate of both formulations were within the accepted 90% confidence interval limits of 80.00% and 125.00%. No significant differences between the test and reference drug products were detected in any of the pharmacokinetic parameters estimated. Notwithstanding the primary conclusion of bioequivalence is focused on the measurement of the parent compound, compliance with the same criteria by the active metabolite reinforces the comparability between the pharmacokinetic profiles of both formulations (ClinicalTrials.gov Identifier: NCT03757338).

RETRACTED: Association of prior HPV vaccination with reduced preterm birth: A population based study.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This paper is being retracted at the request of the authors. The authors report that there was an incorrect interpretation of the odds ratio meaning that instead of HPV vaccination potentially being protective, there may be an associated increased risk of preterm delivery. The authors believe that an increased risk of preterm delivery is unlikely and not consistent with the evidence to date. Further, the authors have not been able to access the original source data as per protocol to check the data validity. The authors wish to repeat the study to reassure themselves that there were no data processing or other errors in the databases in order to reach definitive conclusions. Lastly, it is of serious concern to the Editor-in-Chief that the Conflict of Interest statement was only added to the paper by the authors after acceptance and was not made visible to the editor or reviewers prior to acceptance. The authors state that there was no input to the methodology, implementation and results of this study by any commercial entity. The pharma distribution company CSL mentioned in the conflict of interest statement only knew about the study after publication.

Successful pregnancy following treatment of recurrent chronic histiocytic intervillositis.

Chronic histiocytic intervillositis (CHI) is a rare placental lesion associated with adverse obstetric outcomes and high recurrence rate. We report a case of six consecutive pregnancies in one woman, where CHI was detected following an intrauterine death in the fifth pregnancy, after being missed in four earlier losses. The successful sixth pregnancy was treated with a combination of immunosuppressive and antithrombotic agents. While low-molecular-weight heparin (LMWH) and aspirin had been shown to improve pregnancy outcome in recurrent pregnancy loss, there was limited evidence of improved outcome in CHI. It has been suggested that CHI may result from a maternal immunological process and there have been a few reports of the use of corticosteroids because of this possibility, though without convincing evidence of efficacy. We too tried a corticosteroid, in combination with LMWH and aspirin. Comparative histopathological analysis of the placentae supported post-treatment effectiveness of our intervention strategy.

Osteoconduction in keratin-hydroxyapatite composite bone-graft substitutes.

Reconstituted keratin-hydroxyapatite (K-HA) composites have shown potential as nonload-bearing bone graft substitute material. This in vivo study investigated the bone regeneration response of keratin plus 40% HA composite materials in comparison to collagen counterparts and an unfilled defect site. The implantation site was a noncritical size defect created in the long bones (tibia) of sheep, with observations made at 1, 2, 4, 6, 8, and 12 weeks postimplantation. Porous K-HA materials displayed an excellent biocompatibility similar to collagen counterparts; however, the rate of bone regeneration at K-HA implantation sites was markedly slower than that of the collagen or unfilled defect sites. While collagen materials were undetectable by 4 weeks implantation, K-HA composite remnants were present at 12 weeks. However, there is evidence that K-HA implants participated in the natural remodelling process of bone, with bone regeneration occurring via a creeping substitution mechanism. Observations imply that the rate of bone ingrowth into the K-HA defect site was matched with the rate of K-HA resorption. These results suggest that K-HA materials may offer significant benefits as nonload-bearing bone graft substitutes where it is desirable that the degradation of the scaffolding material be well matched with the rate of bone regeneration. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2034-2044, 2017.

Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma.

Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT-associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (αthalassemia/mental retardation syndrome X-linked) expression and mutant DAXX (death-domain-associated protein) expression by immunohistochemistry (IHC). Overexpression of p16(INK4A) was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management.

Pelvic pseudotumor: an unusual presentation of an extra-articular granuloma in a well-fixed total hip arthroplasty.

A 76-year-old woman developed a pelvic mass and abdominal pain 12 years after cementless total hip arthroplasty. The mass was a cystic granuloma that communicated with the hip joint via a soft tissue herniation under the inguinal ligament. There was no acetabular lysis or defects. The shell and femoral component were well fixed, the polyethylene was worn, and a liner exchange was undertaken. The cyst was debrided, and follow-up computed tomography demonstrated resolution of the granuloma and no recurrence of the cyst. Removal of the source of the particle wear debris via liner exchange or revision surgery combined with cyst debridement via a single incision is recommended.

Multicentric carpal-tarsal osteolysis with nephropathy treated successfully with cyclosporine A: a case report and literature review.

Multicentric carpal-tarsal osteolysis is a rare skeletal disorder characterized by osteolysis of the metacarpal, carpal, and tarsal bones and leading to crippling joint deformities. Progressive nephropathy occurs in more than half the cases. All previously reported series with renal biopsies showed only end-stage renal disease on histological examination because of the late presentation to nephrologists. Accurate diagnosis of the underlying renal pathological state therefore has not been possible. We report the first case in which early and sequential renal biopsies were performed. These show the renal lesion to be focal and segmental glomerulosclerosis, which was treated successfully with cyclosporine A.

Congenital "clear cell sarcoma of the kidney".

At 31 weeks gestation, a hydropic male fetus died in utero with metastatic disease from a renal clear cell sarcoma. The tumor had metastasized to para-aortic and mediastinal lymph nodes, lung, pleura, and liver, leading to superior vena cava obstruction and pulmonary hypoplasia. The pathologic findings and cytogenetic analysis of the fetus and tumor are presented. In addition, review of the literature reveals six other cases aged <6 months of age, including two extrarenal cases.

Spontaneous acroangiodermatitis in a young woman.

We present a case of acroangiodermatitis that for nearly 15 years was unrecognized and treated with skin grafting and radiotherapy. This case is also unusual in that neither venous insufficiency nor an underlying arteriovenous malformation could be demonstrated. Acroangiodermatitis is infrequently reported; a review of the literature emphasizes the similarities to Kaposi sarcoma both clinically and histologically. Because treatment for Kapsoi's sarcoma and hemangioendothelioma involves skin grafting and radiotherapy, awareness of this entity by dermatologists, surgeons, and pathologists is important.